CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation Application, which claims the priority benefit to U.S. patent application Ser. No. 14/843,143, filed on Sep. 2, 2015, which claims the priority benefit of U.S. application Ser. No. 14/152,692, filed Jan. 10, 2014, now U.S. Pat. No. 9,168,312, which is a Continuation Application which claims the priority benefit of U.S. application Ser. No. 12/796,640, filed Jun. 8, 2010, now U.S. Pat. No. 8,703,717; which claim the benefit of U.S. Provisional Application Ser. No. 61/185,112, filed Jun. 8, 2009; 61/236,836, filed Aug. 25, 2009; and 61/280,955, filed Nov. 10, 2009, and U.S. application Ser. No. 12/699,761, filed Feb. 3, 2010, now U.S. Pat. No. 8,673,860, and PCT Application Serial No. PCT/US10/23106, both filed Feb. 3, 2010 which are hereby incorporated herein by reference in their entirety.
SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 22, 2017 is named 32808-716.304.SeqList.txt and is 1,801,534 bytes in size.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under SBIR grant 2R44GM079873-02 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION Human growth hormone (hGH) is a hormone that participates in the regulation of human growth and development. Growth Hormone (herein after “GH”), also known as somatotrophin, represents a class of proteinaceous hormones produced and secreted by the somatotropic cells of the anterior pituitary. Secretion of GH is stimulated by the growth hormone releasing hormone (GHRH) from the hypothalamus and suppressed by somatostatin. This pituitary hormone exhibits a number of biological effects including somatogenesis, lactation, activation of macrophages, insulin-like and diabetogenic effects among others (Chawla, R. K. (1983) Ann. Rev. Med. 34, 519; Edwards, C. K. et al. (1988) Science 239, 769; Thorner, M. O., et al. (1988) J. Clin. Invest. 81, 745). Human growth hormone is a member of a family of homologous hormones that include placental lactogens, prolactins, and other genetic and species variants of GH. GH regulates the secretion of Insulin-like growth factor (IGF-1, formerly known as somatomedin C), among other peptide hormones known collectively as somatomedins, which accounts for most of its biological activity.
A number of diseases and disorders are associated with the deficiency of GH. A deficiency can be congenital, acquired in childhood or in adult life, and can be partial or complete. In some cases, the deficiency is transient, but more commonly is permanent, and may occur in association with deficiencies of other pituitary hormones. Growth hormone deficiency in children leads to dwarfism, growth failure or short stature. Deficiency in adults is rare, but symptoms can include diminished body mass and poor bone density, and a number of psychological symptoms. Other hormonal or glandular disorders frequently coincide with deficiency of growth hormone.
Stimulating the increase in height in childhood is the most widely known effect of GH, and appears to function by at least two mechanisms: GH directly stimulates division and multiplication of chondrocytes of cartilage, and GH also stimulates production of IGF-1. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
Human growth hormone (hGH) plays a key role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids. In addition to its effects on somatic growth, hGH has been shown to stimulate blood cells in vitro (Derfalvi et al., 1998; Merchav et al; 1988), to increase erythrocytes and hemoglobin counts (Valerio et al., 1997; Vihervuori et al., 1996), to enhance both proliferation and Ig production in plasma cell lines (Kimata and Yoshida, 1994) and to stimulate CD8+ cell counts and, to a lesser extent CD4+ cell counts (Geffner, 1997).
Injectable forms of GH have been marketed for GH deficiency in children and adults, Turner Syndrome, Prader-Willi Syndrome, and children small for gestational age. In addition, it has seen use in the battle against aging and for weight management, as well as the mobilization of cells capable of regenerating hematopoiesis in the peripheral blood.
The 22 kDA molecular weight of hGH is well below the threshold value for kidney filtration of about 70 kDa (Caliceti (2003) Adv Drug Deliv Rev 55:1261-1277), which contributes to the serum half-life of native hGH being less than 20 minutes in humans. Thus, commercial preparations of hGH must be dosed daily to achieve clinical benefit. A sustained-release form of GH, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued in 2004.
Chemical modifications to a therapeutic protein can modify its in vivo clearance rate and subsequent serum half-life. One example of a common modification is the addition of a polyethylene glycol (PEG) moiety, typically coupled to the protein via an aldehyde or N-hydroxysuccinimide (NHS) group on the PEG reacting with an amine group (e.g. lysine side chain or the N-terminus). However, the conjugation step can result in the formation of heterogeneous product mixtures that need to be separated, leading to significant product loss and complexity of manufacturing and does not result in a completely chemically-uniform product. Also, the pharmacologic function of GH may be hampered if amino acid side chains in the vicinity of its binding site become modified by the PEGylation process. Other approaches include the genetic fusion of an Fc domain to the therapeutic GH protein. Conjugation of the Fc domain increases the size of the therapeutic protein, hence reducing the rate of clearance through the kidney. Additionally, the Fc domain confers the ability to bind to, and be recycled from lysosomes by, the FcRn receptor, which results in increased pharmacokinetic half-life. Unfortunately, the Fc domain does not fold efficiently during recombinant expression, and tends to form insoluble precipitates known as inclusion bodies. These inclusion bodies must be solubilized and functional protein must be renatured from the misfolded aggregate, a time-consuming, inefficient, and expensive process. Accordingly, there remains a need for growth hormone compositions that can increase the half-life and can be administered less frequently, but are safer and less complicated and costly to produce.
SUMMARY OF THE INVENTION The present disclosure is directed to compositions and methods that can be useful for or the treatment of any disease, disorder or condition that is improved, ameliorated, or inhibited by the administration of growth hormone. In particular, the present invention provides compositions of fusion proteins comprising one or more extended recombinant polypeptides with a non-repetitive sequence and/or unstructured conformation (XTEN) linked to growth hormone (GH). In part, the present disclosure is directed to pharmaceutical compositions comprising the fusion proteins and the uses thereof for treating growth hormone-related diseases, disorders or conditions.
In one embodiment, the invention provides an isolated fusion protein, comprising a growth hormone that is at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% identical to an amino acid sequence selected from Table 1, wherein said growth hormone is linked to an extended recombinant polypeptide (XTEN) of at least about 100, or at least about 200, or at least about 400, or at least about 800, or at least about 900, or at least about 1000, or at least about 2000, up to about 3000 amino acids residues, wherein the XTEN is characterized in that (a) the XTEN comprises at least about 200 contiguous amino acids that exhibits at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% identical to a comparable length of an amino acid sequence selected from a sequence shown in Table 3; (b) the XTEN sequence lacks a predicted T-cell epitope when analyzed by TEPITOPE algorithm, wherein the TEPITOPE algorithm prediction for epitopes within the XTEN sequence is based on a score of −5, or −6, or −7, or −8, or −9 or greater; (c) the XTEN has a subsequence score of less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, or even less; and (d) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the total amino acid residues of the XTEN. In one embodiment, the growth hormone of the isolated fusion protein is human growth hormone. In another embodiment, the isolated fusion protein comprises at least a second XTEN, wherein the fusion protein adopts a multiple-XTEN configuration shown in Table 5, or a variant thereof.
In another embodiment, the XTEN sequence of the GHXTEN fusion proteins is characterized in that is has greater than 90% random coil formation, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% random coil formation as determined by GOR algorithm; and the XTEN sequence has less than 2% alpha helices and 2% beta-sheets as determined by the Chou-Fasman algorithm.
In another embodiment, the invention provides GHXTEN fusion proteins, wherein the XTEN is characterized in that the sum of asparagine and glutamine residues is less than 10% of the total amino acid sequence of the XTEN, the sum of methionine and tryptophan residues is less than 2% of the total amino acid sequence of the XTEN, the XTEN sequence has less than 5% amino acid residues with a positive charge, the XTEN sequence has greater than 90% random coil formation, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% random coil formation as determined by GOR algorithm; and the XTEN sequence has less than 2% alpha helices and 2% beta-sheets as determined by the Chou-Fasman algorithm.
In another embodiment, the invention provides GHXTEN fusion proteins, wherein the XTEN is characterized in that at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the sequence motifs has about 9 to about 14 amino acid residues and wherein the sequence of any two contiguous amino acid residues does not occur more than twice in each of the sequence motifs the sequence motifs consist of four to six types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P).
In some embodiments, no one type of amino acid constitutes more than 30% of the XTEN sequence of the GHXTEN. In other embodiments, the XTEN has a sequence in which no three contiguous amino acids are identical unless the amino acid is serine, in which case no more than three contiguous amino acids are serine residues. In still other embodiments, at least about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or 100% of the XTEN sequence consists of non-overlapping sequence motifs, wherein each of the sequence motifs has 12 amino acid residues. In one embodiment, the XTEN sequence consists of non-overlapping sequence motifs, wherein the sequence motifs are from one or more sequences of Table 2.
In some embodiments, GHXTEN fusion proteins exhibits enhanced pharmacokinetic properties compared to GH not linked to XTEN, wherein the enhanced properties include but are not limited to longer terminal half-life, larger area under the curve, increased time in which the blood concentration remains within the therapeutic window, increased time between consecutive doses, and decreased dose in moles over time. In some embodiments, the terminal half-life of the GHXTEN fusion protein administered to a subject is increased at least about two fold, or at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about ten-fold, or at least about 20-fold, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold, or even higher as compared to GH not linked to XTEN and administered to a subject at a comparable dose. In other embodiments, the enhanced pharmacokinetic property is reflected by the fact that the blood concentrations that remain within the therapeutic window for the GHXTEN fusion protein for a given period are at least about two fold, or at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about ten-fold longer, or at least about 20-fold, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold compared to GH not linked to XTEN and administered to a subject at a comparable dose. The increase in half-life and time spent within the therapeutic window permits less frequent dosing and decreased amounts of the fusion protein (in moles equivalent) that are administered to a subject, compared to the corresponding GH not linked to XTEN. In one embodiment, the therapeutically effective dose regimen results in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold, or at least six-fold, or at least eight-fold, or at least 10-fold, or at least about 20-fold, or at least about 40-fold, or at least about 60-fold, or at least about 100-fold between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH not linked to the fusion protein and administered using a comparable dose regimen to a subject.
In some embodiments, the XTEN enhances thermostability of a biologically active protein when linked to the biologically active protein wherein the thermostability is ascertained by measuring the retention of biological activity after exposure to a temperature of about 37° C. for at least about 7 days of the biologically active protein in comparison to the XTEN linked to the biologically active protein. In one embodiment of the foregoing, the retention of biological activity in increased by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, or about 150%, at least about 200%, at least about 300%, or about 500% longer compared to the GH not linked to the XTEN comprises of the XTEN.
In some embodiments, the isolated fusion protein with at least a first XTEN comprises a GH wherein the GH is human growth hormone. In some embodiments, the isolated fusion protein further comprises a second XTEN, which can be identical or can be different from the first XTEN, and wherein the fusion protein adopts a multiple-XTEN configuration shown in Table 5. In one embodiment of the foregoing, the first and the second XTEN can each be a sequence selected from Table 3, or can exhibit at least at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% or 100% sequence identity to a sequence selected from Table 3. In another embodiment, the isolated fusion protein compring a second XTEN sequence adopts a multiple-XTEN configuration shown in Table 5.
In one embodiment, the isolated fusion protein is less immunogenic compared to the GH not linked to the XTEN, wherein immunogenicity is ascertained by, e.g., measuring production of IgG antibodies selectively binding to the biologically active protein after administration of comparable doses to a subject.
In some embodiments, the growth hormone peptide and the XTEN of the fusion protein is linked via a spacer, wherein the spacer sequence comprises between about 1 to about 50 amino acid residues that optionally comprises a cleavage sequence. In one embodiment, the cleavage sequence is susceptible to cleavage by a protease. Non-limiting examples of such protease include FXIa, FXIIa, kallikrein, FVIIa, FIXa, FXa, thrombin, elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, TEV, enterokinase, rhinovirus 3C protease, and sortase A.
In some embodiments, the isolated fusion protein is configured to have reduced binding affinity for a target receptor of the corresponding GH, as compared to the corresponding GH not linked to the fusion protein. In one embodiment, the GHXTEN fusion protein exhibits binding affinity for a target receptor of the GH in the range of about 0.01%-30%, or about 0.1% to about 20%, or about 1% to about 15%, or about 2% to about 10% of the binding affinity of the corresponding GH that lacks the XTEN. In another embodiment, the GHXTEN fusion protein exhibits binding affinity for a target receptor of the GH that is reduced at least about 3-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold,or at least about 9-fold, or at least about 10-fold, or at least about 12-fold, or at least about 15-fold, or at least about 17-fold, or at least about 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold less binding affinity compared to GH not linked to XTEN. In a related embodiment, a fusion protein with reduced affinity can have reduced receptor-mediated clearance and a corresponding increase in half-life of at least about 3-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold,or at least about 9-fold, or at least about 10-fold, or at least about 12-fold, or at least about 15-fold, or at least about 17-fold, or at least about 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer compared to the corresponding GH that is not linked to the fusion protein.
In one embodiment, the invention provides an isolated GHXTEN fusion protein comprising an amino acids sequence that has at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or 100% sequence identity to a sequence selected from Table 35, Table 36, and Table 37.
In some embodiments, the invention provides GHXTEN fusion proteins wherein the GHXTEN exhibits increased solubility of at least three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about seven-fold, or at least about eight-fold, or at least about nine-fold, or at least about ten-fold, or at least about 15-fold, or at least a 20-fold, or at least 40-fold, or at least 60-fold at physiologic conditions compared to the GH not linked to the fusion protein.
In some embodiments, GHXTEN fusion proteins exhibit an increased apparent molecular weight as determined by size exclusion chromatography, compared to the actual molecular weight, wherein the apparent molecular weight is at least about 100 kD, or at least about 150 kD, or at least about 200 kD, or at least about 300 kD, or at least about 400 kD, or at least about 500 kD, or at least about 600kD, or at least about 700 kD, while the actual molecular weight of each GH component of the fusion protein is less than about 25 kD. Accordingly, the GHXTEN fusion proteins can have an Apparent Molecular Weight that is about 4-fold greater, or about 5-fold greater, or about 6-fold greater, or about 7-fold greater, or about 8-fold greater than the actual molecular weight of the fusion protein. In some cases, the isolated GHXTEN fusion protein of the foregoing embodiments exhibits an apparent molecular weight factor under physiologic conditions that is greater than about 4, or about 5, or about 6, or about 7, or about 8.
The invention contemplates GHXTEN fusion proteins compositions comprising, but not limited to GH selected from Table 1 (or fragments or sequence variants thereof), XTEN selected from Table 3 (or sequence variants thereof) that are in a configuration selected from Table 5. Generally, the resulting GHXTEN will retain at least a portion of the biological activity of the corresponding GH not linked to the XTEN. In other cases, the GH component either becomes biologically active or has an increase in activity upon its release from the XTEN by cleavage of an optional cleavage sequence incorporated within spacer sequences into the GHXTEN.
In one embodiment of the GHXTEN composition, the invention provides a fusion protein of formula I:
(XTEN)x-GH-(XTEN)y I
wherein independently for each occurrence, GH is a is a growth hormone; x is either 0 or 1 and y is either 0 or 1 wherein x+y≥1; and XTEN is an extended recombinant polypeptide.
In some embodiments, the XTEN is fused to the growth hormone on an N- or C-terminus of the growth hormone. In some embodiments, the isolated fusion protein comprises a human growth hormone and a first and a second XTEN selected from AE912, AM923, AE144, and AE288.
In another embodiment of the GHXTEN composition, the invention provides a fusion protein of formula II:
(XTEN)x-(GH)-(S)y-(XTEN)y II
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1 and y is either 0 or 1 wherein x+y≥1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula III:
(GH)-(S)x-(XTEN)-(S)y-(GH)-(S)z-(XTEN)z III
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula IV:
(XTEN)x-(S)y-(GH)-(S)z-(XTEN)-(GH) IV
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion growth hormone, wherein the fusion protein is of formula V:
(GH)x-(S)x-(GH)-(S)y-(XTEN) V
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VI:
(XTEN)-(S)x-(GH)-(S)y-(GH) VI
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VII:
(XTEN)-(S)x-(GH)-(S)y-(GH)-(XTEN) VII
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VIII:
((S)m-(GH)x-(S)n-(XTEN)y-(S)o)t VIII
wherein t is an integer that is greater than 0 (1, 2, 3, etc.); independently each of m, n, o, x, and y is an integer (0, 1, 2, 3, etc.), GH is a is a growth hormone; S is an spacer, optionally comprises a cleavage site; and XTEN is an extended recombinant polypeptide, with the proviso that: (1) x+y>1, (2) when t=1, x>0 and y>0, (3) when there is more than one GH, S, or XTEN, each GH, XTEN, or S are the same or are independently different; and (4) when t>1, each m, n, o, x, or y within each subunit are the same or are independently different.
In some embodiments, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold or more spent within a therapeutic window for the fusion protein compared to the corresponding GH not linked to the XTEN of and administered at a comparable dose to a subject. In other cases, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time between consecutive doses necessary to maintain a therapeutically effective dose regimen of at least 48 h, or at least 72 h, or at least about 96 h, or at least about 120 h, or at least about 7 days, or at least about 14 days, or at least about 21 days between consecutive doses compared to a GH not linked to XTEN and administered at a comparable dose.
The fusion proteins can be designed to have different configurations, N- to C-terminus, of a GH, XTEN, and optional spacer sequences, including but not limited to XTEN-GH, GH-XTEN, XTEN-S-GH, GH-S-XTEN, XTEN-GH-XTEN, GH-GH-XTEN, XTEN-GH-GH, GH-S-GH-XTEN, XTEN-GH-S-GH, and multimers thereof. The choice of configuration can, as disclosed herein, confer particular pharmacokinetic, physico/chemical, or pharmacologic properties.
In some embodiments, the isolated fusion protein is characterized in that: (i) it has a longer half-life compared to the corresponding growth hormone that lacks the XTEN; (ii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; (iii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (iv) when the fusion protein is administered to a subject less frequently in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; (v) when the fusion protein is administered to a subject less frequently in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (vi) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable area under the curve (AUC) as the corresponding growth hormone that lacks the XTEN; or (vii) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding growth hormone that lacks the XTEN administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN.
In one embodiment, the GHXTEN fusion proteins of formulas I-VIII described above exhibit a biological activity of at least about 0.1%, or at least about 0.1%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 4%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95% of the biological activity compared to the GH not linked to the fusion protein. In another embodiment, the GHXTEN fusion proteins of formulas I-VIII bind the same receptors or ligands as the corresponding parental biologically active protein that is not covalently linked to the fusion protein.
The invention provides a method of producing a fusion protein comprising a growth hormone fused to one or more extended recombinant polypeptides (XTEN), comprising: (a) providing host cell comprising a recombinant polynucleotide molecule encoding the fusion protein (b) culturing the host cell under conditions permitting the expression of the fusion protein; and (c) recovering the fusion protein. In one embodiment of the method, the growth hormone of the fusion protein has at least 90% sequence identity to human growth hormone or a sequence selected from Table 1. In another embodiment of the method, the one or more XTEN of the expressed fusion protein has at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% sequence identity to a sequence selected from Table 3. In another embodiment of the method, the polynucleotide encoding the XTEN is codon optimized for enhanced expression of said fusion protein in the host cell. In another embodiment of the method, the host cell is a prokaryotic cell. In another embodiment of the method, the host cell is E. coli. In another embodiment of the method the isolated fusion protein is recovered from the host cell cytoplasm in substantially soluble form.
The invention provides isolated nucleic acids comprising a polynucleotide sequence selected from (a) a polynucleotide encoding the fusion protein of any of the foregoing embodiments, or (b) the complement of the polynucleotide of (a). In one embodiment, the invention provides an isolated nucleic acid comprising a polynucleotide sequence that has at least 80% sequence identity, or about 85%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% sequence identity to (a) a polynucleotide sequence of comparable length selected from Table 35, Table 36, and Table 37; or (b) the complement of the polynucleotide of (a). The invention provides expression vectors comprising the nucleic acid of any of the embodiments hereinabove described in this paragraph. In one embodiment, the expression vector of the foregoing further comprises a recombinant regulatory sequence operably linked to the polynucleotide sequence. In another embodiment, the polynucleotide sequence of the expression vectors of the foregoing is fused in frame to a polynucleotide encoding a secretion signal sequence, which can be a prokaryotic signal sequence. In one embodiment, the secretion signal sequence is selected from OmpA, DsbA, and PhoA signal sequences.
The invention provides a host cell, which can comprise an expression vector disclosed in the foregoing paragraph. In one embodiment, the host cell is a prokaryotic cell. In another embodiment, the host cell is E. coli. In another embodiment, the host cell is a eukaryotic cell.
In one embodiment, the invention provides pharmaceutical compositions comprising the fusion protein of any of the foregoing embodiments and a pharmaceutically acceptable carrier. In another embodiment, the invention provides kits, comprising packaging material and at least a first container comprising the pharmaceutical composition of the foregoing embodiment and a label identifying the pharmaceutical composition and storage and handling conditions, and a sheet of instructions for the reconstitution and/or administration of the pharmaceutical compositions to a subject.
The invention provides a method of treating a growth-hormone related condition in a subject, comprising administering to the subject a therapeutically effective amount of the fusion protein of any of the foregoing embodiments. In one embodiment of the method, the growth-hormone related condition is selected from growth-hormone deficiency, Turner's Syndrome, Prader-Willi Syndrome, idiopathic short stature, AIDS wasting, multiple sclerosis, Crohn's disease, ulcerative colitis, and muscular dystrophy.
In some embodiments, the composition can be administered subcutaneously, intramuscularly, or intravenously. In one embodiment, the composition is administered at a therapeutically effective amount. In one embodiment, the therapeutically effective amount results in a gain in time spent within a therapeutic window for the fusion protein compared to the corresponding GH of the fusion protein not linked to the fusion protein and administered at a comparable dose to a subject. The gain in time spent within the therapeutic window can at least three-fold longer than the corresponding GH not linked to the fusion protein, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer than the corresponding GH not linked to the fusion protein. In some embodiments of the method of treatment, (i) a smaller molar amount of (e.g. of about two-fold less, or about three-fold less, or about four-fold less, or about five-fold less, or about six-fold less, or about eight-fold less, or about 100 fold-less or greater) the fusion protein is administered in comparison to the corresponding growth hormone that lacks the XTEN under an otherwise same dose regimen, and the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; (ii) the fusion protein is administered less frequently (e.g., every two days, about every seven days, about every 14 days, about every 21 days, or about, monthly) in comparison to the corresponding growth hormone that lacks the XTEN under an otherwise same dose amount, and the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN; or (iii) an accumulative smaller molar amount (e.g. about 5%, or about 10%, or about 20%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% less) of the fusion protein is administered in comparison to the corresponding growth hormone that lacks the XTEN under the otherwise same dose regimen the fusion protein achieves a comparable area under the curve and/or a comparable therapeutic effect as the corresponding growth hormone that lacks the XTEN. The accumulative smaller molar amount is measure for a period of at least about one week, or about 14 days, or about 21 days, or about one month. In some embodiments of the method, the therapeutic effect is a measured parameter selected from IGF-1 concentrations, IGFBP3 concentration, height velocity, lean body mass, total body fat, trunk fat, response to insulin challenge, rate of division of chondrocytes, chondrocyte numbers, bone density, bone growth, and increase in epiphyseal plate width.
In another embodiment, invention provides a method of treating a disease, disorder or condition, comprising administering the pharmaceutical composition described above to a subject using multiple consecutive doses of the pharmaceutical composition administered using a therapeutically effective dose regimen. In one embodiment of the foregoing, the therapeutically effective dose regimen can result in a gain in time of at least three-fold, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least about 30-fold, or at least about 50-fold, or at least about 100-fold longer time between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH of the fusion protein not linked to the fusion protein and administered at a comparable dose regimen to a subject. In another embodiment of the foregoing, the administration of the fusion protein results in improvement in at least one measured parameter of a growth hormone-related disease using less frequent dosing or a lower total dosage in moles of the fusion protein of the pharmaceutical composition compared to the corresponding biologically active protein component(s) not linked to the fusion protein and administered to a subject d using a therapeutically effective regimen to a subject.
The invention further provides use of the compositions comprising the fusion protein of any of the foregoing embodiments in the preparation of a medicament for treating a disease, disorder or condition in a subject in need thereof. In one embodiment of the foregoing, the disease, disorder or condition is selected from group consisting of Turner's Syndrome, Prader-Willi Syndrome, idiopathic short stature, AIDS wasting, multiple sclerosis, Crohn's disease, ulcerative colitis, and muscular dystrophy. Any of the disclosed embodiments can be practiced alone or in combination depending on the interested application.
INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS The features and advantages of the invention may be further explained by reference to the following detailed description and accompanying drawings that sets forth illustrative embodiments.
FIG. 1 shows schematic representations of exemplary GHXTEN fusion proteins (FIGS. 1A-H), all depicted in an N- to C-terminus orientation. FIG. 1A shows two different configurations of GHXTEN fusion proteins (100), each comprising a single growth hormone (GH) and an XTEN, the first of which has an XTEN molecule (102) attached to the C-terminus of a GH (103), and the second of which has an XTEN molecule attached to the N-terminus of a GH (103). FIG. 1B shows two different configurations of GHXTEN fusion proteins (100), each comprising a single GH, a spacer sequence and an XTEN, the first of which has an XTEN molecule (102) attached to the C-terminus of a spacer sequence (104) and the spacer sequence attached to the C-terminus of a GH (103) and the second of which has an XTEN molecule attached to the N-terminus of a spacer sequence (104) and the spacer sequence attached to the N-terminus of a GH (103). FIG. 1C shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a first GH and that GH is linked to the C-terminus of a second GH, and the second of which is in the opposite orientation in which the XTEN is linked to the N-terminus of a first GH and that GH is linked to the N-terminus of a second GH. FIG. 1D shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH, a spacer sequence and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a spacer sequence and the spacer sequence linked to the C-terminus of a first GH which is linked to the C-terminus of a second GH, and the second of which is in the opposite orientation in which the XTEN is linked to the N-terminus of a spacer sequence and the spacer sequence is linked to the N-terminus of a first GH that that GH is linked to the N-terminus of a second GH. FIG. 1E shows two different configurations of GHXTEN fusion proteins (101), each comprising two molecules of a single GH, a spacer sequence and one molecule of an XTEN, the first of which has an XTEN linked to the C-terminus of a first GH and the first GH linked to the C-terminus of a spacer sequence which is linked to the C-terminus of a second GH molecule, and the second of which is in the opposite configuration of XTEN linked to the N-terminus of a first GH which is linked to the N-terminus of a spacer sequence which in turn is linked to the N-terminus of a second molecule of GH. FIG. 1F shows a configuration of GHXTEN fusion protein (105), each comprising one molecule of GH and two molecules of an XTEN linked to the N-terminus and the C-terminus of the GH. FIG. 1G shows a configuration (106) of a single GH linked to two XTEN, with the second XTEN separated from the GH by a spacer sequence. FIG. 1H s a configuration (106) of a two GH linked to two XTEN, with the second XTEN linked to the C-terminus of the first GH nad the N-terminus of the second GH, which is at the C-terminus of the GHXTEN.
FIG. 2 is a schematic illustration of exemplary polynucleotide constructs (FIGS. 2A-H) of GHXTEN genes that encode the corresponding GHXTEN polypeptides of FIG. 1; all depicted in a 5′ to 3′ orientation. In these illustrative examples the genes encode GHXTEN fusion proteins with one GH and XTEN (200); or one GH, one spacer sequence and one XTEN (200); two GH and one XTEN (201); or two GH, a spacer sequence and one XTEN (201); one GH and two XTEN (205); or two GH and two XTEN (206). In these depictions, the polynucleotides encode the following components: XTEN (202), GH (203), and spacer amino acids that can include a cleavage sequence (204), with all sequences linked in frame.
FIG. 3 is a schematic illustration of two exemplary monomeric GHXTEN and the ability of the monomeric fusion proteins to bind to a target receptor on a cell surface, with subsequent cell signaling. FIG. 3A shows a GHXTEN fusion protein (100) consisting of a GH (103) and an XTEN (102) and a second GHXTEN fusion protein (105) consisting of a GH linked to two XTEN (105). FIG. 3B shows the interaction of the GHXTEN with the GH on the C-terminus (100) and the GHXTEN with an XTEN on the C-terminus (105) with target receptors (108) to GH on a cell surface (107). In this case, binding to the receptor with high affinity is exhibited when GH has a free C-terminus, while the GHXTEN with a C-terminal XTEN does not bind tightly to the receptor, and disassociates, as seen in FIG. 3C. FIG. 3D shows that the bound GHXTEN (100) with high binding affinity remains bound to the receptor (106) and has been internalized into an endosome (110) within the cell, illustrating receptor-mediated clearance of the bound GH and triggering cell signaling (109), portrayed as stippled cytoplasm.
FIG. 4 is a schematic flowchart of representative steps in the assembly, production and the evaluation of a XTEN.
FIG. 5 is a schematic flowchart of representative steps in the assembly of a GHXTEN polynucleotide construct encoding a fusion protein. Individual oligonucleotides 501 are annealed into sequence motifs 502 such as a 12 amino acid motif (“12-mer”), which is subsequently ligated with an oligo containing BbsI, and KpnI restriction sites 503. Additional sequence motifs from a library are annealed to the 12-mer until the desired length of the XTEN gene 504 is achieved. The XTEN gene is cloned into a stuffer vector. The vector encodes a Flag sequence 506 followed by a stopper sequence that is flanked by BsaI, BbsI, and KpnI sites 507 and an exendin-4 gene 508, resulting in the gene 500 encoding an XTEN-GH fusion protein.
FIG. 6 is a schematic flowchart of representative steps in the assembly of a gene encoding fusion protein comprising a growth homroe (GH) and XTEN, its expression and recovery as a fusion protein, and its evaluation as a candidate GHXTEN product.
FIG. 7 is a schematic representation of the design of GHXTEN expression vectors with different processing strategies. FIG. 7A shows an exemplary expression vector encoding XTEN fused to the 3′ end of the sequence encoding GH. Note that no additional leader sequences are required in this vector. FIG. 7B depicts an expression vector encoding XTEN fused to the 5′ end of the sequence encoding GH with a CBD leader sequence and a TEV protease site. FIG. 7C depicts an expression vector as in FIG. 7B where the CBD and TEV processing site have been replaced with an optimized N-terminal leader sequence (NTS). FIG. 7D depicts an expression vector encoding an NTS sequence, an XTEN, a sequence encoding GH, and than a second sequence encoding an XTEN.
FIG. 8 is a schematic representation of the step-wise construction of GHXTEN genes that contain N-terminal XTEN encoding sequences linked to hGH and the subsequent linkage of sequences encoding either 144 or 288 XTEN linked to the C-terminus of XTEN, as described in Example 22.
FIG. 9 shows results of expression assays for the indicated constructs comprising GFP and XTEN sequences. The expression cultures were assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The results, graphed as box and whisker plots, indicate that while median expression levels were approximately half of the expression levels compared to the “benchmark” CBD N-terminal helper domain, the best clones from the libraries were much closer to the benchmarks, indicating that further optimization around those sequences was warranted. The results also show that the libraries starting with amino acids MA had better expression levels than those beginning with ME (see Example 14).
FIG. 10 shows three randomized libraries used for the third and fourth codons in the N-terminal sequences of clones from LCW546, LCW547 and LCW552. The libraries were designed with the third and fourth residues modified such that all combinations of allowable XTEN codons were present at these positions, as shown. In order to include all the allowable XTEN codons for each library, nine pairs of oligonucleotides encoding 12 amino acids with codon diversities of third and fourth residues were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of the three libraries LCW0569 (SEQ ID NOS 845-846, respectively, in order of appearance), LCW0570 (SEQ ID NOS 847-848, respectively, in order of appearance), and LCW0571 (SEQ ID NOS 849-850, respectively, in order of appearance).
FIG. 11 shows a histogram of a retest of the top 75 clones after the optimization step, as described in Example 15, for GFP fluorescence signal, relative to the benchmark CBD_AM875 construct. The results indicated that several clones were now superior to the benchmark clones.
FIG. 12 is a schematic of a combinatorial approach undertaken for the union of codon optimization preferences for two regions of the N-terminus 48 amino acids. The approach created novel 48mers at the N-terminus of the XTEN protein for evaluation of the optimization of expression that resulted in leader sequences that may be a solution for expression of XTEN proteins where the XTEN is N-terminal to the GH.
FIG. 13 shows an SDS-PAGE gel confirming expression of preferred clones obtained from the XTEN N-terminal codon optimization experiments, in comparison to benchmark XTEN clones comprising CBD leader sequences at the N-terminus of the construct sequences, as described in Example 17.
FIG. 14 shows an SDS-PAGE gel of samples from a stability study of the fusion protein of XTEN_AE864 fused to the N-terminus of GFP (see Example 39). The GFP-XTEN was incubated in cynomolgus plasma and rat kidney lysate for up to 7 days at 37° C. In addition, GFP-XTEN administered to cynomolgus monkeys was also assessed. Samples were withdrawn at 0, 1 and 7 days and analyzed by SDS PAGE followed by detection using Western analysis and detection with antibodies against GFP.
FIG. 15 shows the results of a receptor binding assay for hGH in which the binding activity of hGH fused to K288 polypeptide is compared to free hGH, as described in Example 25.
FIG. 16 shows the results of in vitro binding affinity assay of hGH-AM864 (circles) and AM864-hGH (inverted triangles) to hGHR-Fc, as described in Example 25. Unmodified recombinant hGH (squares) is shown for comparison.
FIG. 17 shows the effects of heat treatment on stability of hGH and AM864-hGH, as described in Example 26. FIG. 17A is an SDS-PAGE gel of the two preparations treated at 25° C. and 80° C. for 15 minutes, while FIG. 17B shows the corresponding percentage of receptor binding activity of the 80° C. sample relative to the 25° C. treatment, indicating that the XTEN conferred heat stability and retention of activity to the hGH and the GHXTEN fusion protein.
FIG. 18 shows results of an ELISA-based assay to determine the ability of addition of a C-terminus XTEN to reduce binding affinity of GHXTEN to bind to GH receptor, as described in Example 25.
FIG. 19 shows SDS-PAGE analysis of hGH fused to K288, with samples from throughout the purification process, as described in Example 19.
FIG. 20 shows SDS-PAGE analysis of 5 μg of final purified protein of hGH fused to Y576 in the configurations of hGH-Y576 and Y576-hGH subjected to both non-reducing and reducing SDS-PAGE, as described in Example 24, using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer's specifications.
FIG. 21 shows size exclusion chromatography profiles of two GHXTEN constructs Y576-GH and hGH-Y576 (N- to C-terminus), shown as an overlay, as described in Example 24.
FIG. 22 shows the pharmacokinetic profile of two GHXTEN constructs Y576-GH and hGH-Y576 (N- to C-terminus) following intravenous administration to cynomolgus monkeys, as described in Example 30. The results show that the orientation (N- versus C-terminal) of hGH relative to the XTEN did not affect the clearance of the fusion proteins.
FIG. 23 shows the pharmacokinetic profile after a single dose of 5 mg/kg AM864-hGH administered subcutaneously to cynomolgus monkeys, with the derived equivalent hGH concentration shown (dashed line), as described in Example 30. Terminal half-life was calculated as 33 hours by WinNonLin using a single compartment fit.
FIG. 24 shows the results of IGF-1 secretion in cynomolgus monkeys in response to administration of hGH or the GHXTEN AM864-hGH at the doses indicated, as described in Example 27.
FIG. 25 shows the effects of administration of hGH or AM864-hGH at the indicated doses on body weight in a hypox rat model, as described in Example 28. The results show retention of biologic activity by the GHXTEN constructs that is equivalent in potency to hGH, yet with less frequent dosing.
FIG. 26 shows the comparative effects of administration of placebo, hGH, and AM864-hGH on growth of cartilage in the tibial epiphyseal plate in hypox rats, shown in histologic cross-sections of the tibia after 9 days of treatment, as described in Example 29.
FIG. 27 shows the pharmacokinetic results of four hGH GHTXEN fusion proteins administered to rats by the subcutaneous route, compared to unmodified recombinant hGH, as described in Example 31.
FIG. 28 shows the concentration profiles of three hGH XTEN constructs after subcutaneous administration to cynomolgus monkeys, as described in Example 32.
FIG. 29 shows the results of a pharmacokinetic study of three doses levels of the GHXTEN AE912-hGH-AE144 administered to male and female cynos SC at 0.3 (open circles), 1.5 (squares), and 7.5 mg/kg (triangles), as described in Example 33.
FIG. 30. Shows the results of IGF-1 levels in cynos in response to the administration of AE912-hGH-AE144, as described in Example 33 (same groups as per FIG. 29).
FIG. 31 shows the results of an experiment to compare bioavailability of the GHXTEN AE912-hGH-AE144 administered by three different routes, as described in Example 34. AE912-hGH-AE144 was administered to male and female cynos SC at 1.5 mg/kg via intravenous (trangle), subcutaneous (open circles), and intramuscular (squares) routes, with plasma concentrations of the GHXTEN shown in the figure.
FIG. 32 shows the effects of administration of vehicle (open circles), recombinant hGH dosed at 5 nmol/kg/day (closed circles), the GHXTEN AE912-hGH-AE144 at varying doses and dose frequency (closed triangles=0.5 nmol/kg/day; open triangles=1.5 nmol/day; squares=3 nmol/kg/Q2D) on body weight in hypox rats, as described in Example 35.
FIG. 33 shows results of a modeled projection of the ability of hGH or the GHXTEN to maintain blood levels within a therapeutic window in the hypox rat model, based on results derived from the data portrayed in FIG. 32, using the same dosing groups.
FIG. 34 shows results of a of a size exclusion chromatography analysis of glucagon-XTEN construct samples measured against protein standards of known molecular weight, with the graph output as absorbance versus retention volume, as described in Example 37. The glucagon-XTEN constructs are 1) glucagon-Y288; 2) glucagonY-144; 3) glucagon-Y72; and 4) glucagon-Y36. The results indicate an increase in apparent molecular weight with increasing length of XTEN moiety.
FIG. 35 shows the pharmacokinetic profile (plasma concentrations) in cynomolgus monkeys after single doses of different compositions of GFP linked to unstructured polypeptides of varying length, administered either subcutaneously or intravenously, as described in Example 38. The compositions were GFP-L288, GFP-L576, GFP-XTEN_AF576, GFP-Y576 and XTEN_AD836-GFP. Blood samples were analyzed at various times after injection and the concentration of GFP in plasma was measured by ELISA using a polyclonal antibody against GFP for capture and a biotinylated preparation of the same polyclonal antibody for detection. Results are presented as the plasma concentration versus time (h) after dosing and show, in particular, a considerable increase in half-life for the XTEN_AD836-GFP, the composition with the longest sequence length of XTEN. The construct with the shortest sequence length, the GFP-L288 had the shortest half-life.
FIG. 36 illustrates allometric scaling results for predicted human response to Ex4-XTEN_AE864 based on measured results from four animal species; i.e., mice, rats, cynomolgus monkeys and dogs. FIG. 36A shows measured terminal half-life versus body mass, with a predicted T½ in humans of 139 h. FIG. 36B shows measured drug clearance versus body mass, with a predicted clearance rate value of 30 ml/h in humans. FIG. 36C shows measured volume of distribution versus body mass, with a predicted value of 5970 ml in humans.
FIG. 37 shows the near UV circular dichroism spectrum of Ex4-XTEN_AE864, performed as described in Example 42.
DETAILED DESCRIPTION OF THE INVENTION Before the embodiments of the invention are described, it is to be understood that such embodiments are provided by way of example only, and that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention.
Definitions As used herein, the following terms have the meanings ascribed to them unless specified otherwise.
As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.
The terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
As used herein the term “amino acid” refers to either natural and/or unnatural or synthetic amino acids, including but not limited to glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics. Standard single or three letter codes are used to designate amino acids.
The term “natural L-amino acid” means the L optical isomer forms of glycine (G), proline (P), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), cysteine (C), phenylalanine (F), tyrosine (Y), tryptophan (W), histidine (H), lysine (K), arginine (R), glutamine (Q), asparagine (N), glutamic acid (E), aspartic acid (D), serine (S), and threonine (T).
The term “non-naturally occurring,” as applied to sequences and as used herein, means polypeptide or polynucleotide sequences that do not have a counterpart to, are not complementary to, or do not have a high degree of homology with a wild-type or naturally-occurring sequence found in a mammal. For example, a non-naturally occurring polypeptide or fragment may share no more than 99%, 98%, 95%, 90%, 80%, 70%, 60%, 50% or even less amino acid sequence identity as compared to a natural sequence when suitably aligned.
The terms “hydrophilic” and “hydrophobic” refer to the degree of affinity that a substance has with water. A hydrophilic substance has a strong affinity for water, tending to dissolve in, mix with, or be wetted by water, while a hydrophobic substance substantially lacks affinity for water, tending to repel and not absorb water and tending not to dissolve in or mix with or be wetted by water Amino acids can be characterized based on their hydrophobicity. A number of scales have been developed. An example is a scale developed by Levitt, M, et al., J Mol Biol (1976) 104:59, which is listed in Hopp, T P, et al., Proc Natl Acad Sci USA (1981) 78:3824. Examples of “hydrophilic amino acids” are arginine, lysine, threonine, alanine, asparagine, and glutamine. Of particular interest are the hydrophilic amino acids aspartate, glutamate, and serine, and glycine. Examples of “hydrophobic amino acids” are tryptophan, tyrosine, phenylalanine, methionine, leucine, isoleucine, and valine.
A “fragment” is a truncated form of a native biologically active protein that retains at least a portion of the therapeutic and/or biological activity. A “variant” is a protein with sequence homology to the native biologically active protein that retains at least a portion of the therapeutic and/or biological activity of the biologically active protein. For example, a variant protein may share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity with the reference biologically active protein. As used herein, the term “biologically active protein moiety” includes proteins modified deliberately, as for example, by site directed mutagenesis, insertions, or accidentally through mutations.
A “host cell” includes an individual cell or cell culture which can be or has been a recipient for the subject vectors. Host cells include progeny of a single host cell. The progeny may not necessarily be completely identical (in morphology or in genomic of total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a vector of this invention.
“Isolated,” when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. In addition, a “concentrated”, “separated” or “diluted” polynucleotide, peptide, polypeptide, protein, antibody, or fragments thereof, is distinguishable from its naturally occurring counterpart in that the concentration or number of molecules per volume is generally greater than that of its naturally occurring counterpart. In general, a polypeptide made by recombinant means and expressed in a host cell is considered to be “isolated.”
An “isolated” polynucleotide or polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal or extra-chromosomal location different from that of natural cells.
A “chimeric” protein contains at least one fusion polypeptide comprising regions in a different position in the sequence than that which occurs in nature. The regions may normally exist in separate proteins and are brought together in the fusion polypeptide; or they may normally exist in the same protein but are placed in a new arrangement in the fusion polypeptide. A chimeric protein may be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship.
“Conjugated”, “linked,” “fused,” and “fusion” are used interchangeably herein. These terms refer to the joining together of two or more chemical elements or components, by whatever means including chemical conjugation or recombinant means. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and in reading phase or in-frame. An “in-frame fusion” refers to the joining of two or more open reading frames (ORFs) to form a continuous longer ORF, in a manner that maintains the correct reading frame of the original ORFs. Thus, the resulting recombinant fusion protein is a single protein containing two or more segments that correspond to polypeptides encoded by the original ORFs (which segments are not normally so joined in nature).
In the context of polypeptides, a “linear sequence” or a “sequence” is an order of amino acids in a polypeptide in an amino to carboxyl terminus direction in which residues that neighbor each other in the sequence are contiguous in the primary structure of the polypeptide. A “partial sequence” is a linear sequence of part of a polypeptide that is known to comprise additional residues in one or both directions.
“Heterologous” means derived from a genotypically distinct entity from the rest of the entity to which it is being compared. For example, a glycine rich sequence removed from its native coding sequence and operatively linked to a coding sequence other than the native sequence is a heterologous glycine rich sequence. The term “heterologous” as applied to a polynucleotide, a polypeptide, means that the polynucleotide or polypeptide is derived from a genotypically distinct entity from that of the rest of the entity to which it is being compared.
The terms “polynucleotides”, “nucleic acids”, “nucleotides” and “oligonucleotides” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
The term “complement of a polynucleotide” denotes a polynucleotide molecule having a complementary base sequence and reverse orientation as compared to a reference sequence, such that it could hybridize with a reference sequence with complete fidelity.
“Recombinant” as applied to a polynucleotide means that the polynucleotide is the product of various combinations of in vitro cloning, restriction and/or ligation steps, and other procedures that result in a construct that can potentially be expressed in a host cell.
The terms “gene” or “gene fragment” are used interchangeably herein. They refer to a polynucleotide containing at least one open reading frame that is capable of encoding a particular protein after being transcribed and translated. A gene or gene fragment may be genomic or cDNA, as long as the polynucleotide contains at least one open reading frame, which may cover the entire coding region or a segment thereof. A “fusion gene” is a gene composed of at least two heterologous polynucleotides that are linked together.
“Homology” or “homologous” refers to sequence similarity or interchangeability between two or more polynucleotide sequences or two or more polypeptide sequences. When using a program such as BestFit to determine sequence identity, similarity or homology between two different amino acid sequences, the default settings may be used, or an appropriate scoring matrix, such as blosum45 or blosum80, may be selected to optimize identity, similarity or homology scores. Preferably, polynucleotides that are homologous are those which hybridize under stringent conditions as defined herein and have at least 70%, preferably at least 80%, more preferably at least 90%, more preferably 95%, more preferably 97%, more preferably 98%, and even more preferably 99% sequence identity to those sequences.
“Ligation” refers to the process of forming phosphodiester bonds between two nucleic acid fragments or genes, linking them together. To ligate the DNA fragments or genes together, the ends of the DNA must be compatible with each other. In some cases, the ends will be directly compatible after endonuclease digestion. However, it may be necessary to first convert the staggered ends commonly produced after endonuclease digestion to blunt ends to make them compatible for ligation.
The terms “stringent conditions” or “stringent hybridization conditions” includes reference to conditions under which a polynucleotide will hybridize to its target sequence, to a detectably greater degree than other sequences (e.g., at least 2-fold over background). Generally, stringency of hybridization is expressed, in part, with reference to the temperature and salt concentration under which the wash step is carried out. Typically, stringent conditions will be those in which the salt concentration is less than about 1.5 M Na ion, typically about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short polynucleotides (e.g., 10 to 50 nucleotides) and at least about 60° C. for long polynucleotides (e.g., greater than 50 nucleotides)—for example, “stringent conditions” can include hybridization in 50% formamide, 1 M NaCl, 1% SDS at 37° C., and three washes for 15 min each in 0.1×SSC/1% SDS at 60° C. to 65° C. Alternatively, temperatures of about 65° C., 60° C., 55° C., or 42° C. may be used. SSC concentration may be varied from about 0.1 to 2×SSC, with SDS being present at about 0.1%. Such wash temperatures are typically selected to be about 5° C. to 20° C. lower than the thermal melting point for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; specifically see volume 2 and chapter 9. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 μg/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art.
The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity may be measured over the length of an entire defined polynucleotide sequence, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polynucleotide sequence, for instance, a fragment of at least 45, at least 60, at least 90, at least 120, at least 150, at least 210 or at least 450 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
“Percent (%) amino acid sequence identity,” with respect to the polypeptide sequences identified herein, is defined as the percentage of amino acid residues in a query sequence that are identical with the amino acid residues of a second, reference polypeptide sequence or a portion thereof, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percent identity may be measured over the length of an entire defined polypeptide sequence, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
The term “non-repetitiveness” as used herein in the context of a polypeptide refers to a lack or limited degree of internal homology in a peptide or polypeptide sequence. The term “substantially non-repetitive” can mean, for example, that there are few or no instances of four contiguous amino acids in the sequence that are identical amino acid types or that the polypeptide has a subsequence score (defined infra) of 10 or less or that there isn't a pattern in the order, from N- to C-terminus, of the sequence motifs that constitute the polypeptide sequence. The term “repetitiveness” as used herein in the context of a polypeptide refers to the degree of internal homology in a peptide or polypeptide sequence. In contrast, a “repetitive” sequence may contain multiple identical copies of short amino acid sequences. For instance, a polypeptide sequence of interest may be divided into n-mer sequences and the number of identical sequences can be counted. Highly repetitive sequences contain a large fraction of identical sequences while non-repetitive sequences contain few identical sequences. In the context of a polypeptide, a sequence can contain multiple copies of shorter sequences of defined or variable length, or motifs, in which the motifs themselves have non-repetitive sequences, rendering the full-length polypeptide substantially non-repetitive. The length of polypeptide within which the non-repetitiveness is measured can vary from 3 amino acids to about 200 amino acids, about from 6 to about 50 amino acids, or from about 9 to about 14 amino acids. “Repetitiveness” used in the context of polynucleotide sequences refers to the degree of internal homology in the sequence such as, for example, the frequency of identical nucleotide sequences of a given length. Repetitiveness can, for example, be measured by analyzing the frequency of identical sequences.
A “vector” is a nucleic acid molecule, preferably self-replicating in an appropriate host, which transfers an inserted nucleic acid molecule into and/or between host cells. The term includes vectors that function primarily for insertion of DNA or RNA into a cell, replication of vectors that function primarily for the replication of DNA or RNA, and expression vectors that function for transcription and/or translation of the DNA or RNA. Also included are vectors that provide more than one of the above functions. An “expression vector” is a polynucleotide which, when introduced into an appropriate host cell, can be transcribed and translated into a polypeptide(s). An “expression system” usually connotes a suitable host cell comprised of an expression vector that can function to yield a desired expression product.
“Serum degradation resistance,” as applied to a polypeptide, refers to the ability of the polypeptides to withstand degradation in blood or components thereof, which typically involves proteases in the serum or plasma. The serum degradation resistance can be measured by combining the protein with human (or mouse, rat, monkey, as appropriate) serum or plasma, typically for a range of days (e.g. 0.25, 0.5, 1, 2, 4, 8, 16 days), typically at about 37° C. The samples for these time points can be run on a Western blot assay and the protein is detected with an antibody. The antibody can be to a tag in the protein. If the protein shows a single band on the western, where the protein's size is identical to that of the injected protein, then no degradation has occurred. In this exemplary method, the time point where 50% of the protein is degraded, as judged by Western blots or equivalent techniques, is the serum degradation half-life or “serum half-life” of the protein.
The term “t1/2” as used herein means the terminal half-life calculated as ln(2)/Kel. Kel is the terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve. Half-life typically refers to the time required for half the quantity of an administered substance deposited in a living organism to be metabolized or eliminated by normal biological processes. The terms “t1/2”, “terminal half-life”, “elimination half-life” and “circulating half-life” are used interchangeably herein.
“Apparent Molecular Weight Factor” or “Apparent Molecular Weight” are related terms referring to a measure of the relative increase or decrease in apparent molecular weight exhibited by a particular amino acid sequence. The Apparent Molecular Weight is determined using size exclusion chromatography (SEC) and similar methods compared to globular protein standards and is measured in “apparent kD” units. The Apparent Molecular Weight Factor is the ratio between the Apparent Molecular Weight and the actual molecular weight; the latter predicted by adding, based on amino acid composition, the calculated molecular weight of each type of amino acid in the composition.
The “hydrodynamic radius” or “Stokes radius” is the effective radius (Rh in nm) of a molecule in a solution measured by assuming that it is a body moving through the solution and resisted by the solution's viscosity. In the embodiments of the invention, the hydrodynamic radius measurements of the XTEN fusion proteins correlate with the ‘Apparent Molecular Weight Factor’, which is a more intuitive measure. The “hydrodynamic radius” of a protein affects its rate of diffusion in aqueous solution as well as its ability to migrate in gels of macromolecules. The hydrodynamic radius of a protein is determined by its molecular weight as well as by its structure, including shape and compactness. Methods for determining the hydrodynamic radius are well known in the art, such as by the use of size exclusion chromatography (SEC), as described in U.S. Pat. Nos. 6,406,632 and 7,294,513. Most proteins have globular structure, which is the most compact three-dimensional structure a protein can have with the smallest hydrodynamic radius. Some proteins adopt a random and open, unstructured, or ‘linear’ conformation and as a result have a much larger hydrodynamic radius compared to typical globular proteins of similar molecular weight.
“Physiological conditions” refer to a set of conditions in a living host as well as in vitro conditions, including temperature, salt concentration, pH, that mimic those conditions of a living subject. A host of physiologically relevant conditions for use in in vitro assays have been established. Generally, a physiological buffer contains a physiological concentration of salt and is adjusted to a neutral pH ranging from about 6.5 to about 7.8, and preferably from about 7.0 to about 7.5. A variety of physiological buffers is listed in Sambrook et al. (1989). Physiologically relevant temperature ranges from about 25° C. to about 38° C., and preferably from about 35° C. to about 37° C.
A “reactive group” is a chemical structure that can be coupled to a second reactive group. Examples for reactive groups are amino groups, carboxyl groups, sulfhydryl groups, hydroxyl groups, aldehyde groups, azide groups. Some reactive groups can be activated to facilitate coupling with a second reactive group. Non-limiting examples for activation are the reaction of a carboxyl group with carbodiimide, the conversion of a carboxyl group into an activated ester, or the conversion of a carboxyl group into an azide function.
“Controlled release agent”, “slow release agent”, “depot formulation” or “sustained release agent” are used interchangeably to refer to an agent capable of extending the duration of release of a polypeptide of the invention relative to the duration of release when the polypeptide is administered in the absence of agent. Different embodiments of the present invention may have different release rates, resulting in different therapeutic amounts.
The terms “antigen”, “target antigen” or “immunogen” are used interchangeably herein to refer to the structure or binding determinant that an antibody fragment or an antibody fragment-based therapeutic binds to or has specificity against.
The term “payload” as used herein refers to a protein or peptide sequence that has biological or therapeutic activity; the counterpart to the pharmacophore of small molecules. Examples of payloads include, but are not limited to, cytokines, enzymes, hormones and blood and growth factors. Payloads can further comprise genetically fused or chemically conjugated moieties such as chemotherapeutic agents, antiviral compounds, toxins, or contrast agents. These conjugated moieties can be joined to the rest of the polypeptide via a linker that may be cleavable or non-cleavable.
The term “antagonist”, as used herein, includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein. Methods for identifying antagonists of a polypeptide may comprise contacting a native polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide. In the context of the present invention, antagonists may include proteins, nucleic acids, carbohydrates, antibodies or any other molecules that decrease the effect of a biologically active protein.
The term “agonist” is used in the broadest sense and includes any molecule that mimics a biological activity of a native polypeptide disclosed herein. Suitable agonist molecules specifically include agonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, small organic molecules, etc. Methods for identifying agonists of a native polypeptide may comprise contacting a native polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the native polypeptide.
“Activity” for the purposes herein refers to an action or effect of a component of a fusion protein consistent with that of the corresponding native biologically active protein, wherein “biological activity” refers to an in vitro or in vivo biological function or effect, including but not limited to receptor binding, antagonist activity, agonist activity, or a cellular or physiologic response.
As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” is used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
A “therapeutic effect”, as used herein, refers to a physiologic effect, including but not limited to the cure, mitigation, amelioration, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental wellbeing of humans or animals, caused by a fusion polypeptide of the invention other than the ability to induce the production of an antibody against an antigenic epitope possessed by the biologically active protein. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
The terms “therapeutically effective amount” and “therapeutically effective dose”, as used herein, refers to an amount of a biologically active protein, either alone or as a part of a fusion protein composition, that is capable of having any detectable, beneficial effect on any symptom, aspect, measured parameter or characteristics of a disease state or condition when administered in one or repeated doses to a subject. Such effect need not be absolute to be beneficial.
The term “therapeutically effective dose regimen”, as used herein, refers to a schedule for consecutively administered doses of a biologically active protein, either alone or as a part of a fusion protein composition, wherein the doses are given in therapeutically effective amounts to result in sustained beneficial effect on any symptom, aspect, measured parameter or characteristics of a disease state or condition.
I). General Techniques The practice of the present invention employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See Sambrook, J. et al., “Molecular Cloning: A Laboratory Manual,” 3rd edition, Cold Spring Harbor Laboratory Press, 2001; “Current protocols in molecular biology”, F. M. Ausubel, et al. eds.,1987; the series “Methods in Enzymology,” Academic Press, San Diego, Calif.; “PCR 2: a practical approach”, M. J. MacPherson, B. D. Hames and G. R. Taylor eds., Oxford University Press, 1995; “Antibodies, a laboratory manual” Harlow, E. and Lane, D. eds., Cold Spring Harbor Laboratory,1988; “Goodman & Gilman's The Pharmacological Basis of Therapeutics,” 11th Edition, McGraw-Hill, 2005; and Freshney, R. I., “Culture of Animal Cells: A Manual of Basic Technique,” 4th edition, John Wiley & Sons, Somerset, N.J., 2000, the contents of which are incorporated in their entirety herein by reference.
II). Growth Hormone The present invention relates in part to fusion protein compositions of growth hormone (GH), including human growth hormone (hGH).
(1) Growth Hormone Proteins
“Growth Hormone” or “GH” means a growth hormone protein and species and sequence variants thereof, and includes, but is not limited to, the 191 single-chain amino acid sequence of human GH. The GH can be the native, full-length protein or can be a truncated fragment or a sequence variant that retains at least a portion of the biological activity of the native protein. There are two known types of human GH (hereinafter “hGH”) derived from the pituitary gland: one having a molecular weight of about 22,000 daltons (22 kD hGH) and the other having a molecular weight of about 20,000 daltons (20 kD hGH). The 20 kD HGH has an amino acid sequence that corresponds to that of 22 kD hGH consisting of 191 amino acids except that 15 amino acid residues from the 32nd to the 46th of 22 kD hGH are missing. Some reports have shown that the 20 kD hGH has been found to exhibit lower risks and higher activity than 22 kD hGH. The invention contemplates use of the 22 kD, the 20 kD hGH, as well as species and sequence variants and truncated fragments thereof as being appropriate for use as a fusion partner with XTEN disclosed herein for GHXTEN compositions. The cloned gene for hGH has been expressed in a secreted form in Eschericha coli (U.S. Pat. No. 4,898,830; Chang, C. N., et al., Gene 55:189 [1987]) and its DNA and amino acid sequence has been reported (Goeddel, et al. Nature, 281:544 [1979); Gray, et al., Gene 39: 247[1985]).
The invention contemplates inclusion in the GHXTEN compositions sequences with homology to GH sequences, sequence fragments that are natural, such as from humans, non-human primates, mammals (including domestic animals), and non-natural sequence variants which retain at least a portion of the biologic activity or biological function of GH and/or that are useful for preventing, treating, mediating, or ameliorating a GH-related disease, deficiency, disorder or condition. Non-mammalian GH sequences are well-described in the literature. For example, a sequence alignment of fish GHs can be found in Genetics and Molecular Biology 2003 26 p. 295-300. An analysis of the evolution of avian GH sequences is presented in Journal of Evolutionary Biology 2006 19 p. 844-854. In addition, native sequences homologous to human GH may be found by standard homology searching techniques, such as NCBI BLAST.
Effects of GH on the tissues of the body can generally be described as anabolic. Like most other protein hormones, native GH acts by interacting with a specific plasma membrane receptor, referred to as growth hormone receptor. GH acts on the liver and other tissues to stimulate production of IGF-1, which is responsible for the growth promoting effects of GH and also reflects the amount produced. IGF-1, in turn, has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth. In one embodiment, the invention provides a GHXTEN that exhibits at least one of the properties of native GH hereinabove described herein.
In one embodiment, the GH incorporated into the subject compositions is a recombinant polypeptide with a sequence corresponding to a protein found in nature. In another embodiment, the GH is a sequence variant, fragment, homolog, or a mimetics of a natural sequence that retains at least a portion of the biological activity of the corresponding native GH. Table 1 provides a non-limiting list of sequences of GHs from a wide variety of mammalian species that are encompassed by the GHXTEN fusion proteins of the invention. Any of these GH sequences or homologous derivatives constructed by shuffling individual mutations between species or families that retain at least a portion of the biological activity of the native GH may be useful for the fusion proteins of this invention. GH that can be incorporated into a GHXTEN fusion protein can include a protein that exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from Table 1.
TABLE 1
Growth hormone amino acid sequences from animal species
SEQ ID
Species GH NO: Amino Acid Sequence
Human 1 FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCF
SESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSN
VYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGL
LYCFRKDMDKVETFLRIVQCRSVEGSCGF
Pig 2 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Alpaca 3 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILRQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Camel 4 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILRQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Horse 5 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDMELLRFSLLLIQSWLGPVQLLSRVFTNSLVFGTSDR
VYEKLRDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Elephant 6 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRPGQVLKQTYDKFDTNMRSDDALLKNY
GLLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Red fox 7 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLVLIQSWLGPLQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Dog 8 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Cat 9 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRGGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
American 10 FPAMPLSSLFANAVLRAQHLHQLAADTYKDFERAYIPEGQRYSIQNAQAAFCF
mink SETIPAPTGKDEAQQRSDMELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGPILKQTYDKFDTNLRSDDALLKNYGL
LSCFKKDLHKAETYLRV MKCRRFVESSCAF
Finback 11 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
whale SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Dolphin 12 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNTQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Hippo 13 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNTQAAFCF
SETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Rabbit 14 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDMELLRFSLLLIQSWLGPVQFLSRAFTNTLVFGTSDR
VYEKLKDLEEGIQALMRELEDGSPRVGQLLKQTYDKFDTNLRGDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCVF
Rat 15 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKEEAQQRTDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRV
YEKLKDLEEGIQALMQELEDGSPRIGQILKQTYDKFDANMRSDDALLKNYGL
LSCFKKDLHKAETYLRV MKCRRFAESSCAF
Mouse 16 FPAMPLSSLFSNAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKEEAQQRTDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRV
YEKLKDLEEGIQALMQELEDGSPRVGQILKQTYDKFDANMRSDDALLKNYGL
LSCFKKDLHKAETYLRV MKCRRFVESSCAF
Hamster 17 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQTAFCF
SETIPAPTGKEEAQQRSDMELLRFSLLLIQSWLGPVQFLSRIFTNSLMFGTSDRV
YEKLKDLEEGIQALMQELEDGSPRVGQILKQTYDKFDTNMRSDDALLKNYGL
LSCFKKDLHKAETYLRV MKCRRFVESSCAF
Mole rat 18 FPAMPLSNLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKEEAQQRSDMELLRFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDR
VFEKLKDLEEGIQALMRELEDGSLRAGQLLKQTYDKFDTNMRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Guinea pig 19 FPAMPLSSLFGNAVLRAQHLHQLAADTYKEFERTYIPEGQRYSIHNTQTAFCFS
ETIPAPTDKEEAQQRSDVELLHFSLLLIQSWLGPVQFLSRVFTNSLVFGTSDRV
YEKLKDLEEGIQALMRELEDGTPRAGQILKQTYDKFDTNLRSNDALLKNYGL
LSCFRKDLHRTETYLRV MKCRRFVESSCAF
Ox 20 AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFC
FSETIPAPTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGILALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFRKDLHKTETYLRV MKCRRFGEASCAF
Sheep/Goat 21 AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFC
FSETIPAPTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDR
VYEKLKDLEEGILALMRELEDVTPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFRKDLHKTETYLRV MKCRRFGEASCAF
Red deer 22 FPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCF
SETIPAPTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRV
YEKLKDLEEGILALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYGL
LSCFRKDLHKTETYLRV MKCRRFGEASCAF
Giraffe 23 AFPAMSLSGLFANAVLRAQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFC
FSETIPAPTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFSNSLVFGTSDR
VYEKLKDLEEGILALMRELEDGTPRAGQILKQTYDKFDTNMRSDDALLKNYG
LLSCFRKDLHKTETYLRV MKCRRFGEASCAF
Chevrotain-1 24 FPAMSLSGLFANAVLRVQHLHQLAADTFKEFERTYIPEGQRYSIQNTQVAFCF
SETIPAPTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFTNSLVFGTSDRV
YEKLKDLEEGILALMRELEDGPPRAGQILKQTYDKFDTNMRSDDALLKNYGL
LSCFRKDLHKTETYLRV MKCRRFGEASCAF
Slow loris 25 FPAMPLSSLFANAVLRAQHLHQLAADTYKEFERAYIPEGQRYSIQNAQAAFCF
SETIPAPTGKDEAQQRSDMELLRFSLLLIQSWLGPVQLLSRVFTNSLVLGTSDR
VYEKLKDLEEGIQALMRELEDGSPRVGQILKQTYDKFDTNLRSDDALLKNYG
LLSCFKKDLHKAETYLRV MKCRRFVESSCAF
Marmoset 26 FPTIPLSRLLDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCF
SESIPTPASKKETQQKSNLELLRMSLLLIQSWFEPVQFLRSVFANSLLYGVSDSD
VYEYLKDLEEGIQTLMGRLEDGSPRTGEIFMQTYRKFDVNSQNNDALLKNYG
LLYCFRKDMDKVETFLRI VQCR-SVEGSCGF
BrTailed 27 FPAMPLSSLFANAVLRAQHLHQLVADTYKEFERTYIPEAQRHSIQSTQTAFCFS
Possum ETIPAPTGKDEAQQRSDVELLRFSLLLIQSWLSPVQFLSRVFTNSLVFGTSDRV
YEKLRDLEEGIQALMQELEDGSSRGGLVLKTTYDKFDTNLRSDEALLKNYGL
LSCFKKDLHKAETYLRV MKCRRFVESSCAF
Monkey 28 FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCF
(rhesus) SESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGTSYSD
VYDLLKDLEEGIQTLMGRLEDGSSRTGQIFKQTYSKFDTNSHNNDALLKNYGL
LYCFRKDMDKIETFLRI VQCR-SVEGSCGF
III). Growth Hormone Fusion Protein Compositions The present invention relates in part to fusion protein compositions of growth hormone (GH). In one aspect, the invention provides isolated monomeric fusion proteins of GH comprising the full-length sequence or sequence variants of GH covalently linked to extended recombinant recombinant polypeptides (“XTEN” or “XTENs”). As described more fully below, the fusion proteins optionally include spacer sequences that further comprise cleavage sequences to release the GH from the fusion protein when acted on by a protease, releasing GH from the XTEN sequence(s).
In one aspect, the invention provides an isolated fusion protein comprising at least a first biologically active growth hormone protein covalently linked to one or more extended recombinant polypeptides (“XTEN”), resulting in a growth hormone-XTEN fusion protein composition (hereinafter “GHXTEN”). In one embodiment, the growth hormone is human growth hormone or a sequence variant of hGH. As described more fully below, the fusion proteins optionally include spacer sequences that further comprise cleavage sequences to release the GH from the fusion protein when acted on by a protease.
The term “GHXTEN”, as used herein, is meant to encompass fusion polypeptides that comprise one or more payload regions each comprising a biologically active GH that mediates one or more biological or therapeutic activities associated with growth hormone and at least one other region comprising at least a first XTEN polypeptide that serves as a carrier.
The GH of the subject compositions, particularly those disclosed in Table 1, together with their corresponding nucleic acid and amino acid sequences, are well known in the art and descriptions and sequences are available in public databases such as Chemical Abstracts Services Databases (e.g., the CAS Registry), GenBank, The Universal Protein Resource (UniProt) and subscription provided databases such as GenSeq (e.g., Derwent). Polynucleotide sequences may be a wild type polynucleotide sequence encoding a given GH (e.g., either full length or mature), or in some instances the sequence may be a variant of the wild type polynucleotide sequence (e.g., a polynucleotide which encodes the wild type biologically active protein, wherein the DNA sequence of the polynucleotide has been optimized, for example, for expression in a particular species; or a polynucleotide encoding a variant of the wild type protein, such as a site directed mutant or an allelic variant. It is well within the ability of the skilled artisan to use a wild-type or consensus cDNA sequence or a codon-optimized variant of a GH to create GHXTEN constructs contemplated by the invention using methods known in the art and/or in conjunction with the guidance and methods provided herein, and described more fully in the Examples.
The GH for inclusion in the GHXTEN of the invention include any growth hormone or sequence variant of biologic, therapeutic, prophylactic, or diagnostic interest or function, or that is useful for mediating or preventing or ameliorating a disease, disorder or condition associated with growth, growth hormone deficiency or defect when administered to a subject. Of particular interest are GHXTEN fusion protein compositions for which an increase in a pharmacokinetic parameter, increased solubility, increased stability, or some other enhanced pharmaceutical property compared to native GH is sought, or for which increasing the terminal half-life would improve efficacy, safety, or result in reduce dosing frequency and/or improve patient compliance. Thus, the GHXTEN fusion protein compositions are prepared with various objectives in mind, including improving the therapeutic efficacy of the bioactive GH by, for example, increasing the in vivo exposure or the length that the GHXTEN remains within the therapeutic window when administered to a subject, compared to a GH not linked to XTEN.
In one embodiment, the GH incorporated into the subject compositions can be a recombinant polypeptide with a sequence corresponding to a protein found in nature. In another embodiment, the GH is a sequence variant, fragment, homolog, or mimetic of a natural sequence that retain at least a portion of the biological activity of the native GH. In non-limiting examples, a GH is a sequence that exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99%, or 100% sequence identity to a protein sequence selected from Table 1. In one embodiment, a GHXTEN fusion protein comprises a single GH molecule linked to an XTEN (as described more fully below). In another embodiment, the GHXTEN comprises a first GH and a second molecule of the same GH, resulting in a fusion protein comprising the two GH linked to one or more XTEN (for example, or two molecules of hGH). In some cases of the foregoing embodiments, the GH and XTEN components are of an N- to C-terminus configuration selected from Table 5. In another embodiment, the GHXTEN fusion protein comprises a single GH molecule linked to a first and a second XTEN, with an N- to C-terminus configuration of XTEN-GH-XTEN, in which the GH is a sequence that exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99%, or 100% sequence identity to a protein sequence selected from Table 1, and the first and/or the second XTEN are sequences that exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99%, or 100% sequence identity to a sequence selected from Table 3.
In general, the GH fusion partner component of the GHXTEN exhibits a binding specificity to a given target or another desired biological characteristic when used in vivo or when utilized in an in vitro assay. For example, the GHXTEN is an agonist, having the ability to bind to a transmembrane receptor for growth hormone. In one embodiment, the binding of GHXTEN to growth receptor leads to receptor dimerization and lead to at least a portion of the activation of intercellular signal transduction pathway compared to native growth hormone. In one embodiment, the GHXTEN bound to a transmembrane receptor for growth hormone would exhibit at least about 1%, or about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or at least about 95% of the activation of intercellular signal transduction pathway compared to native growth hormone not linked to XTEN.
The subject GHXTEN of the present invention exhibits an enhancement of one or more pharmacokinetic parameters, which optionally is enhanced by release of GH from the fusion protein by cleavage of a spacer sequence. The GHXTEN with enhanced pharmacokinetic paramters permits less frequent dosing or an enhanced pharmacologic effect, such as but not limited to maintaining the biologically active GHXTEN wthin the therapeutic window between the minimum effective dose or blood concentration (Cmin) and the maximum tolerated dose or blood concentration (Cmax). In such cases, the linking of the GH to a fusion protein comprising a select XTEN sequence(s) can result in an improvement in these properties, making them more useful as therapeutic or preventive agents compared to GH not linked to XTEN.
IV). Xtended Recombinant Polypeptides In one aspect, the invention provides XTEN polypeptide compositions that are useful as a fusion protein partner to which GH is linked, resulting in a GHXTEN fusion protein. XTEN are generally extended length polypeptides with non-naturally occurring, substantially non-repetitive sequences that are composed mainly of small hydrophilic amino acids, with the sequence having a low degree or no secondary or tertiary structure under physiologic conditions.
XTENs have utility as a fusion protein partners partner in that they serve as a “carrier”, conferring certain desirable pharmacokinetic, physicochemical and pharmaceutical properties when linked to a GH protein to a create a fusion protein. Such desirable properties include but are not limited to enhanced pharmacokinetic parameters and solubility characteristicsthe compositions, amongst other properties described herein. Such fusion protein compositions have utility to treat certain growth hormone-related diseases, disorders or conditions, as described herein. As used herein, “XTEN” specifically excludes antibodies or antibody fragments such as single-chain antibodies or Fc fragments of a light chain or a heavy chain.
In some embodiments, XTEN are long polypeptides having greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues when used as a carrier or cumulatively when more than one XTEN unit is used in a single fusion protein. In other embodiments, when used as a linker between fusion protein components or where an increase in half-life of the fusion protein is not needed but where an increase in solubility or other physico/chemical property for the GH fusion partner component is desired, an XTEN sequence shorter than 100 amino acid residues, such as about 96, or about 84, or about 72, or about 60, or about 48, or about 36 amino acid residues are incorporated into a fusion protein composition with the GH to effect the property.
The selection criteria for the XTEN to be linked to the biologically active proteins used to create the inventive fusion proteins compositions generally relate to attributes of physical/chemical properties and conformational structure of the XTEN that is, in turn, used to confer enhanced pharmaceutical and pharmacokinetic properties to the fusion proteins.compositions. The XTEN of the present invention exhibit one or more of the following advantageous properties: conformational flexibility, enhanced aqueous solubility, high degree of protease resistance, low immunogenicity, low binding to mammalian receptors, and increased hydrodynamic (or Stokes) radii; properties that make them particularly useful as fusion protein partners. Non-limiting examples of the properties of the fusion proteins comprising GH that is enhanced by XTEN include increases in the overall solubility and/or metabolic stability, reduced susceptibility to proteolysis, reduced immunogenicity, reduced rate of absorption when administered subcutaneously or intramuscularly, and enhanced pharmacokinetic properties such as longer terminal half-life and increased area under the curve (AUC), slower absorption after subcutaneous or intramuscular injection (compared to GH not linked to XTEN and administered by a similar route) such that the Cmax is lower, which, in turn, results in reductions in adverse effects of the GH that, collectively, results in an increased period of time that a fusion protein of a GHXTEN composition administered to a subject retains therapeutic activity.
A variety of methods and assays are known in the art for determining the physical/chemical properties of proteins such as the compositions comprising the inventive XTEN; properties such as secondary or tertiary structure, solubility, protein aggregation, melting properties, contamination and water content. Such methods include analytical centrifugation, EPR, HPLC-ion exchange, HPLC-size exclusion, HPLC-reverse phase, light scattering, capillary electrophoresis, circular dichroism, differential scanning calorimetry, fluorescence, HPLC-ion exchange, HPLC-size exclusion, IR, NMR, Raman spectroscopy, refractometry, and UV/Visible spectroscopy. Additional methods are disclosed in Arnau et al, Prot Expr and Purif (2006) 48, 1-13. Application of these methods to the invention would be within the grasp of a person skilled in the art.
Typically, XTEN are designed to behave like denatured peptide sequences under physiological conditions, despite the extended length of the polymer. Denatured describes the state of a peptide in solution that is characterized by a large conformational freedom of the peptide backbone. Most peptides and proteins adopt a denatured conformation in the presence of high concentrations of denaturants or at elevated temperature. Peptides in denatured conformation have, for example, characteristic circular dichroism (CD) spectra and are characterized by a lack of long-range interactions as determined by NMR. “Denatured conformation” and “unstructured conformation” are used synonymously herein. In some embodiments, the invention provides XTEN sequences that, under physiologic conditions, resemble denatured sequences largely devoid in secondary structure. In other cases, the XTEN sequences are substantially devoid of secondary structure under physiologic conditions. “Largely devoid,” as used in this context, means that less than 50% of the XTEN amino acid residues of the XTEN sequence contribute to secondary structure as measured or determined by the means described herein. “Substantially devoid,” as used in this context, means that at least about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or at least about 99% of the XTEN amino acid residues of the XTEN sequence do not contribute to secondary structure, as measured or determined by the methods described herein.
A variety of methods have been established in the art to discern the presence or absence of secondary and tertiary structures in a given polypeptide. In particular, secondary structure can be measured spectrophotometrically, e.g., by circular dichroism spectroscopy in the “far-UV” spectral region (190-250 nm). Secondary structure elements, such as alpha-helix and beta-sheet, each give rise to a characteristic shape and magnitude of CD spectra. Secondary structure can also be predicted for a polypeptide sequence via certain computer programs or algorithms, such as the well-known Chou-Fasman algorithm (Chou, P. Y., et al. (1974) Biochemistry, 13: 222-45) and the Garnier-Osguthorpe-Robson (“GOR”) algorithm (Garnier J, Gibrat J F, Robson B. (1996), GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540-553), as described in US Patent Application Publication No. 20030228309A1. For a given sequence, the algorithms can predict whether there exists some or no secondary structure at all, expressed as the total and/or percentage of residues of the sequence that form, for example, alpha-helices or beta-sheets or the percentage of residues of the sequence predicted to result in random coil formation (which lacks secondary structure).
In some embodiments, the XTEN sequences used in the inventive fusion protein compositions can have an alpha-helix percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In other cases, the XTEN sequences of the fusion protein compositions have a beta-sheet percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In some embodiments, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage ranging from 0% to less than about 5% and a beta-sheet percentage ranging from 0% to less than about 5% as determined by the Chou-Fasman algorithm. In some embodiments, the XTEN sequences of the fusion protein compositions have an alpha-helix percentage less than about 2% and a beta-sheet percentage less than about 2%. In other cases, the XTEN sequences of the fusion protein compositions have a high degree of random coil percentage, as determined by the GOR algorithm. In some embodiments, an XTEN sequence have at least about 80%, more preferably at least about 90%, more preferably at least about 91%, more preferably at least about 92%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, and most preferably at least about 99% random coil, as determined by the GOR algorithm.
1. Non-Repetitive Sequences
In some embodiments, XTEN sequences of the compositions are substantially non-repetitive. In general, repetitive amino acid sequences have a tendency to aggregate or form higher order structures, as exemplified by natural repetitive sequences such as collagens and leucine zippers, or form contacts resulting in crystalline or pseudocrystaline structures. In contrast, the low tendency of non-repetitive sequences to aggregate enables the design of long-sequence XTENs with a relatively low frequency of charged amino acids that would be likely to aggregate if the sequences were otherwise repetitive. Typically, the GHXTEN fusion proteins comprise XTEN sequences of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 cumuclative residues, wherein the sequences are substantially non-repetitive. In one embodiment, the XTEN sequences have greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 amino acid residues, in which no three contiguous amino acids in the sequence are identical amino acid types unless the amino acid is serine, in which case no more than three contiguous amino acids are serine residues. In the foregoing embodiment, the XTEN sequence would be substantially non-repetitive.
The degree of repetitiveness of a polypeptide or a gene are measured by computer programs or algorithms or by other means known in the art. Repetitiveness in a polypeptide sequence can, for example, be assessed by determining the number of times shorter sequences of a given length occur within the polypeptide. For example, a polypeptide of 200 amino acid residues has 192 overlapping 9-amino acid sequences (or 9-mer “frames”) and 198 3-mer frames, but the number of unique 9-mer or 3-mer sequences will depend on the amount of repetitiveness within the sequence. A score is generated (hereinafter “subsequence score”) that is reflective of the degree of repetitiveness of the subsequences in the overall polypeptide sequence. In the context of the present invention, “subsequence score” means the sum of occurrences of each unique 3-mer frame across a 200 consecutive amino acid sequence of the polypeptide divided by the absolute number of unique 3-mer subsequences within the 200 amino acid sequence. Examples of such subsequence scores derived from the first 200 amino acids of repetitive and non-repetitive polypeptides are presented in Example 44. In some embodiments, the present invention provides GHXTEN each comprising one or more XTEN in which the XTEN have a subsequence score less than 12, more preferably less than 10, more preferably less than 9, more preferably less than 8, more preferably less than 7, more preferably less than 6, and most preferably less than 5. In the embodiments hereinabove described in this paragraph, an XTEN with a subsequence score less than about 10 (i.e., 9, 8, 7, etc.) is “substantially non-repetitive.”
The non-repetitive characteristic of XTEN impart to fusion proteins with GH a greater degree of solubility and less tendency to aggregate compared to polypeptides having repetitive sequences. These properties facilitate the formulation of XTEN-comprising pharmaceutical preparations containing extremely high drug concentrations, in some cases exceeding 100 mg/ml.
Furthermore, the XTEN polypeptide sequences of the embodiments are designed to have a low degree of internal repetitiveness in order to reduce or substantially eliminate immunogenicity when administered to a mammal Polypeptide sequences composed of short, repeated motifs largely limited to three amino acids, such as glycine, serine and glutamate, may result in relatively high antibody titers when administered to a mammal despite the absence of predicted T-cell epitopes in these sequences. This may be caused by the repetitive nature of polypeptides, as it has been shown that immunogens with repeated epitopes, including protein aggregates, cross-linked immunogens, and repetitive carbohydrates are highly immunogenic and can, for example, result in the cross-linking of B-cell receptors causing B-cell activation. (Johansson, J., et al. (2007) Vaccine, 25 :1676-82; Yankai, Z., et al. (2006) Biochem Biophys Res Commun, 345 :1365-71; Hsu, C. T., et al. (2000) Cancer Res, 60:3701-5); Bachmann M F, et al. Eur J Immunol. (1995) 25(12):3445-3451).
2. Exemplary Sequence Motifs
The present invention encompasses XTEN that comprise multiple units of shorter sequences, or motifs, in which the amino acid sequences of the motifs are non-repetitive. In designing XTEN sequences, it was discovered that the non-repetitive criterion may be met despite the use of a “building block” approach using a library of sequence motifs that are multimerized to create the XTEN sequences. Thus, while an XTEN sequence may consist of multiple units of as few as four different types of sequence motifs, because the motifs themselves generally consist of non-repetitive amino acid sequences, the overall XTEN sequence is rendered substantially non-repetitive.
In one embodiment, XTEN have a non-repetitive sequence of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues, wherein at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence consists of non-overlapping sequence motifs, wherein each of the motifs has about 9 to 36 amino acid residues. In other embodiments, at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 14 amino acid residues. In still other embodiments, at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 100% of the XTEN sequence component consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues. In these embodiments, it is preferred that the sequence motifs be composed mainly of small hydrophilic amino acids, such that the overall sequence has an unstructured, flexible characteristic. Examples of amino acids that are included in XTEN, are, e.g., arginine, lysine, threonine, alanine, asparagine, glutamine, aspartate, glutamate, serine, and glycine. As a result of testing variables such as codon optimization, assembly polynucleotides encoding sequence motifs, expression of protein, charge distribution and solubility of expressed protein, and secondary and tertiary structure, it was discovered that XTEN compositions with enhanced characteristics mainly include glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues wherein the sequences are designed to be substantially non-repetitive. In one embodiment, XTEN sequences have predominately four to six types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) or proline (P) that are arranged in a substantially non-repetitive sequence that is greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues in length. In some embodiments, XTEN have sequences of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues, wherein at least about 80% of the sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 36 amino acid residues wherein each of the motifs consists of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In other embodiments, at least about 90% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 9 to 36 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In other embodiments, at least about 90% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues consisting of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In yet other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, to about 100% of the XTEN sequence consists of non-overlapping sequence motifs wherein each of the motifs has 12 amino acid residues consisting of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%.
In still other embodiments, XTENs comprise non-repetitive sequences of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 amino acid residues wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the sequence consists of non-overlapping sequence motifs of 9 to 14 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one motif is not repeated more than twice in the sequence motif In other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of an XTEN sequence consists of non-overlapping sequence motifs of 12 amino acid residues wherein the motifs consist of 4 to 6 types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif. In other embodiments, at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of an XTEN sequence consists of non-overlapping sequence motifs of 12 amino acid residues wherein the motifs consist of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif. In yet other embodiments, XTENs consist of 12 amino acid sequence motifs wherein the amino acids are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and wherein the sequence of any two contiguous amino acid residues in any one sequence motif is not repeated more than twice in the sequence motif, and wherein the content of any one amino acid type in the full-length XTEN does not exceed 30%. In the foregoing embodiments hereinabove described in this paragraph, the XTEN sequences would be substantially non-repetitive.
In some embodiments, the invention provides compositions comprising non-repetitive XTEN sequence(s) of greater than about 100 to about 3000 amino acid residues, of cumulatively greater than 400 to about 3000 residues, wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% of the sequence consists of multiple units of two or more non-overlapping sequence motifs selected from the amino acid sequences of Table 2. In some embodiments, the XTEN comprises non-overlapping sequence motifs in which about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% of the sequence consists of two or more non-overlapping sequences selected from a single motif family of Table 2, resulting in a “family” sequence in which the overall sequence remains substantially non-repetitive. Accordingly, in these embodiments, an XTEN sequence comprises multiple units of non-overlapping sequence motifs of the AD motif family, or the AE motif family, or the AF motif family, or the AG motif family, or the AM motif family, or the AQ motif family, or the BC family, or the BD family of sequences of Table 2. In other embodiments, the XTEN comprises motif sequences from two or more of the motif families of Table 2.
TABLE 2
XTEN Sequence Motifs of 12
Amino Acids and Motif Families
Motif Family* SEQ ID NO: MOTIF SEQUENCE
AD 29 GESPGGSSGSES
AD 30 GSEGSSGPGESS
AD 31 GSSESGSSEGGP
AD 32 GSGGEPSESGSS
AE, AM 33 GSPAGSPTSTEE
AE, AM, AQ 34 GSEPATSGSETP
AE, AM, AQ 35 GTSESATPESGP
AE, AM, AQ 36 GTSTEPSEGSAP
AF, AM 37 GSTSESPSGTAP
AF, AM 38 GTSTPESGSASP
AF, AM 39 GTSPSGESSTAP
AF, AM 40 GSTSSTAESPGP
AG, AM 41 GTPGSGTASSSP
AG, AM 42 GSSTPSGATGSP
AG, AM 43 GSSPSASTGTGP
AG, AM 44 GASPGTSSTGSP
AQ 45 GEPAGSPTSTSE
AQ 46 GTGEPSSTPASE
AQ 47 GSGPSTESAPTE
AQ 48 GSETPSGPSETA
AQ 49 GPSETSTSEPGA
AQ 50 GSPSEPTEGTSA
BC 51 GSGASEPTSTEP
BC 52 GSEPATSGTEPS
BC 53 GTSEPSTSEPGA
BC 54 GTSTEPSEPGSA
BD 55 GSTAGSETSTEA
BD 56 GSETATSGSETA
BD 57 GTSESATSESGA
BD 58 GTSTEASEGSAS
*Denotes individual motif sequences that, when used together in various permutations, results in a “family sequence”
In other embodiments, the GHXTEN composition comprises a non-repetitive XTEN sequence of greater than about 100 to about 3000 amino acid residues, preferably greater than 400 to about 3000 residues, wherein at least about 80%, or at least about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% to about 100% of the sequence consists of non-overlapping 36 amino acid sequence motifs selected from one or more of the polypeptide sequences of Tables 8-11.
In those embodiments wherein the XTEN component of the GHXTEN fusion protein has less than 100% of its amino acids consisting of four to six amino acid selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), or less than 100% of the sequence consisting of the sequence motifs of Table 2, or less than 100% sequence identity with an XTEN from Table 3, the other amino acid residues are selected from any other of the 14 natural L-amino acids, but are preferentially selected from hydrophilic amino acids such that the XTEN sequence contains at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% hydrophilic amino acids. The XTEN amino acids that are not glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) are interspersed throughout the XTEN sequence, are located within or between the sequence motifs, or are concentrated in one or more short stretches of the XTEN sequence. In such cases where the XTEN component of the GHXTEN comprises amino acids other than glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), it is preferred that the amino acids not be hydrophobic residues and should not substantially confer secondary structure of the XTEN component. Hydrophobic residues that are less favored in construction of XTEN include tryptophan, phenylalanine, tyrosine, leucine, isoleucine, valine, and methionine. Additionally, one can design the XTEN sequences to contain few (e.g. less than 5%) or none of the following amino acids: cysteine (to avoid disulfide formation and oxidation), methionine (to avoid oxidation), asparagine and glutamine (to avoid desamidation). Thus, in some embodiments, the XTEN component of the GHXTEN fusion protein comprising other amino acids in addition to glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) would have a sequence with less than 5% of the residues contributing to alpha-helices and beta-sheets as measured by the Chou-Fasman algorithm and have at least 90%, or at least about 95% or more random coil formation as measured by the GOR algorithm.
3. Length of Sequence
In another aspect of the present invention, the invention encompasses GHXTEN compositions comprising carriers of XTEN polypeptides with extended length sequences. The present invention makes use of the discovery that increasing the length of non-repetitive, unstructured polypeptides enhances the unstructured nature of the XTENs and correspoindingly enhances the biological and pharmacokinetic properties of fusion proteins comprising the XTEN carrier. As described more fully in the Examples, proportional increases in the length of the XTEN, even if created by a fixed repeat order of single family sequence motifs (e.g., the four AE motifs of Table 2), result in a sequence with a higher percentage of random coil formation, as determined by GOR algorithm, compared to shorter XTEN lengths. In general, increasing the length of the unstructured polypeptide fusion partner, as described in the Examples, results in a fusion protein with a disproportional increase in terminal half-life compared to fusion proteins with unstructured polypeptide partners with shorter sequence lengths.
Non-limiting examples of XTEN contemplated for inclusion in the GHXTEN of the invention are presented in Table 3. In one embodiment, the invention provides GHXTEN compositions wherein the XTEN sequence length of the fusion protein(s) is greater than about 100 to about 3000 amino acid residues, and in some cases is greater than 400 to about 3000 amino acid residues, wherein the XTEN confers enhanced pharmacokinetic properties on the GHXTEN in comparison to GH not linked to XTEN. In some embodiments, the XTEN sequences of the GHXTEN compositions of the present invention can be about 100, or about 144, or about 288, or about 401, or about 500, or about 600, or about 700, or about 800, or about 900, or about 1000, or about 1500, or about 2000, or about 2500 or up to about 3000 amino acid residues in length. In other cases, the XTEN sequences can be about 100 to 150, about 150 to 250, about 250 to 400, 401 to about 500, about 500 to 900, about 900 to 1500, about 1500 to 2000, or about 2000 to about 3000 amino acid residues in length. In one embodiment, the GHXTEN can comprise an XTEN sequence wherein the sequence exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a XTEN selected from Table 3. In some embodiments, the XTEN sequence is designed for optimized expression as the N-terminal component of the GHXTEN by inclusion of encoding nucleotides for an optimized N-terminal leader sequence (NTS) in the XTEN portion of the gene encoding the fusion protein. In one embodiment, the N-terminal XTEN sequence of the expressed GHXTEN has at least 90% sequence identity to the sequence of AE48 or AM48, AE624, or AE912 or AM923. In another embodiment, the XTEN has the N-terminal residues described in Examples 14-17.
In other embodiments, the GHXTEN fusion protein comprises a first and a second XTEN sequence, wherein the cumulative total of the residues in the XTEN sequences is greater than about 400 to about 3000 amino acid residues. In embodiments of the foregoing, the GHXTEN fusion protein comprises a first and a second XTEN sequence wherein the sequences each exhibit at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to at least a first or additionally a second XTEN selected from Table 3. Examples where more than one XTEN is used in a GHXTEN composition include, but are not limited to constructs with an XTEN linked to both the N- and C-termini of at least one GH.
As described more fully below, the invention provides methods in which the GHXTEN is designed by selecting the length of the XTEN to confer a target half-life on a fusion protein administered to a subject. In general, XTEN lengths longer that about cumulative 400 residues incorporated into the GHXTEN compositions result in longer half-life compared to shorter cumulative lengths; e.g., shorter than about 280 residues. However, in another embodiment, GHXTEN fusion proteins are designed to comprise XTEN with a longer sequence length that is selected to additionally confer slower rates of systemic absorption after subcutaneous or intramuscular administration to a subject. In such embodiments, the Cmax is reduced in comparison to a comparable dose of a GH not linked to XTEN, thereby contributing to the ability to keep the GHXTEN within the therapeutic window for the composition. Thus, the XTEN confers the property of a depot to the administered GHXTEN, in addition to the other physical/chemical properties described herein.
TABLE 3
XTEN Polypeptides
XTEN SEQ ID
Name NO: Amino Acid Sequence
AE48 59 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS
AM48 60 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS
AE144 61 GSEPATSGSETPGTSESATPESGPGSEPATSGSETPGSPAGSPTSTEEGTSTE
PSEGSAPGSEPATSGSETPGSEPATSGSETPGSEPATSGSETPGTSTEPSEGS
APGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAP
AF144 62 GTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGSTSES
PSGTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPG
PGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAP
AE288 63 GTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSES
ATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSE
TPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTS
ESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSG
SETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPG
TSESATPESGPGTSTEPSEGSAP
AF504 64 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTP
SGATGSPGSXPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGAT
GSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGS
STPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSXPSAS
TGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSP
GASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASP
GTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSST
GSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPG
ASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPS
GATGSPGSSPSASTGTGPGASPGTSSTGSP
AF540 65 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSST
AESPGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTA
PGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPS
GESSTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSA
SPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGTST
PESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGS
ASPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSSTAESPGPGT
STPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG
SASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGESSTAPGS
TSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGSTSESPS
GTAP
AD576 66 GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSES
GSSEGGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPG
ESSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGE
SPGGSSGSESGESPGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPS
ESGSSGSGGEPSESGSSGSEGSSGPGESSGESPGGSSGSESGSGGEPSESGSS
GSGGEPSESGSSGSGGEPSESGSSGSSESGSSEGGPGESPGGSSGSESGESPG
GSSGSESGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGSSESGSSEG
GPGSGGEPSESGSSGSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSS
ESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSSESGSS
EGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSS
GESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSGPGESS
AE576 67 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE
PSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSE
TPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSP
AGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSE
GSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPG
TSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPAT
SGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTST
EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGS
ETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGS
PAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP
AF576 68 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSST
AESPGPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTA
PGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPS
GESSTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSA
SPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGTST
PESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGTSTPESGS
ASPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSSTAESPGPGT
STPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG
SASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGESSTAPGS
TSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGSTSESPS
GTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASP
AE624 69 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSP
AGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE
GSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPG
SPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGS
PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSA
PGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSE
SATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS
ETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT
STEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS
EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETP
GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAG
SPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP
AD836 70 GSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGESPG
GSSGSESGESPGGSSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEG
GPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGSSESGSSEGGPGSS
ESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSSESGSS
EGGPGSGGEPSESGSSGESPGGSSGSESGESPGGSSGSESGSGGEPSESGSS
GSEGSSGPGESSGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSES
GSSEGGPGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSSGSGGEPSES
GSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSSGSEGSSGPGESSGE
SPGGSSGSESGSEGSSGPGESSGSEGSSGPGESSGSGGEPSESGSSGSSESGS
SEGGPGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGSEGSSGPGESS
GESPGGSSGSESGSEGSSGPGSSESGSSEGGPGSGGEPSESGSSGSEGSSGP
GESSGSEGSSGPGESSGSEGSSGPGESSGSGGEPSESGSSGSGGEPSESGSSG
ESPGGSSGSESGESPGGSSGSESGSGGEPSESGSSGSEGSSGPGESSGESPGG
SSGSESGSSESGSSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGS
SGSSESGSSEGGPGESPGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGESP
GGSSGSESGSGGEPSESGSSGESPGGSSGSESGSGGEPSESGSS
AE864 71 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE
PSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSE
TPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSP
AGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSE
GSAPGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPG
TSESATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPAT
SGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTST
EPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGS
ETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGS
PAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESAT
PESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGP
GTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSES
ATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPES
GPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSP
AGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAP
AF864 72 GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPE
SGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAP
GSTSESPSGTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPS
GESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSA
SPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGPGTST
PESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESST
APGTSTPESGSASPGSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGST
SSTAESPGPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGP
XXXGASASGAPSTXXXXSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGS
TSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSPSGES
STAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPG
STSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGTSTPES
GSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGP
GSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPS
GESSTAPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESST
APGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSSPSASTGTGPGSS
TPSGATGSPGSSTPSGATGSP
AG864 73 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTP
SGATGSPGSSPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGAT
GSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGS
STPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSAS
TGTGPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSP
GASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASP
GTSSTGSPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGASPGTSST
GSPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPG
ASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSTPS
GATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASS
SPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGTP
GSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGT
ASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTGTGP
GASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPS
ASTGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGT
GPGASPGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSS
TPSGATGSPGASPGTSSTGSP
AM875 74 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTP
ESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSA
SPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTS
ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE
GSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPG
TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGS
PTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSA
PGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTST
EPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTST
EEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSS
TPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEPATSG
SETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGS
EPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPS
GTAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPG
SSPSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGS
PTSTEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESG
PGTSTEPSEGSAPGTSTEPSEGSAP
AE912 75 MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGSPGSP
AGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE
GSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPG
SPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGS
PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSA
PGTSESATPESGPGSEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSE
SATPESGPGTSESATPESGPGSPAGSPTSTEEGTSESATPESGPGSEPATSGS
ETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGT
STEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPS
EGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETP
GTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPAGSPTSTEEGSPAG
SPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSESATPES
GPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTS
TEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATP
ESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPG
TSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGS
PTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGTSESATPESG
PGTSTEPSEGSAP
AM923 76 MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGSPGTS
TEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESG
SASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGS
EPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESAT
PESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP
GTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTE
PSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST
EEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSAPGTS
TEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSE
GSAPGASASGAPSTGGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEG
STSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSGTASSSPGSSTPSG
ATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETP
GSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGSEPA
TSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGT
APGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSS
PSASTGTGPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPT
STEEGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPG
TSTEPSEGSAPGTSTEPSEGSAP
AM1318 77 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTP
ESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSA
SPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTS
ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE
GSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSTEPSEGSAPG
TSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGSEPATSGSETPGSPAGS
PTSTEEGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSPGTSTEPSEGSA
PGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEGTST
EPSEGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATPESGPGSPAGSPTST
EEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGSP
AGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGES
STAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPG
TSESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESA
TPESGPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTA
PGTSPSGESSTAPGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTST
EPSEGSAPGSSPSASTGTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGAT
GSPGSSTPSGATGSPGASPGTSSTGSPGASASGAPSTGGTSPSGESSTAPGS
TSSTAESPGPGTSPSGESSTAPGTSESATPESGPGTSTEPSEGSAPGTSTEPSE
GSAPGSSPSASTGTGPGSSTPSGATGSPGASPGTSSTGSPGTSTPESGSASPG
TSPSGESSTAPGTSPSGESSTAPGTSESATPESGPGSEPATSGSETPGTSTEPS
EGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSPAGSPTSTEE
GTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPA
TSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTSESPSGT
APGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGTP
GSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAP
BC 864 78 GTSTEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPA
TSGTEPSGSEPATSGTEPSGSEPATSGTEPSGSGASEPTSTEPGTSTEPSEPG
SAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTS
TEPSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSEPATSGTEPSGTSEPSTS
EPGAGSGASEPTSTEPGTSEPSTSEPGAGSEPATSGTEPSGSEPATSGTEPSG
TSTEPSEPGSAGTSTEPSEPGSAGSGASEPTSTEPGSEPATSGTEPSGSEPAT
SGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEP
SGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGTST
EPSEPGSAGSGASEPTSTEPGSEPATSGTEPSGSGASEPTSTEPGSEPATSGT
EPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGT
STEPSEPGSAGSEPATSGTEPSGTSTEPSEPGSAGSEPATSGTEPSGTSTEPS
EPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSAGTSTEPSEPGSA
GTSTEPSEPGSAGTSEPSTSEPGAGSGASEPTSTEPGTSTEPSEPGSAGTSTE
PSEPGSAGTSTEPSEPGSAGSEPATSGTEPSGSGASEPTSTEPGSEPATSGTE
PSGSEPATSGTEPSGSEPATSGTEPSGSEPATSGTEPSGTSEPSTSEPGAGSE
PATSGTEPSGSGASEPTSTEPGTSTEPSEPGSAGSEPATSGTEPSGSGASEPT
STEPGTSTEPSEPGSA
BD864 79 GSETATSGSETAGTSESATSESGAGSTAGSETSTEAGTSESATSESGAGSET
ATSGSETAGSETATSGSETAGTSTEASEGSASGTSTEASEGSASGTSESATS
ESGAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATSESGA
GTSESATSESGAGSETATSGSETAGTSESATSESGAGTSTEASEGSASGSET
ATSGSETAGSETATSGSETAGTSTEASEGSASGSTAGSETSTEAGTSESATS
ESGAGTSTEASEGSASGSETATSGSETAGSTAGSETSTEAGSTAGSETSTEA
GSETATSGSETAGTSESATSESGAGTSESATSESGAGSETATSGSETAGTSE
SATSESGAGTSESATSESGAGSETATSGSETAGSETATSGSETAGTSTEASE
GSASGSTAGSETSTEAGSETATSGSETAGTSESATSESGAGSTAGSETSTEA
GSTAGSETSTEAGSTAGSETSTEAGTSTEASEGSASGSTAGSETSTEAGSTA
GSETSTEAGTSTEASEGSASGSTAGSETSTEAGSETATSGSETAGTSTEASE
GSASGTSESATSESGAGSETATSGSETAGTSESATSESGAGTSESATSESGA
GSETATSGSETAGTSESATSESGAGSETATSGSETAGTSTEASEGSASGTST
EASEGSASGSTAGSETSTEAGSTAGSETSTEAGSETATSGSETAGTSESATS
ESGAGTSESATSESGAGSETATSGSETAGSETATSGSETAGSETATSGSETA
GTSTEASEGSASGTSESATSESGAGSETATSGSETAGSETATSGSETAGTSE
SATSESGAGTSESATSESGAGSETATSGSETA
4. XTEN Segments
In one embodiment, the invention provides an isolated GHXTEN fusion protein wherein the cumulative length of the XTEN component is greater than about 100 to about 3000 amino acid residues containing at least one polypeptide sequence segment selected from Tables 3, 8, 9, 10, 11, and 12 and wherein at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% or more of the remainder of the XTEN sequence by and large contains hydrophilic amino acids and less than about 2% of the remainder of the XTEN consists of hydrophobic or aromatic amino acids, or cysteine. In some embodiments, the XTEN contains multiple segments wherein the segments are identical or different. In another embodiment, the invention provides an isolated GHXTEN fusion protein wherein the cumulative length of the XTEN component is greater than about 100 to about 3000 amino acid residues and comprises at least one sequence segment of at least about 100 to about 923, or at least about 100 to about 875, or at least about 100 to about 576, or at least about 100 to about 288, or at least about 100 to about 144 amino acid residues wherein the sequence segment(s) consists of at least three different types of amino acids and the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues in the sequence segment(s) constitutes at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total amino acid sequence of the sequence segment and at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% of the remainder of the XTEN sequence(s) consist of hydrophilic amino acids and less than about 2% of the remainder of the XTEN sequence(s) consists of hydrophobic oraromatic amino acids, or cysteine. In another embodiment, the invention provides an isolated GHXTEN fusion protein wherein the cumulative length of the XTEN component is greater than about 100 to about 3000 amino acid residues and comprises at least one sequence segment of at least about 200 to about 923, or at least about 200 to about 875, or at least about 200 to about 576, or at least about 200 to about 288 amino acid residues wherein the sequence segment(s) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues in the sequence segment(s) constitutes at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total amino acid sequence of the sequence segment and wherein the subsequence score of the segment is less than 12, more preferably less than 10, more preferably less than 9, more preferably less than 8, more preferably less than 7, more preferably less than 6, and most preferably less than 5, and at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98% of the remainder of the XTEN sequence(s) consist of hydrophilic amino acids and less than about 2% of the remainder of the XTEN sequence(s) consists of hydrophobic, aromatic or cysteine amino acids.
5. N-Terminal XTEN Expression-Enhancing Sequences
In some embodiments, the invention provides a short-length XTEN sequence incorporated as the N-terminal portion of the GHXTEN fusion protein. The expression of the fusion protein is enhanced in a host cell transformed with a suitable expression vector comprising an optimized N-terminal leader polynucleotide sequence (that encodes the N-terminal XTEN) incorporated into the polynucleotide encoding the binding fusion protein. It has been discovered, as described in Examples 14-17, that a host cell transformed with such an expression vector comprising an optimized N-terminal leader sequence (NTS) in the binding fusion protein gene results in greatly-enhanced expression of the fusion protein compared to the expression of a corresponding fusion protein from a polynucleotide not comprising the NTS, and obviates the need for incorporation of a non-XTEN leader sequence used to enhance expression. In one embodiment, the invention provides GHXTEN fusion proteins comprising an NTS wherein the expression of the binding fusion protein from the encoding gene in a host cell is enhanced about 50%, or about 75%, or about 100%, or about 150%, or about 200%, or about 400% compared to expression of a GHXTEN fusion protein not comprising the N-terminal XTEN sequence (where the encoding gene lacks the NTS).
In one embodiment, the N-terminal XTEN polypeptide of the GHXTEN comprises a sequence that exhibits at least about 80%, more preferably at least about 90%, more preferably at least about 91%, more preferably at least about 92%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, more preferably at least 99%, or exhibits 100% sequence identity to the amino acid sequence of AE48 or AM48, the respective amino acid sequences of which are as follows:
AE48:
(SEQ ID NO: 80)
MAEPAGSPTSTEEGTPGSGTASSSPGSSTPSGATGSPGASPGTSSTGS
AM48:
(SEQ ID NO: 81)
MAEPAGSPTSTEEGASPGTSSTGSPGSSTPSGATGSPGSSTPSGATGS
In another embodiment, the short-length N-terminal XTEN is linked to an XTEN of longer length to form the N-terminal region of the GHXTEN fusion protein, wherein the polynucleotide sequence encoding the short-length N-terminal XTEN confers the property of enhanced expression in the host cell, and wherein the long length of the expressed XTEN contributes to the enhanced properties of the XTEN carrier in the fusion protein, as described above. In the foregoing, the short-length XTEN is linked to any of the XTEN disclosed herein (e.g., an XTEN of Table 3) and the resulting XTEN, in turn, is linked to the N-terminal of any of the GH disclosed herein (e.g., a GH of Table 1) as a component of the fusion protein. Alternatively, polynucleotides encoding the short-length XTEN (or its complement) is linked to polynucleotides encoding any of the XTEN (or its complement) disclosed herein and the resulting gene encoding the N-terminal XTEN, in turn, is linked to the 5′ end of polynucleotides encoding any of the GH (or to the 3′ end of its complement) disclosed herein. In some embodiments, the N-terminal XTEN polypeptide with long length exhibits at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least 99%, or exhibits 100% sequence identity to an amino acid sequence selected from the group consisting of the sequences AE624, AE912, and AM923.
In any of the foregoing N-terminal XTEN embodiments described above, the N-terminal XTEN can have from about one to about six additional amino acid residues, preferably selected from GESTPA, to accommodate the restriction endonuclease restriction sites that would be employed to join the nucleotides encoding the N-terminal XTEN to the gene encoding the targeting moiety of the fusion protein. The methods for the generation of the N-terminal sequences and incorporation into the fusion proteins of the invention are described more fully in the Examples.
6. Net Charge
In other embodiments, the XTEN polypeptides have an unstructured characteristic imparted by incorporation of amino acid residues with a net charge and/or reducing the proportion of hydrophobic amino acids in the XTEN sequence. The overall net charge and net charge density is controlled by modifying the content of charged amino acids in the XTEN sequences. In some embodiments, the net charge density of the XTEN of the compositions may be above +0.1 or below −0.1 charges/residue. In other embodiments, the net charge of a XTEN can be about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% or more.
Since most tissues and surfaces in a human or animal have a net negative charge, in some embodiments, the XTEN sequences are designed to have a net negative charge to minimize non-specific interactions between the XTEN containing compositions and various surfaces such as blood vessels, healthy tissues, or various receptors. Not to be bound by a particular theory, the XTEN can adopt open conformations due to electrostatic repulsion between individual amino acids of the XTEN polypeptide that individually carry a net negative charge and that are distributed across the sequence of the XTEN polypeptide. Such a distribution of net negative charge in the extended sequence lengths of XTEN can lead to an unstructured conformation that, in turn, can result in an effective increase in hydrodynamic radius. In preferred embodiments, the negative charge is conferred by incorporation of glutamic acid residues. Accordingly, in one embodiment the invention provides XTEN in which the XTEN sequences contain about 8, 10, 15, 20, 25, or even about 30% glutamic acid. Generally, the glutamic residues would be spaced uniformly across the XTEN sequence. In some cases, the XTEN can contain about 10-80, or about 15-60, or about 20-50 glutamic residues residues per 20 kD of XTEN that can result in an XTEN with charged residues that would have very similar pKa, which can increase the charge homogeneity of the product and sharpen its isoelectric point, enhancing the physicochemical properties of the resulting GHXTEN fusion protein for, example, simplifying purification procedures.
The XTEN of the compositions of the present invention generally have no or a low content of positively charged amino acids. In some embodimentsthe XTEN may have less than about 10% amino acid residues with a positive charge, or less than about 7%, or less than about 5%, or less than about 2%, or less than about 1% amino acid residues with a positive charge. However, the invention contemplates constructs where a limited number of amino acids with a positive charge, such as lysine, are incorporated into XTEN to permit conjugation between the epsilon amine of the lysine and a reactive group on a peptide, a linker bridge, or a reactive group on a drug or small molecule to be conjugated to the XTEN backbone. In one embodiment of the foregoing, the XTEN has between about 1 to about 100 lysine residues, or about 1 to about 70 lysine residues, or about 1 to about 50 lysine residues, or about 1 to about 30 lysine residues, or about 1 to about 20 lysine residues, or about 1 to about 10 lysine residues, or about 1 to about 5 lysine residues, or alternatively only a single lysine residue. Using the foregoing lysine-containing XTEN, fusion proteins are constructed that comprises XTEN, a growth hormone, plus a chemotherapeutic agent useful in the treatment of growth-related diseases or disorders, wherein the maximum number of molecules of the agent incorporated into the XTEN component is determined by the numbers of lysines or other amino acids with reactive side chains (e.g., cysteine) incorporated into the XTEN.
In some embodiments, the XTEN sequence comprises charged residues separated by other residues such as serine or glycine, which leads to better expression or purification behavior. Based on the net charge, some XTENs have an isoelectric point (pI) of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, or even 6.5. In preferred embodiments, the XTEN will have an isoelectric point between 1.5 and 4.5. In these embodiments, the XTEN incorporated into the GHXTEN fusion protein compositions of the present invention carry a net negative charge under physiologic conditions that contribute to the unstructured conformation and reduced binding of the XTEN component to mammalian proteins and tissues.
As hydrophobic amino acids impart structure to a polypeptide, the invention provides that the content of hydrophobic amino acids in the XTEN will typically be less than 5%, or less than 2%, or less than 1% hydrophobic amino acid content. In one embodiment, the amino acid content of methionine and tryptophan in the XTEN component of a GHXTEN fusion protein is typically less than 5%, or less than 2%, and most preferably less than 1%. In another embodiment, the XTEN will have a sequence that has less than 10% amino acid residues with a positive charge, or less than about 7%, or less that about 5%, or less than about 2% amino acid residues with a positive charge, the sum of methionine and tryptophan residues will be less than 2%, and the sum of asparagine and glutamine residues will be less than 10% of the total XTEN sequence.
7. Low Immunogenicity
In another aspect, the invention provides compositions in which the XTEN sequences have a low degree of immunogenicity or are substantially non-immunogenic. Several factors can contribute to the low immunogenicity of XTEN, e.g., the non-repetitive sequence, the unstructured conformation, the high degree of solubility, the low degree or lack of self-aggregation, the low degree or lack of proteolytic sites within the sequence, and the low degree or lack of epitopes in the XTEN sequence.
Conformational epitopes are formed by regions of the protein surface that are composed of multiple discontinuous amino acid sequences of the protein antigen. The precise folding of the protein brings these sequences into a well-defined, stable spatial configurations, or epitopes, that can be recognized as “foreign” by the host humoral immune system, resulting in the production of antibodies to the protein or the activation of a cell-mediated immune response. In the latter case, the immune response to a protein in an individual is heavily influenced by T-cell epitope recognition that is a function of the peptide binding specificity of that individual's HLA-DR allotype. Engagement of a MHC Class II peptide complex by a cognate T-cell receptor on the surface of the T-cell, together with the cross-binding of certain other co-receptors such as the CD4 molecule, can induce an activated state within the T-cell. Activation leads to the release of cytokines further activating other lymphocytes such as B cells to produce antibodies or activating T killer cells as a full cellular immune response.
The ability of a peptide to bind a given MHC Class II molecule for presentation on the surface of an APC (antigen presenting cell) is dependent on a number of factors; most notably its primary sequence. In one embodiment, a lower degree of immunogenicity is achieved by designing XTEN sequences that resist antigen processing in antigen presenting cells, and/or choosing sequences that do not bind MHC receptors well. The invention provides GHXTEN fusion proteins with substantially non-repetitive XTEN polypeptides designed to reduce binding with MHC II receptors, as well as avoiding formation of epitopes for T-cell receptor or antibody binding, resulting in a low degree of immunogenicity. Avoidance of immunogenicity is, in part, a direct result of the conformational flexibility of XTEN sequences; i.e., the lack of secondary structure due to the selection and order of amino acid residues. For example, of particular interest are sequences having a low tendency to adapt compactly folded conformations in aqueous solution or under physiologic conditions that could result in conformational epitopes. The administration of fusion proteins comprising XTEN, using conventional therapeutic practices and dosing, would generally not result in the formation of neutralizing antibodies to the XTEN sequence, and also reduce the immunogenicity of the GH fusion partner in the GHXTEN compositions.
In one embodiment, the XTEN sequences utilized in the subject fusion proteins can be substantially free of epitopes recognized by human T cells. The elimination of such epitopes for the purpose of generating less immunogenic proteins has been disclosed previously; see for example WO 98/52976, WO 02/079232, and WO 00/3317 which are incorporated by reference herein. Assays for human T cell epitopes have been described (Stickler, M., et al. (2003) J Immunol Methods, 281: 95-108). Of particular interest are peptide sequences that can be oligomerized without generating T cell epitopes or non-human sequences. This is achieved by testing direct repeats of these sequences for the presence of T-cell epitopes and for the occurrence of 6 to 15-mer and, in particular, 9-mer sequences that are not human, and then altering the design of the XTEN sequence to eliminate or disrupt the epitope sequence. In some embodiments, the XTEN sequences are substantially non-immunogenic by the restriction of the numbers of epitopes of the XTEN predicted to bind MHC receptors. With a reduction in the numbers of epitopes capable of binding to MHC receptors, there is a concomitant reduction in the potential for T cell activation as well as T cell helper function, reduced B cell activation or upregulation and reduced antibody production. The low degree of predicted T-cell epitopes can be determined by epitope prediction algorithms such as, e.g., TEPITOPE (Sturniolo, T., et al. (1999) Nat Biotechnol, 17: 555-61), as shown in Example 45. The TEPITOPE score of a given peptide frame within a protein is the log of the Kd (dissociation constant, affinity, off-rate) of the binding of that peptide frame to multiple of the most common human MHC alleles, as disclosed in Sturniolo, T. et al. (1999) Nature Biotechnology 17:555). The score ranges over at least 20 logs, from about 10 to about -10 (corresponding to binding constraints of 10e10Kd to 10e−10 Kd), and can be reduced by avoiding hydrophobic amino acids that serve as anchor residues during peptide display on MHC, such as M, I, L, V, F. In some embodiments, an XTEN component incorporated into a GHXTEN does not have a predicted T-cell epitope at a TEPITOPE score of about −5 or greater, or −6 or greater, or −7 or greater, or −8 or greater, or at a TEPITOPE score of −9 or greater. As used herein, a score of “−9 or greater” would encompass TEPITOPE scores of 10 to −9, inclusive, but would not encompass a score of −10, as −10 is less than −9.
In another embodiment, the inventive XTEN sequences, including those incorporated into the subject GHXTEN fusion proteins, are rendered substantially non-immunogenic by the restriction of known proteolytic sites from the sequence of the XTEN, reducing the processing of XTEN into small peptides that can bind to MHC II receptors. In another embodiment, the XTEN sequence is rendered substantially non-immunogenic by the use a sequence that is substantially devoid of secondary structure, conferring resistance to many proteases due to the high entropy of the structure. Accordingly, the reduced TEPITOPE score and elimination of known proteolytic sites from the XTEN render the XTEN compositions, including the XTEN of the GHXTEN fusion protein compositions, substantially unable to be bound by mammalian receptors, including those of the immune system. In one embodiment, an XTEN of a GHXTEN fusion protein can have >100 nM Kd binding to a mammalian receptor, or greater than 500 nM Kd, or greater than 1 μM Kd towards a mammalian cell surface or circulating polypeptide receptor.
Additionally, the non-repetitive sequence and corresponding lack of epitopes of XTEN limit the ability of B cells to bind to or be activated by XTEN. A repetitive sequence is recognized and can form multivalent contacts with even a few B cells and, as a consequence of the cross-linking of multiple T-cell independent receptors, can stimulate B cell proliferation and antibody production. In contrast, while a XTEN can make contacts with many different B cells over its extended sequence, each individual B cell may only make one or a small number of contacts with an individual XTEN due to the lack of repetitiveness of the sequence. Not being to be bound by any theory, XTENs typically have a much lower tendency to stimulate proliferation of B cells and thus an immune response. In one embodiment, the GHXTEN have reduced immunogenicity as compared to the corresponding GH that is not fused. In one embodiment, the administration of up to three parenteral doses of a GHXTEN to a mammal result in detectable anti-GHXTEN IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In another embodiment, the administration of up to three parenteral doses of a GHXTEN to a mammal result in detectable anti-GH IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In another embodiment, the administration of up to three parenteral doses of a GHXTEN to a mammal result in detectable anti-XTEN IgG at a serum dilution of 1:100 but not at a dilution of 1:1000. In the foregoing embodiments, the mammal can be a mouse, a rat, a rabbit, or a cynomolgus monkey.
An additional feature of XTENs with non-repetitive sequences relative to sequences with a high degree of repetitiveness is non-repetitive XTENs form weaker contacts with antibodies. Antibodies are multivalent molecules. For instance, IgGs have two identical binding sites and IgMs contain 10 identical binding sites. Thus antibodies against repetitive sequences can form multivalent contacts with such repetitive sequences with high avidity, which can affect the potency and/or elimination of such repetitive sequences. In contrast, antibodies against non-repetitive XTENs may yield monovalent interactions, resulting in less likelihood of immune clearance such that the GHXTEN compositions can remain in circulation for an increased period of time.
8. Increased Hydrodynamic Radius
In another aspect, the present invention provides XTEN in which the XTEN polypeptides have a high hydrodynamic radius that confers a corresponding increased Apparent Molecular Weight to the GHXTEN fusion protein incorporating the XTEN. As detailed in Example 37, the linking of XTEN to GH sequences results in GHXTEN compositions that can have increased hydrodynamic radii, increased Apparent Molecular Weight, and increased Apparent Molecular Weight Factor compared to a GH not linked to an XTEN. For example, in therapeutic applications in which prolonged half-life is desired, compositions in which a XTEN with a high hydrodynamic radius is incorporated into a fusion protein comprising one or more GH can effectively enlarge the hydrodynamic radius of the composition beyond the glomerular pore size of approximately 3-5 nm (corresponding to an apparent molecular weight of about 70 kDA) (Caliceti. 2003. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 55:1261-1277), resulting in reduced renal clearance of circulating proteins. The hydrodynamic radius of a protein is determined by its molecular weight as well as by its structure, including shape or compactness. Not to be bound by a particular theory, the XTEN can adopt open conformations due to electrostatic repulsion between individual charges of the peptide or the inherent flexibility imparted by the particular amino acids in the sequence that lack potential to confer secondary structure. The open, extended and unstructured conformation of the XTEN polypeptide can have a greater proportional hydrodynamic radius compared to polypeptides of a comparable sequence length and/or molecular weight that have secondary and/or tertiary structure, such as typical globular proteins. Methods for determining the hydrodynamic radius are well known in the art, such as by the use of size exclusion chromatography (SEC), as described in U.S. Pat. Nos. 6,406,632 and 7,294,513. As the results of Example 37 demonstrate, the addition of increasing lengths of XTEN results in proportional increases in the parameters of hydrodynamic radius, Apparent Molecular Weight, and Apparent Molecular Weight Factor, permitting the tailoring of GHXTEN to desired characteristic cut-off Apparent Molecular Weights or hydrodynamic radii. Accordingly, in certain embodiments, the GHXTEN fusion protein can be configured with an XTEN such that the fusion protein can have a hydrodynamic radius of at least about 5 nm, or at least about 8 nm, or at least about 10 nm, or 12 nm, or at least about 15 nm. In the foregoing embodiments, the large hydrodynamic radius conferred by the XTEN in an GHXTEN fusion protein can lead to reduced renal clearance of the resulting fusion protein, leading to a corresponding increase in terminal half-life, an increase in mean residence time, and/or a decrease in renal clearance rate.
In another embodiment, an XTEN of a chosen length and sequence can be selectively incorporated into a GHXTEN to create a fusion protein that have, under physiologic conditions, an Apparent Molecular Weight of at least about 150 kDa, or at least about 300 kDa, or at least about 400 kDa, or at least about 500 kDA, or at least about 600 kDa, or at least about 700 kDA, or at least about 800 kDa, or at least about 900 kDa, or at least about 1000 kDa, or at least about 1200 kDa, or at least about 1500 kDa, or at least about 1800 kDa, or at least about 2000 kDa, or at least about 2300 kDa or more. In another embodiment, an XTEN of a chosen length and sequence can be selectively linked to a GH to result in a GHXTEN fusion protein that has, under physiologic conditions, an Apparent Molecular Weight Factor of at least three, alternatively of at least four, alternatively of at least five, alternatively of at least six, alternatively of at least eight, alternatively of at least 10, alternatively of at least 15, or an Apparent Molecular Weight Factor of at least 20 or greater. In another embodiment, the GHXTEN fusion protein has, under physiologic conditions, an Apparent Molecular Weight Factor that is about 4 to about 20, or is about 6 to about 15, or is about 8 to about 12, or is about 9 to about 10 relative to the actual molecular weight of the fusion protein.
V). GHXTEN Structural Configurations and Properties The GH of the subject compositions are not limited to native, full-length polypeptides, but also include recombinant versions as well as biologically and/or pharmacologically active variants or fragments thereof. For example, it will be appreciated that various amino acid deletions, insertions and substitutions can be made in the GH to create variants without departing from the spirit of the invention with respect to the biological activity or pharmacologic properties of the GH. Examples of conservative substitutions for amino acids in polypeptide sequences are shown in Table 4. However, in embodiments of the GHXTEN in which the sequence identity of the GH is less than 100% compared to a specific sequence disclosed herein, the invention contemplates substitution of any of the other 19 natural L-amino acids for a given amino acid residue of the given GH, which may be at any position within the sequence of the GH, including adjacent amino acid residues. If any one substitution results in an undesirable change in biological activity, then one of the alternative amino acids can be employed and the construct evaluated by the methods described herein, or using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934, the contents of which is incorporated by reference in its entirety, or using methods generally known in the art. In addition, variants can include, for instance, polypeptides wherein one or more amino acid residues are added or deleted at the N- or C-terminus of the full-length native amino acid sequence of a GH that retains some if not all of the biological activity of the native peptide.
TABLE 4
Exemplary conservative amino acid substitutions
Original Residue Exemplary Substitutions
Ala (A) val; leu; ile
Arg (R) lys; gin; asn
Asn (N) gin; his; Iys; arg
Asp (D) glu
Cys (C) ser
Gln (Q) asn
Glu (E) asp
Gly (G) pro
His (H) asn: gin: Iys: arg
xIle (I) leu; val; met; ala; phe: norleucine
Leu (L) norleucine: ile: val; met; ala: phe
Lys (K) arg: gin: asn
Met (M) leu; phe; ile
Phe (F) leu: val: ile; ala
Pro (P) gly
Ser (S) thr
Thr (T) ser
Trp (W) tyr
Tyr (Y) trp: phe: thr: ser
Val (V) ile; leu; met; phe; ala; norleucine
(2) GHXTEN Fusion Protein Configurations
The invention provides GHXTEN fusion protein compositions with the GH and XTEN components linked in specific N- to C-terminus configurations. In some embodiments, one or more GHs are linked to one or more XTENs, either at the N-terminus or at the C-terminus, with or without a spacer, to form a block copolymer, and the sequential arrangement of the GHs and the XTENs in the GHXTEN fusion protein are the same as the configuration known in the block copolymer chemistry. When there is more than one GH, XTEN, or spacer, each of the GH, the XTEN, or the spacer have the same or different sequences, and the GHs and/or XTENs are linked either continously or alternately (regular or irregular). Thus, in all of the fomulae provided herein, when there is more than one GH, XTEN, or spacer, each of the GH, XTEN, and spacer are the same or different. In some embodiments, the GHXTEN is a monomeric fusion protein with a GH linked to one XTEN polypeptide. In other embodiments, the GHXTEN is a monomeric fusion protein with a GH linked to two or more XTEN polypeptides. In still other embodiments, the GHXTEN is a monomeric fusion protein with two or more GH linked to one XTEN polypeptide. In still other embodiments, the GHXTEN is a monomeric fusion protein with two or more GH linked to two or more XTEN polypeptide. Table 5 provides non-limiting examples of configurations that are encompassed by the GHXTEN fusion proteins of the invention; numerous other variations will be apparent to the ordinarily skilled artisan, including the incorporation the spacer and cleavage sequences disclosed herein or known in the art.
TABLE 5
GHXTEN configurations
Components* Configuration**
Single GH; Single XTEN GH-XTEN
XTEN-GH
Single GH; Multiple XTEN XTEN-GH-XTEN
GH-XTEN-XTEN
XTEN-XTEN-GH
XTEN-GH-XTEN-XTEN
XTEN-XTEN-GH-XTEN
XTEN-XTEN-GH-XTEN
Multiple GH, Single XTEN GH-XTEN-GH
XTEN-GH-GH
GH-GH-XTEN
GH-XTEN-GH-GH
Multiple GH; Multiple XTEN GH-XTEN-GH-XTEN
XTEN-GH-XTEN-GH
XTEN-XTEN-GH-XTEN-GH
XTEN-XTEN-GH-GH
GH-XTEN-XTEN-GH
GH-GH-XTEN-XTEN
GH-GH-XTEN-XTEN-GH
GH-XTEN-GH-XTEN-GH
*Characterized as single for 1 component or multiple for 2 or more of that component
**Reflects N- to C-terminus configuration of the growth factor and XTEN components
The invention contemplates GHXTEN fusion proteins compositions comprising, but not limited to single or multiple GH selected from Table 1 (or fragments or sequence variants thereof), single or multiple XTEN selected from Table 3 (or sequence variants thereof) that are in a configuration shown in Table 5. Generally, the resulting GHXTEN retains at least a portion of the biological activity of the corresponding GH not linked to the XTEN. In other embodiments, the GH component either becomes biologically active or has an increase in activity upon its release from the XTEN by cleavage of an optional cleavage sequence incorporated within spacer sequences into the GHXTEN, described more fully below.
In one embodiment of the GHXTEN composition, the invention provides a fusion protein of formula I:
(XTEN)x-GH-(XTEN)y I
wherein independently for each occurrence, GH is a is a growth hormone; x is either 0 or 1 and y is either 0 or 1 wherein x+y≥1; and XTEN is an extended recombinant polypeptide.
In another embodiment of the GHXTEN composition, the invention provides a fusion protein of formula II:
(XTEN)x(GH)-(S)y-(XTEN)y II
wherein independently for each occurrence, GH is a is a growth hormone a; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1 and y is either 0 or 1 wherein x+y≥1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula III:
(GH)-(S)x-(XTEN)-(S)y-(GH)-(S)z-(XTEN)z III
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula IV:
(XTEN)x-(S)y-(GH)-(S)z-(XTEN)-(GH) IV
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; z is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion growth hormone, wherein the fusion protein is of formula V:
(GH)x-(S)x-(GH)-(S)y-(XTEN) V
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VI:
(XTEN)-(S)x-(GH)-(S)y-(GH) VI
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VII:
(XTEN)-(S)x-(GH)-(S)y-(GH)-(XTEN) VII
wherein independently for each occurrence, GH is a is a growth hormone; S is a spacer sequence having between 1 to about 50 amino acid residues that can optionally include a cleavage sequence; x is either 0 or 1; y is either 0 or 1; and XTEN is an extended recombinant polypeptide.
In another embodiment, the invention provides an isolated fusion protein, wherein the fusion protein is of formula VIII:
((S)m-(GH)x-(S)n-(XTEN)y-(S)o)t VIII
wherein t is an integer that is greater than 0 (1, 2, 3, etc.); independently each of m, n, o, x, and y is an integer (0, 1, 2, 3, etc.), GH is a is a growth hormone; S is an spacer, optionally comprising a cleavage site; and XTEN is an extended recombinant polypeptide, with the proviso that: (1) x+y>1, (2) when t=1, x>0 and y>0, (3) when there is more than one GH, S, or XTEN, each GH, XTEN, or S are the same or are independently different; and (4) when t>1, each m, n, o, x, or y within each subunit are the same or are independently different.
In some embodiments, administration of a therapeutically effective amount of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof results in a gain in time of at least two-fold, or at least three-fold, or at least four-fold, or at least five-fold, or at least 10-fold, or at least 20-fold, or at least 40-fold, or at least 100-fold or more spent within a therapeutic window for the fusion protein compared to the corresponding GH not linked to the XTEN of and administered at a comparable amount administered to a subject. In other embodiments, administration of a therapeutically effective dose of a fusion protein of an embodiment of formulas I-VIII to a subject in need thereof can result in a gain in time between consecutive doses necessary to maintain a therapeutically effective dose regimen of at least 48 h, or at least 72 h, or at least about 96 h, or at least about 120 h, or at least about 7 days, or at least about 14 days, or at least about 21 days between consecutive doses compared to a GH not linked to XTEN and administered at a comparable dose.
Any spacer sequence group is optional in the fusion proteins encompassed by the invention. The spacer is provided to enhance expression of the fusion protein from a host cell or to decrease steric hindrance such that the GH component may assume its desired tertiary structure and/or interact appropriately with its target receptor. For spacers and methods of identifying desirable spacers, see, for example, George, et al. (2003) Protein Engineering 15:871-879, specifically incorporated by reference herein. In one embodiment, the spacer comprises one or more peptide sequences that are between 1-50 amino acid residues in length, or about 1-25 residues, or about 1-10 residues in length. Spacer sequences, exclusive of cleavage sites, can comprise any of the 20 natural L amino acids, and will preferably comprise hydrophilic amino acids that are sterically unhindered that can include, but not be limited to, glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P). In some cases, the spacer can be polyglycines or polyalanines, or is predominately a mixture of combinations of glycine and alanine residues. The spacer polypeptide exclusive of a cleavage sequence is largely to substantially devoid of secondary structure; e.g., less than about 10%, or less than about 5% as determined by the Chou-Fasman and/or GOR algorithms. In one embodiment, one or both spacer sequences in a GHXTEN fusion protein composition each further contains a cleavage sequence, which are identical or different, wherein the cleavage sequence may be acted on by a protease to release the GH from the fusion protein.
In some embodiments, the incorporation of the cleavage sequence into the GHXTEN is designed to permit release of a GH that becomes active or more active upon its release from the XTEN. The cleavage sequences are located sufficiently close to the GH sequences, generally within 18, or within 12, or within 6, or within 2 amino acids of the GH sequence terminus, such that any remaining residues attached to the GH after cleavage do not appreciably interfere with the activity (e.g., such as binding to a receptor) of the GH, yet provide sufficient access to the protease to be able to effect cleavage of the cleavage sequence. In some embodiments, the cleavage site is a sequence that can be cleaved by a protease endogenous to the mammalian subject such that the GHXTEN can be cleaved after administration to a subject. In such cases, the GHXTEN can serve as a prodrug or a circulating depot for the GH. Examples of cleavage sites contemplated by the invention include, but are not limited to, a polypeptide sequence cleavable by a mammalian endogenous protease selected from FXIa, FXIIa, kallikrein, FVIIa, FIXa, FXa, FIIa (thrombin), Elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, or by non-mammalian proteases such as TEV, enterokinase, PreScission™ protease (rhinovirus 3C protease), and sortase A. Sequences known to be cleaved by the foregoing proteases and others are known in the art. Exemplary cleavage sequences and cut sites within the sequences are presented in Table 6, as well as sequence variants thereof. For example, thrombin (activated clotting factor II) acts on the sequence LTPRSLLV (SEQ ID NO: 82) [Rawlings N. D., et al. (2008) Nucleic Acids Res., 36: D320], which would be cut after the arginine at position 4 in the sequence. Active FIIa is produced by cleavage of FIT by FXa in the presence of phospholipids and calcium and is down stream from factor IX in the coagulation pathway. Once activated its natural role in coagulation is to cleave fibrinogen, which then in turn, begins clot formation. FIIa activity is tightly controlled and only occurs when coagulation is necessary for proper hemostasis. However, as coagulation is an on-going process in mammals, by incorporation of the LTPRSLLV sequence (SEQ ID NO: 83) into the GHXTEN between the GH and the XTEN, the XTEN domain would be removed from the adjoining GH concurrent with activation of either the extrinsic or intrinsic coagulation pathways when coagulation is required physiologically, thereby releasing GH over time. Similarly, incorporation of other sequences into GHXTEN that are acted upon by endogenous proteases would provide for sustained release of GH that, in certain embodiments, provide a higher degree of activity for the GH from the “prodrug” form of the GHXTEN.
In some embodiments, only the two or three amino acids flanking both sides of the cut site (four to six amino acids total) are incorporated into the cleavage sequence. In other embodiments, the known cleavage sequence have one or more deletions or insertions or one or two or three amino acid substitutions for any one or two or three amino acids in the known sequence, wherein the deletions, insertions or substitutions result in reduced or enhanced susceptibility but not an absence of susceptibility to the protease, resulting in an ability to tailor the rate of release of the GH from the XTEN. Exemplary substitutions are shown in Table 6.
TABLE 6
Protease Cleavage Sequences
Exemplary SEQ SEQ
Protease Acting Cleavage ID ID
Upon Sequence Sequence NO: Minimal Cut Site* NO:
FXIa KLTR↓VVGG 84 KD/FL/T/R↓VA/VE/GT/GV
FXIIa TMTR↓IVGG 85 NA
Kallikrein SPFR↓STGG 86 -/-/FL/RY↓SR/RT/-/-
FVIIa LQVR↓IVGG 87 NA
FIXa PLGR,↓IVGG 88 -/-/G/R↓-/-/-/-
FXa IEGR↓TVGG 89 IA/E/GFP/R↓STI/VFS/-/G
FIIa (thrombin) LTPR↓SLLV 90 -/-/PLA/R↓SAG/-/-/-
Elastase-2 LGPV↓SGVP 91 -/-/-/VIAT↓-/-/-/-
Granzyme-B VAGD↓SLEE 92 V/-/-/D↓-/-/-/-
MMP-12 GPAG↓LGGA 93 G/PA/-/G↓L/-/G/- 94
MMP-13 GPAG↓LRGA 95 G/P/-/G↓L/-/GA/- 96
MMP-17 APLG↓LRLR 97 -/PS/-/-↓LQ/-/LT/-
MMP-20 PALP↓LVAQ 98 NA
TEV ENLYFQ↓G 99 ENLYFQ↓G/S 100
Enterokinase DDDK↓IVGG 101 DDDK↓IVGG 102
Protease 3C LEVLFQ↓GP 103 LEVLFQ↓GP 104
(PreScission ™)
Sortase A LPKT↓GSES 105 L/P/KEAD/T↓G/-/EKS/S 106
↓indicates cleavage site
NA: not applicable
*the listing of multiple amino acids before, between, or after a slash indicate alternative amino acids that can be substituted at the position; “-” indicates that any amino acid may be substituted for the corresponding amino acid indicated in the middle column
In one embodiment, a GH incorporated into a GHXTEN fusion protein have a sequence that exhibits at least about 80% sequence identity to a sequence from Table 1, alternatively at least about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 100% sequence identity as compared with a sequence from Table 1. The GH of the foregoing embodiment can be evaluated for activity using assays or measured or determined parameters as described herein, and those sequences that retain at least about 40%, or about 50%, or about 55%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95% or more activity compared to the corresponding native GH sequence would be considered suitable for inclusion in the subject GHXTEN. The GH found to retain a suitable level of activity can be linked to one or more XTEN polypeptides described hereinabove. In one embodiment, a GH found to retain a suitable level of activity can be linked to one or more XTEN polypeptides having at least about 80% sequence identity to a sequence from Table 3, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100% sequence identity as compared with a sequence of Table 3, resulting in a chimeric fusion protein.
Non-limiting examples of sequences of fusion proteins containing a single GH linked to a single XTEN are presented in Table 35. In one embodiment, a GHXTEN composition would comprise a fusion protein having at least about 80% sequence identity to a GHXTEN from Table 35, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100% sequence identity as compared with a GHXTEN from Table 35. Non-limiting examples of sequences of fusion proteins containing two molecules of XTEN linked to one or more GH are presented in Table 36, but the invention also contemplates substitution of other GH with sequences exhibiting at least about 90% sequence identity to a sequence selected from Table 1 linked to one or two XTEN, which may be the same or different, exhibiting at least about 90% sequence identity selected from Table 3. In the foregoing fusion proteins hereinabove described in this paragraph, the GHXTEN fusion protein can further comprise a cleavage sequence from Table 6; the cleavage sequence being located between the GH and the XTEN or between adjacent GH (if more than one GH is included in the GHXTEN). In some cases, the GHXTEN comprising the cleavage sequences will also have one or more spacer sequence amino acids between the GH and the cleavage sequence or the XTEN and the cleavage sequence to facilitate access of the protease; the spacer amino acids comprising any natural amino acid, including glycine and alanine as preferred amino acids. Non-limiting examples of GHXTEN comprising GH, XTEN, cleavage sequence(s) and spacer amino acids are presented in Table 37. However, the invention also contemplates substitution of any of the GH sequences of Table 1 for a GH sequence of Table 37, substitution of any XTEN sequence of Table 3 for an XTEN sequence of Table 37, and substitution of any cleavage sequence of Table 6 for a cleavage sequence of Table 37.
(3) Pharmacokinetic Properties of GHXTEN
The invention provides GHXTEN fusion proteins with enhanced pharmacokinetics compared to the GH not linked to XTEN that, when used at the dose determined for the composition by the methods described herein, can achieve a circulating concentration resulting in a pharmacologic effect, yet stay within the safety range for biologically active component of the composition for an extended period of time compared to a comparable dose of the GH not linked to XTEN. In such cases, the GHXTEN remains within the therapeutic window for the fusion protein composition for the extended period of time. As used herein, a “comparable dose” means a dose with an equivalent moles/kg for the active GH pharmacophore that is administered to a subject in a comparable fashion. It will be understood in the art that a “comparable dosage” of GHXTEN fusion protein would represent a greater weight of agent but would have essentially the same mole-equivalents of GH in the dose of the fusion protein and/or would have the same approximate molar concentration relative to the GH.
The pharmacokinetic properties of a GH that can be enhanced by linking a given XTEN to the GH include terminal half-life, area under the curve (AUC), Cmax volume of distribution, and bioavailability providing enhanced utility in the treatment of growth hormone-related disorders, diseases and related conditions. The GH of the GHXTEN compositions can be a sequence that exhibits at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a protein sequence selected from Table 1, linked to one or more XTEN that exhibit at least about 80% sequence identity, or alternatively 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a protein sequence selected from Table 3.
As described more fully in the Examples pertaining to pharmacokinetic characteristics of fusion proteins comprising XTEN, it was surprisingly discovered that increasing the length of the XTEN sequence confers a disproportionate increase in the terminal half-life of a fusion protein comprising the XTEN. Accordingly, the invention provides GHXTEN fusion proteins comprising XTEN wherein the XTEN is selected to provide a targeted half-life for the GHXTEN composition administered to a subject. In some embodiments, the invention provides monomeric fusion proteins comprising XTEN wherein the XTEN is selected to confer an increase in the terminal half-life for the GHXTEN administered to a subject, compared to the corresponding GH not linked to the fusion protein and administered at a comparable dose, of at least about two-fold longer, or at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about seven-fold, or at least about eight-fold, or at least about nine-fold, or at least about ten-fold, or at least about 15-fold, or at least a 20-fold, or at least a 40-fold, or at least a 80-fold, or at least a 100-fold or greater an increase in terminal half-life compared to the GH not linked to the fusion protein. Exogenously administered human growth hormone has been reported to have a terminal half-life in humans of less than 15 minutes (Hindmarch, P.C., et al., Clinical Endocrinology (2008) 30(4): 443-450), whereas various GHXTEN compositions disclosed herein that have been experimentally administered to various animals species, as described in the Examples, have resulted in terminal half-life values of several hours. Similarly, the GHXTEN fusion proteins can have an increase in AUC of at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about a 100%, or at least about 150%, or at least about 200%, or at least about 300%, or at least about 500%, or at least about 1000%, or at least about a 2000% increase in AUC compared to the corresponding GH not linked to the fusion protein and administered to a subject at a comparable dose. The pharmacokinetic parameters of a GHXTEN can be determined by standard methods involving dosing, the taking of blood samples at times intervals, and the assaying of the protein using ELISA, HPLC, radioassay, or other methods known in the art or as described herein, followed by standard calculations of the data to derive the half-life and other PK parameters.
The invention further provides GHXTEN comprising a first and a second GH molecule, optionally separated by a spacer sequence that may further comprise a cleavage sequence, or separated by a second XTEN sequence. In one embodiment, the GH has less activity when linked to the fusion protein compared to a corresponding GH not linked to the fusion protein. In such case, as illustrated in FIG. 38, the GHXTEN is designed such that upon administration to a subject, the GH component is gradually released by cleavage of the cleavage sequence(s), whereupon it regains activity or the ability to bind to its target receptor or ligand. Accordingly, the GHXTEN of the foregoing serves as a prodrug or a circulating depot, resulting in a longer terminal half-life compared to GH not linked to the fusion protein.
(4) Pharmacology and Pharmaceutical Properties of GHXTEN
The present invention provides GHXTEN compositions comprising GH covalently linked to XTEN that can have enhanced properties compared to GH not linked to XTEN, as well as methods to enhance the therapeutic and/or biologic activity or effect of the respective two GH components of the compositions. In addition, the invention provides GHXTEN compositions with enhanced properties compared to those art-known fusion proteins containing immunoglobulin polypeptide partners, polypeptides of shorter length and/or polypeptide partners with repetitive sequences. In addition, GHXTEN fusion proteins provide significant advantages over chemical conjugates, such as pegylated constructs, notably the fact that recombinant GHXTEN fusion proteins can be made in bacterial cell expression systems, which can reduce time and cost at both the research and development and manufacturing stages of a product, as well as result in a more homogeneous, defined product with less toxicity for both the product and metabolites of the GHXTEN compared to pegylated conjugates.
As therapeutic agents, the GHXTEN possesses a number of advantages over therapeutics not comprising XTEN including one or more of the following non-limiting exemplary enhance properties; increased solubility, increased thermal stability, reduced immunogenicity, increased apparent molecular weight, reduced renal clearance, reduced proteolysis, reduced metabolism, enhanced therapeutic efficiency, a lower effective therapeutic dose, increased bioavailability, increased time between dosages capable of maintain blood levels within the therapeutic window for the GH, a “tailored” rate of absorption, enhanced lyophilization stability, enhanced serum/plasma stability, increased terminal half-life, increased solubility in blood stream, decreased binding by neutralizing antibodies, decreased receptor-mediated clearance, reduced side effects, retention of receptor/ligand binding affinity or receptor/ligand activation, stability to degradation, stability to freeze-thaw, stability to proteases, stability to ubiquitination, ease of administration, compatibility with other pharmaceutical excipients or carriers, persistence in the subject, increased stability in storage (e.g., increased shelf-life), reduced toxicity in an organism or environment and the like. The net effect of the enhanced properties is that the GHXTEN results in enhanced therapeutic and/or biologic effect or improved patient compliance when administered to a subject with a growth hormone-related disease or disorder.
Specific assays and methods for measuring the physical and structural properties of expressed proteins are known in the art, including methods for determining properties such as protein aggregation, solubility, secondary and tertiary structure, melting properties, contamination and water content, etc. Such methods include analytical centrifugation, EPR, HPLC-ion exchange, HPLC-size exclusion, HPLC-reverse phase, light scattering, capillary electrophoresis, circular dichroism, differential scanning calorimetry, fluorescence, HPLC-ion exchange, HPLC-size exclusion, IR, NMR, Raman spectroscopy, refractometry, and UV/Visible spectroscopy. Additional methods are disclosed in Arnau et al, Prot Expr and Purif (2006) 48, 1-13. Application of these methods to the invention would be within the grasp of a person skilled in the art.
In a particular feature of the invention, XTEN as a fusion partner increases the solubility of the GH payload, particularly in the expression of GH, which is typically expressed as insoluble inclusion bodies in transformed host cells, such as E. coli (see, e.g., Singh, S. M., et al. (2005) J Biosci Bioeng, 99: 303; Patra, A. K., et al. (2000) Protein Expr Purif, 18: 182). Accordingly, where enhancement of the pharmaceutical or physicochemical properties of the GH is desirable, such as the degree of aqueous solubility or stability, the length and/or the motif family composition of the first and the second XTEN sequences of the first and the second fusion protein may each be selected to confer a different degree of solubility and/or stability on the respective fusion proteins such that the overall pharmaceutical properties of the GHXTEN composition are enhanced. The GHXTEN fusion proteins can be constructed and assayed, using methods described herein, to confirm the physicochemical properties and the XTEN adjusted, as needed, to result in the desired properties. In one embodiment, the XTEN sequence of the GHXTEN is selected such that the fusion protein has an aqueous solubility that is within at least about 25% greater compared to a GH not linked to the fusion protein, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300%, or at least about 400%, or at least about 500%, or at least about 1000% greater than the corresponding GH not linked to the fusion protein.
The invention provides methods to produce and recover expressed GHXTEN from a host cell with enhanced solubility and ease of recovery compared to GH not linked to XTEN. In some embodiments, the method includes the steps of transforming a prokaryotic host cell (e. g, E. coli) with a polynucleotide encoding a GHXTEN with one or more XTEN components of cumulative sequence length greater than about 800, or greater than about 900, or greater than about 1000, or greater than about 1100 amino acid residues, expressing the GHXTEN fusion protein in the host cell, lysing the host cell to recover cytoplasmic contents, and acidifying the host cell cytoplasmic contents wherein the GH can remain in soluble form while the majority of host cell proteins are precipitated to insoluble form. In one embodiment of the foregoing, the post-expression crude host cell lysates can be acidified to a pH of less than about 5.0, or to a pH of less than about 4.7, or to a pH of less than about 4.5, or to a pH of less than about 4.2 and greater than about 50%, or about 60%, or about 70%, or about 80% or more of the expressed GH can be recovered in soluble form. In a feature of the foregoing embodiment, enriched GHXTEN can be separated from precipitated from host cell protein contaminants by centrifugation of the acidified lysate, a reflection of the increased solubility imparted to the GH by fusion to the XTEN carrier. In the embodiments hereinabove described in this paragraph, the XTEN of the GHXTEN fusion proteins can have at least about 80% sequence identity, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, to about 100% sequence identity to one or more XTEN selected from Table 3 and the GH can have at least about 80% sequence identity, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or 100% sequence identity to a GH selected from Table 1 and the GHXTEN components can be in an N- to C-teriminus configuration selected from Table 5.
In one embodiment, the invention provides GHXTEN compositions and methods to produce the compositions that can maintain the GH component within a therapeutic window for a greater period of time compared to comparable dosages of the corresponding GH not linked to XTEN. It will be understood in the art that a “comparable dosage” of GHXTEN fusion protein would represent a greater weight of agent but would have the same approximate mole-equivalents of GH in the dose of the fusion protein and/or would have the same approximate molar concentration relative to the GH. The method to produce the compositions that can maintain the GH component within a therapeutic window includes the steps of selecting the XTEN appropriate for conjugation to a GH to provide the desired pharmacokinetic properties in view of a given dose and dose regiment, followed by assays to verify the pharmacokinetic properties, the activity of the GHXTEN fusion protein, and the safey of the administered composition. By the methods, GHXTEN can be produced that enables increased efficacy of the administered composition by maintaining the circulating concentrations of the GH within the therapeutic window for an enhanced period of time. As used herein, “therapeutic window” means that the amount of drug or biologic as a blood or plasma concentration range, which provides efficacy or a desired pharmacologic effect over time for the disease or condition without unacceptable toxicity, i.e. the range of the circulating blood concentrations between the minimal amount to achieve any positive therapeutic effect and the maximum amount which results in a response that is the response immediately before toxicity to the subject (at a higher dose or concentration). Additionally, therapeutic window generally encompasses an aspect of time; the maximum and minimum concentration that results in a desired pharmacologic effect over time that does not result in unacceptable toxicity or adverse events. A dosed composition that stays within the therapeutic window for the subject could also be said to be within the “safety range.”
The characteristics of GHXTEN compositions of the invention, including functional characteristics or biologic and pharmacologic activity and parameters that result, are determined by any suitable screening assay known in the art for measuring the desired characteristic. The invention provides methods to assay the GHXTEN fusion proteins of differing composition or configuration in order to provide GHXTEN with the desired degree of biologic and/or therapeutic activity, as well as safety profile. Specific in vivo and ex vivo biological assays are used to assess the activity of each configured GHXTEN and/or GH component to be incorporated into GHXTEN, including but not limited to the assays of the Examples, those assays of Table 34, as well as the following assays or other such assays known in the art for assaying the properties and effects of GH. Assays can be conducted that allow determination of binding characteristics of the GHXTEN for GH receptors or a ligand, including binding constant (Kd), EC50 values, as well as their half-life of dissociation of the ligand-receptor complex (T1/2). Binding affinity can be measured, for example, by a competition-type binding assay that detects changes in the ability to specifically bind to a receptor or ligand (see, e.g., Examples). Additionally, techniques such as flow cytometry or surface plasmon resonance can be used to detect binding events. The assays may comprise soluble receptor molecules, or may determine the binding to cell-expressed receptors. Such assays may include cell-based assays, including assays for proliferation, cell death, apoptosis and cell migration. Other possible assays may determine receptor binding of expressed polypeptides, wherein the assay may comprise soluble receptor molecules, or may determine the binding to cell-expressed receptors. The binding affinity of a GHXTEN for the target receptors or ligands of the corresponding GH can be assayed using binding or competitive binding assays, such as Biacore assays with chip-bound receptors or binding proteins or ELISA assays, as described in U.S. Pat. No. 5,534,617, assays described in the Examples herein, radio-receptor assays, or other assays known in the art. In addition, GH sequence variants (assayed as single components or as GHXTEN fusion proteins) can be compared to the native GH using a competitive ELISA binding assay to determine whether they have the same binding specificity and affinity as the native GH, or some fraction thereof such that they are suitable for inclusion in GHXTEN. Functional assays can include the increase of IGF-1 secretion and/or generation within target cells as a result of exposure to GHXTEN, and/or the resulting stimulatory effects of IGF-1 on osteoblast and chondrocyte activity to promote bone growth; all are suitable paramaters to assess the activity of GH for inclusion in the GHXTEN fusion protein or the resulting GHXTEN. In addition, human growth hormone (hGH) is known to play a role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids, as well as the the stimulation of the production of blood cells in vitro (Derfalvi et al., 1998; Merchav et al; 1988), to increase numbers of erythrocytes and hemoglobin content in blood (Valerio et al., 1997; Vihervuori et al., 1996), as wells as the enhancement of proliferation of and Ig production in plasma cell lines (Kimata and Yoshida, 1994), the stimulation of CD8+ cell counts and, to a lesser extent CD4+ cell counts (Geffner, 1997). Parameters that can be measured chronically include velocity of growth, physical maturation, and comparative bone rate of growth. All of the foregoing can be used to assess the activity of GH components to be incorporated into GHXTEN and the resulting GHXTEN.
Dose optimization is important for all drugs, especially for those with a narrow therapeutic window. For example, a standardized single dose of GH for all patients presenting with a diverse symptoms or anbnormal clinical parameters may not always be effective. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically or pharmacologically effective amount of the GHXTEN, versus that amount that would result in unacceptable toxicity and place it outside of the safety range, or insufficient potency such that clinical improvement is not achieved.
In many cases, the therapeutic window for GH in subjects of different ages or degree of disease have been established and are available in published literature or are stated on the drug label for approved products containing the GH. In other cases, the therapeutic window can be established for new compositions, including those GHXTEN of the disclosure. The methods for establishing the therapeutic window for a given composition are known to those of skill in the art (see, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, McGraw-Hill (2005)). For example, by using dose-escalation studies in subjects with the target disease or disorder to determine efficacy or a desirable pharmacologic effect, appearance of adverse events, and determination of circulating blood levels, the therapeutic window for a given subject or population of subjects can be determined for a given drug or biologic, or combinations of biologics or drugs. The dose escalation studies can evaluate the activity of a GHXTEN through metabolic studies in a subject or group of subjects that monitor physiological or biochemical parameters, as known in the art or as described herein for one or more parameters associated with the metabolic disease or disorder, or clinical parameters associated with a beneficial outcome for the particular indication, together with observations and/or measured parameters to determine the no effect dose, adverse events, maximum tolerated dose and the like, together with measurement of pharmacokinetic parameters that establish the determined or derived circulating blood levels. The results can then be correlated with the dose administered and the blood concentrations of the therapeutic that are coincident with the foregoing determined parameters or effect levels. By these methods, a range of doses and blood concentrations can be correlated to the minimum effective dose as well as the maximum dose and blood concentration at which a desired effect occurs and above which toxicity occurs, thereby establishing the therapeutic window for the dosed therapeutic. Blood concentrations of the fusion protein (or as measured by the GH component) above the maximum would be considered outside the therapeutic window or safety range. Thus, by the foregoing methods, a Cmin blood level would be established, below which the GHXTEN fusion protein would not have the desired pharmacologic effect, and a Cmax blood level would be established that would represent the highest circulating concentration before reaching a concentration that would elicit unacceptable side effects, toxicity or adverse events, placing it outside the safety range for the GHXTEN. With such concentrations established, the frequency of dosing and the dosage can be further refined by measurement of the Cmax and Cmin to provide the appropriate dose and dose frequency to keep the fusion protein(s) within the therapeutic window. One of skill in the art can, by the means disclosed herein or by other methods known in the art, confirm that the administered GHXTEN remains in the therapeutic window for the desired interval or requires adjustment in dose or length or sequence of XTEN. Further, the determination of the appropriate dose and dose frequency to keep the GHXTEN within the therapeutic window establishes the therapeutically effective dose regimen; the schedule for administration of multiple consecutive doses using a therapeutically effective dose of the fusion protein to a subject in need thereof resulting in consecutive Cmax peaks and/or Cmin troughs that remain within the therapeutic window and results in an improvement in at least one measured parameter relevant for the target disease, disorder or condition. In some cases, the GHXTEN administered at an appropriate dose to a subject results in blood concentrations of the GHXTEN fusion protein that remains within the therapeutic window for a period at least about two-fold longer compared to the corresponding GH not linked to XTEN and administered at a comparable dose; alternatively at least about three-fold longer; alternatively at least about four-fold longer; alternatively at least about five-fold longer; alternatively at least about six-fold longer; alternatively at least about seven-fold longer; alternatively at least about eight-fold longer; alternatively at least about nine-fold longer or at least about ten-fold longer or greater compared to the corresponding GH not linked to XTEN and administered at a comparable dose. As used herein, an “appropriate dose” means a dose of a drug or biologic that, when administered to a subject, would result in a desirable therapeutic or pharmacologic effect and a blood concentration within the therapeutic window.
In one embodiment, the GHXTEN administered at a therapeutically effective dose regimen results in a gain in time of at least about three-fold longer; alternatively at least about four-fold longer; alternatively at least about five-fold longer; alternatively at least about six-fold longer; alternatively at least about seven-fold longer; alternatively at least about eight-fold longer; alternatively at least about nine-fold longer or at least about ten-fold longer between at least two consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding biologically active protein of the fusion protein not linked to the fusion protein and administered at a comparable dose regimen to a subject. In another embodiment, the GHXTEN administered at a therapeutically effective dose regimen results in a comparable improvement in one, or two, or three or more measured parameter using less frequent dosing or a lower total dosage in moles of the fusion protein of the pharmaceutical composition compared to the corresponding biologically active protein component(s) not linked to the fusion protein and administered to a subject using a therapeutically effective dose regimen for the GH. The measured parameters include any of the clinical, biochemical, or physiological parameters disclosed herein, or others known in the art for assessing subjects with growth hormone-related disorders.
The invention provides isolated GHXTEN in which the binding affinity for GH target receptors or ligands by the GHXTEN can be at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99%, or at least about 100% or more of the affinity of a native GH not bound to XTEN for the target receptor or ligand. In some cases, the binding affinity Kd between the subject GHXTEN and a native receptor or ligand of the GHXTEN is at least about 10−4M, alternatively at least about 10−5M, alternatively at least about 10−6M, or at least about 10−7M, or at least about 10−8M, or at least about 10−9M of the affinity between the GHXTEN and a native receptor or ligand.
In other embodiments, the invention provides isolated GHXTEN fusion proteins specifically designed to have reduced binding affinity to the GH receptor. In one embodiments, such as fusion proteins comprising an XTEN fused to the C-terimnus of the GH 1 about 97% sequence identity, or at least about 99% sequence identity to GH fusion proteins selected from AE912-hGH-AE144, AE912-hGH-AF144, AE912-hGH-AE288, AM923-hGH-AE144, AM923-hGH-AF144, AM923-hGH-AE288, and the sequences of Tables 36-37.
In some embodiments, the GHXTEN fusion proteins of the invention retain at least about 0.05%, or about 0.1%, or about 1%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 98%, or or about 99% percent of the biological activity of the corresponding GH not linked to the fusion protein with regard to an in vitro biologic activity or pharmacologic effect known or associated with the use of the native GH in the treatment and prevention of growth hormone-related diseases, disortder and conditions. Non-limiting examples of activities or pharmacologic effects that can be assayed to assess the retained activity of the GHXTEN fusion proteins include signal transduction markers in cells with GH receptors, elicited IGF-1 concentrations, elicited IGFBP3 concentrations, changes in height velocity, lean body mass, total body fat, trunk fat, parameters associated with insulin resistance syndrome, measurement of division and multiplication rates of chondrocytes, changes in bone density, and bone growth (e.g. increase in epiphyseal plate width). In some embodiments, the activity of the GH component is manifest by the intact GHXTEN fusion protein, while in other cases the activity of the GH component would be primarily manifested upon cleavage and release of the GH from the fusion protein by action of a protease that acts on a cleavage sequence incorporated into the GHXTEN fusion protein. In the foregoing, the GHXTEN is designed to reduce the binding affinity of the GH component for the receptor or ligand when linked to the XTEN but have restored or increased affinity when released from XTEN through the cleavage of cleavage sequence(s) incorporated into the GHXTEN sequence, as described more fully above.
In other cases, the GHXTEN can be designed to reduce the binding affinity of the GH component to the GH receptor to increase the terminal half-life of GHXTEN administered to a subject by reducing receptor-mediated clearance; e.g., by adding an XTEN to the C-terminus of the GH component of the fusion protein. In other cases, the GHXTEN are designed to reduce the binding affinity of the GH component to the GH receptor to reduce toxicity or side effects due to the administered composition.
Accordingly, the invention provides a method for increasing the terminal half-life of a GHXTEN by producing a single-chain fusion protein construct with a specific N- to C-terminus configuration of the components comprising at least a first GH and a first and a second XTEN, wherein the fusion protein in a first N- to C-terminus configuration of the GH and XTEN components has reduced receptor-mediated clearance (RMC) and a corresponding increase in terminal half-life compared to a GHXTEN in a second N- to C-terminus configuration. In one embodiment of the foregoing, the GHXTEN is configured, N- to C-terminus as XTEN-GH-XTEN, which has reduced receptor binding compared to a GHXTEN configures, N- to C-terminus XTEN-GH. In another embodiment of the foregoing, the GHXTEN is configured GH-XTEN. In the foregoing embodiments, the two XTEN molecules can be identical or they can be of a different sequence composition or length. Non-limiting examples of the foregoing embodiment with two XTEN linked to a single GH include the constructs AE912-hGH-AE144, AE912-hGH-AE288, AE864-hGH-AE144, AM923-hGH-AE144, and AM923-hGH-AE288. The invention contemplates other such constructs in which a GH from Table 1 and XTEN from Table 3 are substituted for the respective components of the foregoing examples, and are produced, for example, in a configuration from Table 5 such that the construct has reduced receptor mediated clearance compared to an alterntive configuration of the respective components. In some embodiments, the foregoing method for increasing the terminal half-life provides configured GHXTEN that can result in an increase in the terminal half-life of at least about 30%, or about 50%, or about 75%, or about 100%, or about 150%, or about 200%, or about 300%, or about 400% or more compared to the half-life of a GHXTEN in a second configuration where receptor binding is not reduced. The invention takes advantage of the fact that certain ligands wherein reduced binding affinity to a receptor, either as a result of a decreased on-rate or an increased off-rate, may be effected by the obstruction of either the N- or C-terminus (as shown in FIG. 3), and using that terminus as the linkage to another polypeptide of the composition, whether another molecule of a GH, an XTEN, or a spacer sequence results in the reduced binding affinity. The choice of the particular configuration of the GHXTEN fusion protein reduces the degree of binding affinity to the receptor such that a reduced rate of receptor-mediated clearance is achieved. Generally, activation of the receptor is coupled to RMC such that binding of a polypeptide to its receptor without activation does not lead to RMC, while activation of the receptor leads to RMC. However, in some cases, particularly where the ligand has an increased off rate, the ligand may nevertheless be able to bind sufficiently to initiate cell signaling without triggering receptor mediated clearance, with the net result that the GHXTEN remains bioavailable. In such cases, the configured GHXTEN has an increased half-life compared to those configurations that lead to a higher degree of RMC.
In cases where a reduction in binding affinity to the growth hormone receptor is desired in order to reduce receptor-mediated clearance but retention of at least a portion of the biological activity is also desired, sufficient binding affinity to obtain the desired receptor activation must nevertheless be maintained e.g., by initiation of signal transduction. Thus, in one embodiment, the invention provides a GHXTEN configured such that the binding affinity of the GHXTEN for a target receptor is in the range of about 0.01%-40%, or about 0.01%-30%, or about 0.01%-20% of the binding affinity compared to a corresponding GHXTEN in a configuration wherein the binding affinity is not reduced. The binding affinity of the configured BXTEN is thus preferably reduced by at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99%, or at least about 99.99% as compared to the binding affinity of a corresponding GHXTEN in a configuration wherein the binding affinity of the GH component to the target receptor is not reduced or compared to the GH not linked to the fusion protein, determined under comparable conditions. Expressed differently, the GH component of the configured GHXTEN has a binding affinity that is as small as about 0.01%, or at least about 0.1%, or at least about 1%, or at least about 2%, or at least about 3%, or at least about 4%, or at least about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least 40% of that of the corresponding GH component of a GHXTEN in a configuration wherein the binding affinity of the GH component is not reduced. In the foregoing embodiments, the binding affinity of the configured GHXTEN for the target receptor are “substantially reduced” compared to a corresponding native GH or a GHXTEN with a configuration in which the binding affinity of the corresponding GH component is not reduced. Accordingly, the present invention provides compositions and methods to produce compositions with reduced RMC by configuring the GHXTEN, examples of which areprovided above, so as to be able to bind and activate a sufficient number of receptors to obtain a desired in vivo biological response yet avoid activation of more receptors than is required for obtaining such response. The increased half-life permits higher dosages and reduced frequency of dosing compared to GH not linked to XTEN or compared to GHXTEN configurations wherein the GH component retains sufficient biological or pharmacological activity to result in a composition with clinical efficacy maintained despite reduced dosing frequency.
VI). Uses of the Compositions of the Present Invention In another aspect, the invention provides a method for achieving a beneficial effect in a disease, disorder or condition mediated by GH. The present invention addresses disadvantages and/or limitations of GH that have a relatively short terminal half-life and/or a narrow therapeutic window.
Most processes involved in growth of the body are regulated by multiple peptides and hormones, and such peptides and hormones, as well as analogues thereof, have found utility in the treatment of growth hormone-related diseases, disorders and conditions. However, the use of commercially-avaiable growth hormones, has met with less than optimal success in the management of subjects afflicted with such diseases, disorders and conditions. In particular, dose optimization and frequency of dosing is important for peptide and hormone biologics used in the treatment of growth hormone-related diseases and disorders. The fact that growth hormone has a short half-life, necessitates frequent dosing in order to achieve clinical benefit, which results in difficulties in the management of such patients.
In one embodiment, the invention provides a method for achieving a beneficial affect in a subject with a growth hormone-related disease, disorder or condition comprising the step of administering to the subject a therapeutically- or prophylactically-effective amount of a GHXTEN wherein said administration results in the improvement of one or more biochemical or physiological parameters or clinical endpoints associated with a growth hormone-related disease, disorder or condition. The effective amount produces a beneficial effect in helping to treat (e.g., cure or reduce the severity) or prevent (e.g., reduce the likelihood of onset or severity) a growth hormone-related disease, disorder or condition. In some cases, the method for achieving a beneficial effect includes administering a therapeutically effective amount of a GHXTEN fusion protein composition to treat a subject with a growth hormone-related disease, disorder, or condition, including, but not limited to, congenital or acquired GH deficiency in adults and children, Turner's Syndrome, Prader-Willi Syndrome, chronic renal failure, intrauterine growth retardation, idiopathic short stature, AIDS wasting, obesity, multiple sclerosis, aging, fibromyalgia, Crohn's disease, ulcerative colitis, muscular dystrophy, low muscle mass (e.g. bodybuilding), low bone density, or any other indication for which GH can be utilized (but for which endogenous growth hormone levels in a subject are not necessarily deficient).
In another embodiment, the invention provides a method of stimulating IGF-1 production in individuals with GH deficiency. The method comprises the step of administering therapeutically effective amount of GHXTEN to a subject that results in the increased blood levels and/or duration in increased blood levels of IGF-1 compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose. In some cases, the increase in IGF-1 is at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300%. In another embodiment, the invention provides a method of stimulating the division and numbers of chrondrocytes. The method comprises the step of administering therapeutically effective amount of GHXTEN that results in the increased production of chrondrocytes by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300% compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose. In another embodiment, the invention provides a method comprising the step of administering therapeutically effective amount of GHXTEN that results in increased bone growth as measured by increase in epiphyseal plate width by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 75%, or at least about 100%, or at least about 200%, or at least about 300% compared to a subject receiving a GH not linked to an XTEN and administered at a comparable dose.
As a result of the enhanced PK parameters of GHXTEN, as described herein, the GH is administered using longer intervals between doses compared to the corresponding GH not linked to XTEN to prevent, treat, alleviate, reverse or ameliorate symptoms or clinical abnormalities of the growth hormone-related disease, disorder or condition or prolong the survival of the subject being treated.
The methods of the invention includes administration of consecutive doses of a therapeutically effective amount of the GHXTEN for a period of time sufficient to achieve and/or maintain the desired parameter or clinical effect, and such consecutive doses of a therapeutically effective amount establishes the therapeutically effective dose regimen for the GHXTEN; i.e., the schedule for consecutively administered doses of the fusion protein composition, wherein the doses are given in therapeutically effective amounts to result in a sustained beneficial effect on any clinical sign or symptom, aspect, measured parameter or characteristic of a metabolic disease state or condition, including, but not limited to, those described herein. In one embodiment, the method comprises administering a therapeutically-effective amount of a pharmaceutical composition comprising a GHXTEN fusion protein composition comprising a GH linked to an XTEN sequence(s) and at least one pharmaceutically acceptable carrier to a subject in need thereof that results in greater improvement in at least one parameter, physiologic condition, or clinical outcome mediated by the GH component(s) (non-limiting examples of which are described above) compared to the effect mediated by administration of a pharmaceutical composition comprising a GH not linked to XTEN and administered at a comparable dose. In one embodiment, the pharmaceutical composition is administered at a therapeutically effective dose. In another embodiment, the pharmaceutical composition is administered using multiple consecutive doses using a therapeutically effective dose regimen (as defined herein) for the length of the dosing period.
A therapeutically effective amount of the GHXTEN varies according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the GHXTEN are outweighed by the therapeutically beneficial effects. A prophylactically effective amount refers to an amount of GHXTEN required for the period of time necessary to achieve the desired prophylactic result.
For the inventive methods, longer acting GHXTEN compositions are preferred, so as to improve patient convenience, to increase the interval between doses and to reduce the amount of drug required to achieve a sustained effect. In one embodiment, a method of treatment comprises administration of a therapeutically effective dose of a GHXTEN to a subject in need thereof that results in a gain in time spent within a therapeutic window established for the fusion protein of the composition compared to the corresponding GH component(s) not linked to the fusion protein and administered at a comparable dose to a subject. In some cases, the gain in time spent within the therapeutic window is at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold, or at least about 80-fold, or at least about 100-fold longer, compared to the corresponding GH component not linked to the fusion protein and administered at a comparable dose to a subject. The methods further provide that administration of multiple consecutive doses of a GHXTEN administered using a therapeutically effective dose regimen to a subject in need thereof results in a gain in time between consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding GH not linked to the fusion protein and administered using a dose regimen established for that GH. In the foregoing embodiment, the gain in time spent between consecutive Cmax peaks and/or Cmin troughs is at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold, or at least about eight-fold, or at least about 10-fold, or at least about 20-fold, or at least about 40-fold or at least about 80-fold, or at least about 100-fold longer, compared to the corresponding GH component not linked to the fusion protein and administered using a dose regimen established for that GH. In the embodiments hereinabove described in this paragraph the administration of the fusion protein results in an improvement in at least one of the parameters (disclosed herein as being useful for assessing the subject diseases, conditions or disorders) using a lower unit dose in moles of fusion protein compared to the corresponding GH component not linked to the fusion protein and administered at a comparable unit dose or dose regimen to a subject.
The method of treatment comprises administration of a GHXTEN using a therapeutically effective dose regimen to effect improvements in one or more parameters associated with growth hormone diseases, disorders or conditions. In some embodiments, administration of the GHXTEN to a subject results in an improvement in one or more of the biochemical, physiologic, or clinical parameters that is of greater magnitude than that of the corresponding GH component not linked to XTEN, determined using the same assay or based on a measured clinical parameter. In other embodiments, administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in activity in one or more of the biochemical, physiologic, or clinical parameters that is of longer duration than the activity of one of the single GH components not linked to XTEN, determined using that same assay or based on a measured clinical parameter. In one embodiment of the foregoing, the administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in an improvement in peak concentrations and area under the curve of blood IGF-1 levels of at least about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 100% or more in the subject compared to a comparable dose of GH not linked to XTEN administered to a subject. In another embodiment of the foregoing, the administration of the GHXTEN to a subject using a therapeutically effective dose regimen results in increased weight gain in the subject of at least about 10%, or about 20%, or about 30%, or about 40%, or about 50% or more compared to a comparable dose regimen of GH not linked to XTEN administered to a subject.
The invention further contemplates that GHXTEN used in accordance with the methods provided herein is administered in conjunction with other treatment methods and pharmaceutical compositions useful for treating growth hormone-related diseases, disorders, and conditions, or conditions for which growth hormone is adjunctive therapy; e.g., insulin resistance and poor glycemic control. Such compositions, include for example, DPP-IV inhibitors, insulin, insulin analogues, PPAR gamma agonists, dual-acting PPAR agonists, GLP-1 agonists or analogues, PTP1B inhibitors, SGLT inhibitors, insulin secretagogues, RXR agonists, glycogen synthase kinase-3 inhibitors, insulin sensitizers, immune modulators, beta-3 adrenergic receptor agonists, Pan-PPAR agonists, 11beta-HSD1 inhibitors, biguanides, alpha-glucosidase inhibitors, meglitinides, thiazolidinediones, sulfonylureas and other diabetes medicants known in the art, or anti-hypertensive drugs, calcium channel blockers, and related products. In some embodiments, the administration of a GHXTEN permits use of lower dosages of the co-administered pharmaceutical composition to achieve a comparable clinical effect or measured parameter for the disease, disorder or condition in the subject.
In another aspect, the invention provides a method of designing the GHXTEN compositions with desired pharmacologic or pharmaceutical properties. The GHXTEN fusion proteins are designed and prepared with various objectives in mind (compared to the GH components not linked to the fusion protein), including improving the therapeutic efficacy for the treatment of growth hormone-related diseases, disorders, and conditions, enhancing the pharmacokinetic characteristics of the fusion proteins compared to the GH, lowering the dose or frequency of dosing required to achieve a pharmacologic effect, enhancing the pharmaceutical properties, and to enhance the ability of the GH components to remain within the therapeutic window for an extended period of time.
In general, the steps in the design and production of the fusion proteins and the inventive compositions, as illustrated in FIGS. 4-6, include: (1) the selection of GHs (e.g., native proteins, analogs or derivatives with activity) to treat the particular disease, disorder or condition; (2) selecting the XTEN that will confer the desired PK and physicochemical characteristics on the resulting GHXTEN (e.g., the administration of the composition to a subject results in the fusion protein being maintained within the therapeutic window for a greater period compared to GH not linked to XTEN); (3) establishing a desired N- to C-terminus configuration of the GHXTEN to achieve the desired efficacy or PK parameters; (4) establishing the design of the expression vector encoding the configured GHXTEN; (5) transforming a suitable host with the expression vector; and (6) expression and recovery of the resultant fusion protein. For those GHXTEN for which an increase in half-life (greater than 24 h) or an increased period of time spent within a therapeutic window is desired, the XTEN chosen for incorporation generally has at least about 500, or about 576, or about 864, or about 875, or about 912, or about 923 amino acid residues where a single XTEN is to be incorporated into the GHXTEN. In another embodiment, the GHXTEN comprises a first XTEN of the foregoing lengths, and a second XTEN of about 144, or about 288, or about 576, or about 864, or about 875, or about 912, or about 923 amino acid residues.
In other embodiments, where an increase in half-life is not required, but an increase in a pharmaceutical property (e.g., solubility) is desired, a GHXTEN is designed to include XTEN of shorter lengths. In some embodiments of the foregoing, the GHXTEN comprises a GH linked to an XTEN having at least about 24, or about 36, or about 48, or about 60, or about 72, or about 84, or about 96 amino acid residues, in which the solubility of the fusion protein under physiologic conditions is at least three-fold greater than the corresponding GH not linked to XTEN, or alternatively, at least four-fold, or five-fold, or six-fold, or seven-fold, or eight-fold, or nine-fold, or at least 10-fold, or at least 20-fold, or at least 30-fold, or at least 50-fold, or at least 60-fold or greater than GH not linked to XTEN. In one embodiment of the foregoing, the GH is human growth hormone.
In another aspect, the invention provides methods of making GHXTEN compositions to improve ease of manufacture, result in increased stability, increased water solubility, and/or ease of formulation, as compared to the native GH. In one embodiment, the invention includes a method of increasing the water solubility of a GH comprising the step of linking the GH to one or more XTEN such that a higher concentration in soluble form of the resulting GHXTEN can be achieved, under physiologic conditions, compared to the GH in an un-fused state. Factors that contribute to the property of XTEN to confer increased water solubility of GHs when incorporated into a fusion protein include the high solubility of the XTEN fusion partner and the low degree of self-aggregation between molecules of XTEN in solution. In some embodiments, the method results in a GHXTEN fusion protein wherein the water solubility is at least about 20%, or at least about 30% greater, or at least about 50% greater, or at least about 75% greater, or at least about 90% greater, or at least about 100% greater, or at least about 150% greater, or at least about 200% greater, or at least about 400% greater, or at least about 600% greater, or at least about 800% greater, or at least about 1000% greater, or at least about 2000% greater, or at least about 4000% greater, or at least about 6000% greater under physiologic conditions, compared to the un-fused GH.
In another embodiment, the invention includes a method of increasing the shelf-life of a GH comprising the step of linking the GH with one or more XTEN selected such that the shelf-life of the resulting GHXTEN is extended compared to the GH in an un-fused state. As used herein, shelf-life refers to the period of time over which the functional activity of a GH or GHXTEN that is in solution or in some other storage formulation remains stable without undue loss of activity. As used herein, “functional activity” refers to a pharmacologic effect or biological activity, such as the ability to bind a receptor or ligand, or an enzymatic activity, or to display one or more known functional activities associated with a GH, as known in the art. A GH that degrades or aggregates generally has reduced functional activity or reduced bioavailability compared to one that remains in solution. Factors that contribute to the ability of the method to extend the shelf life of GHs when incorporated into a fusion protein include increased water solubility, reduced self-aggregation in solution, and increased heat stability of the XTEN fusion partner. In particular, the low tendency of XTEN to aggregate facilitates methods of formulating pharmaceutical preparations containing higher drug concentrations of GHs, and the heat-stability of XTEN contributes to the property of GHXTEN fusion proteins to remain soluble and functionally active for extended periods. In one embodiment, the method results in GHXTEN fusion proteins with “prolonged” or “extended” shelf-life that exhibit greater activity relative to a standard that has been subjected to the same storage and handling conditions. The standard may be the un-fused full-length GH. In one embodiment, the method includes the step of formulating the isolated GHXTEN with one or more pharmaceutically acceptable excipients that enhance the ability of the XTEN to retain its unstructured conformation and for the GHXTEN to remain soluble in the formulation for a time that is greater than that of the corresponding un-fused GH. In one embodiment, the method comprises linking a GH to one or more XTEN to create a GHXTEN fusion protein results in a solution that retains greater than about 100% of the functional activity, or greater than about 105%, 110%, 120%, 130%, 150% or 200% of the functional activity of a standard when compared at a given time point and when subjected to the same storage and handling conditions as the standard, thereby increasing its shelf-life.
Shelf-life may also be assessed in terms of functional activity remaining after storage, normalized to functional activity when storage began. GHXTEN fusion proteins of the invention with prolonged or extended shelf-life as exhibited by prolonged or extended functional activity retains about 50% more functional activity, or about 60%, 70%, 80%, or 90% more of the functional activity of the equivalent GH not linked to XTEN when subjected to the same conditions for the same period of time. For example, a GHXTEN fusion protein of the invention comprising human growth hormone fused to one or more XTEN sequences retains about 80% or more of its original activity in solution for periods of up to 2 weeks, or 4 weeks, or 6 weeks or longer under various temperature conditions. In some embodiments, the GHXTEN retains at least about 50%, or about 60%, or at least about 70%, or at least about 80%, and most preferably at least about 90% or more of its original activity in solution when heated at 80° C. for 10 min. In other embodiments, the GHXTEN retains at least about 50%, preferably at least about 60%, or at least about 70%, or at least about 80%, or alternatively at least about 90% or more of its original activity in solution when heated or maintained at 37° C. for about 7 days. In another embodiment, GHXTEN fusion protein retains at least about 80% or more of its functional activity after exposure to a temperature of about 30° C. to about 70° C. over a period of time of about one hour to about 18 hours. In the foregoing embodiments hereinabove described in this paragraph, the retained activity of the GHXTEN is at least about two-fold, or at least about three-fold, or at least about four-fold, or at least about five-fold, or at least about six-fold greater at a given time point than that of the corresponding GH not linked to the fusion protein.
VII). The Nucleic Acids Sequences of the Invention The present invention provides isolated polynucleic acids encoding GHXTEN chimeric fusion proteins and sequences complementary to polynucleic acid molecules encoding GHXTEN chimeric fusion proteins, including homologous variants thereof. In another aspect, the invention encompasses methods to produce polynucleic acids encoding GHXTEN chimeric fusion proteins and sequences complementary to polynucleic acid molecules encoding GHXTEN chimeric fusion protein, including homologous variants thereof. In general, and as illustrated in FIGS. 4-6, the methods of producing a polynucleotide sequence coding for a GHXTEN fusion protein and expressing the resulting gene product include assembling nucleotides encoding GH and XTEN, ligating the components in frame, incorporating the encoding gene into an expression vector appropriate for a host cell, transforming the appropriate host cell with the expression vector, and culturing the host cell under conditions causing or permitting the fusion protein to be expressed in the transformed host cell, thereby producing the biologically-active GHXTEN polypeptide, which is recovered as an isolated fusion protein by standard protein purification methods known in the art. Standard recombinant techniques in molecular biology is used to make the polynucleotides and expression vectors of the present invention.
In accordance with the invention, nucleic acid sequences that encode GHXTEN (or its complement) is used to generate recombinant DNA molecules that direct the expression of GHXTEN fusion proteins in appropriate host cells. Several cloning strategies are suitable for performing the present invention, many of which is used to generate a construct that comprises a gene coding for a fusion protein of the GHXTEN composition of the present invention, or its complement. In some embodiments, the cloning strategy is used to create a gene that encodes a monomeric GHXTEN that comprises at least a first GH and at least a first XTEN polypeptide, or their complement. In one embodiment of the foregoing, the gene comprises a sequence encoding a hGH or sequence variant. In other embodiments, the cloning strategy is used to create a gene that encodes a monomeric GHXTEN that comprises nucleotides encoding at least a first molecule of GH or its complement and a first and at least a second XTEN or their complement that is used to transform a host cell for expression of the fusion protein of the GHXTEN composition. In the foregoing embodiments hereinabove described in this paragraph, the genes can further comprise nucleotides encoding spacer sequences that also encodes cleavage sequence(s).
In designing a desired XTEN sequences, it was discovered that the non-repetitive nature of the XTEN of the inventive compositions is achieved despite use of a “building block” molecular approach in the creation of the XTEN-encoding sequences. This was achieved by the use of a library of polynucleotides encoding peptide sequence motifs, described above, that are then ligated and/or multimerized to create the genes encoding the XTEN sequences (see FIGS. 4 and 5 and Examples). Thus, while the XTEN(s) of the expressed fusion protein may consist of multiple units of as few as four different sequence motifs, because the motifs themselves consist of non-repetitive amino acid sequences, the overall XTEN sequence is rendered non-repetitive. Accordingly, in one embodiment, the XTEN-encoding polynucleotides comprise multiple polynucleotides that encode non-repetitive sequences, or motifs, operably linked in frame and in which the resulting expressed XTEN amino acid sequences are non-repetitive.
In one approach, a construct is first prepared containing the DNA sequence corresponding to GHXTEN fusion protein. DNA encoding the GH of the compositions is obtained from a cDNA library prepared using standard methods from tissue or isolated cells believed to possess GH mRNA and to express it at a detectable level. Libraries is screened with probes containing, for example, about 20 to 100 bases designed to identify the GH gene of interest by hybridization using conventional molecular biology techniques. The best candidates for probes are those that represent sequences that are highly homologous for human growth hormone, and should be of sufficient length and sufficiently unambiguous that false positives are minimized, but may be degenerate at one or more positions. If necessary, the coding sequence can be obtained using conventional primer extension procedures as described in Sambrook, et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA. One can then use polymerase chain reaction (PCR) methodology to amplify the target DNA or RNA coding sequence to obtain sufficient material for the preparatin of the GHXTEN constructs containing the GH gene(s). Assays can then be conducted to confirm that hybridizing full-length genes are the desired GH gene(s). By these conventional methods, DNA can be conveniently obtained from a cDNA library prepared from such sources. The GH encoding gene(s) is also be obtained from a genomic library or created by standard synthetic procedures known in the art (e.g., automated nucleic acid synthesis using, for example one of the methods described in Engels et al. (Agnew. Chem. Int. Ed. Engl., 28:716-734 1989)), using DNA sequences obtained from publicly available databases, patents, or literature references. Such procedures are well known in the art and well described in the scientific and patent literature. For example, sequences can be obtained from Chemical Abstracts Services (CAS) Registry Numbers (published by the American Chemical Society) and/or GenBank Accession Numbers (e.g., Locus ID, NP_XXXXX, and XP_XXXXX) Model Protein identifiers available through the National Center for Biotechnology Information (NCBI) webpage, available on the world wide web at ncbi.nlm.nih.gov that correspond to entries in the CAS Registry or GenBank database that contain an amino acid sequence of the protein of interest or of a fragment or variant of the protein. For such sequence identifiers provided herein, the summary pages associated with each of these CAS and GenBank and GenSeq Accession Numbers as well as the cited journal publications (e.g., PubMed ID number (PMID)) are each incorporated by reference in their entireties, particularly with respect to the amino acid sequences described therein. In one embodiment, the GH encoding gene encodes a protein from any one of Table 1, or a fragment or variant thereof.
A gene or polynucleotide encoding the GH portion of the subject GHXTEN protein, in the case of an expressed fusion protein that comprises a single GH is then be cloned into a construct, which is a plasmid or other vector under control of appropriate transcription and translation sequences for high level protein expression in a biological system. In a later step, a second gene or polynucleotide coding for the XTEN is genetically fused to the nucleotides encoding the N- and/or C-terminus of the GH gene by cloning it into the construct adjacent and in frame with the gene(s) coding for the GH. This second step occurs through a ligation or multimerization step. In the foregoing embodiments hereinabove described in this paragraph, it is to be understood that the gene constructs that are created can alternatively be the complement of the respective genes that encode the respective fusion proteins.
The gene encoding for the XTEN can be made in one or more steps, either fully synthetically or by synthesis combined with enzymatic processes, such as restriction enzyme-mediated cloning, PCR and overlap extension, including methods more fully described in the Examples. The methods disclosed herein can be used, for example, to ligate short sequences of polynucleotides encoding XTEN into longer XTEN genes of a desired length and sequence. In one embodiment, the method ligates two or more codon-optimized oligonucleotides encoding XTEN motif or segment sequences of about 9 to 14 amino acids, or about 12 to 20 amino acids, or about 18 to 36 amino acids, or about 48 to about 144 amino acids, or about 144 to about 288 or longer, or any combination of the foregoing ranges of motif or segment lengths.
Alternatively, the disclosed method is used to multimerize XTEN-encoding sequences into longer sequences of a desired length; e.g., a gene encoding 36 amino acids of XTEN can be dimerized into a gene encoding 72 amino acids, then 144, then 288, etc. Even with multimerization, XTEN polypeptides can be constructed such that the XTEN-encoding gene has low or vitually no repetitiveness through design of the codons selected for the motifs of the shortest unit used, which can reduce recombination and increase stability of the encoding gene in the transformed host. Genes encoding XTEN with non-repetitive sequences is assembled from oligonucleotides using standard techniques of gene synthesis. The gene design can be performed using algorithms that optimize codon usage and amino acid composition. In one method of the invention, a library of relatively short XTEN-encoding polynucleotide constructs is created and then assembled, as illustrated in FIGS. 4 and 5. This can be a pure codon library such that each library member has the same amino acid sequence but many different coding sequences are possible. Such libraries can be assembled from partially randomized oligonucleotides and used to generate large libraries of XTEN segments comprising the sequence motifs. The randomization scheme can be optimized to control amino acid choices for each position as well as codon usage. Exemplary methods to achieve the foregoing are disclosed in the Examples.
Polynucleotide Libraries
In another aspect, the invention provides libraries of polynucleotides that encode XTEN sequences that is used to assemble genes that encode XTEN of a desired length and sequence.
In certain embodiments, the XTEN-encoding library constructs comprise polynucleotides that encode polypeptide segments of a fixed length. As an initial step, a library of oligonucleotides that encode motifs of 9-14 amino acid residues can be assembled. In a preferred embodiment, libraries of oligonucleotides that encode motifs of 12 amino acids are assembled.
The XTEN-encoding sequence segments can be dimerized or multimerized into longer encoding sequences. Dimerization or multimerization can be performed by ligation, overlap extension, PCR assembly or similar cloning techniques known in the art. This process of can be repeated multiple times until the resulting XTEN-encoding sequences have reached the organization of sequence and desired length, providing the XTEN-encoding genes. As will be appreciated, a library of polynucleotides that encodes, e.g., 12 amino acid motifs can be dimerized and/or ligated into a library of polynucleotides that encode 36 amino acids. Libraries encoding motifs of different lengths; e.g., 9-14 amino acid motifs leading to libraries encoding 27 to 42 amino acids are contemplated by the invention. In turn, the library of polynucleotides that encode 27 to 42 amino acids, and preferably 36 amino acids (as described in the Examples) can be serially dimerized into a library containing successively longer lengths of polynucleotides that encode XTEN sequences of a desired length for incorporation into the gene encoding the GHXTEN fusionprotein, as disclosed herein. In some embodiments, libraries are assembled of polynucleotides that encode amino acids that are limited to specific sequence XTEN families; e.g., AD, AE, AF, AG, AM, or AQ sequences of Table 2. In other embodiments, libraries comprise sequences that encode two or more of the motif family sequences from Table 2. The names and sequences of representative, non-limiting polynucleotide sequences of libraries that encode 36mers are presented in Tables 8-11, and the methods used to create them are described more fully in the Examples. In other embodiments, libraries that encode XTEN are constructed from segments of polynucleotide codons linked in a randomized sequence that encode amino acids wherein at least about 80%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% of the codons are selected from the group consisting of condons for glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) amino acids. The libraries can be used, in turn, for serial dimerization or ligation to achieve polynucleotide sequence libraries that encode XTEN sequences, for example, of 48, 72, 144, 288, 576, 864, 875, 912, 923, 1318 amino acids, or up to a total length of about 3000 amino acids, as well as intermediate lengths, in which the encoded XTEN can have one or more of the properties disclosed herein, when expressed as a component of a GHXTEN fusion protein. In some cases, the polynucleotide library sequences may also include additional bases used as “sequencing islands,” described more fully below.
FIG. 5 is a schematic flowchart of representative, non-limiting steps in the assembly of a XTEN polynucleotide construct and a GHXTEN polynucleotide construct in the embodiments of the invention. Individual oligonucleotides 501 are annealed into sequence motifs 502 such as a 12 amino acid motif (“12-mer”), which is subsequently ligated with an oligo containing BbsI, and KpnI restriction sites 503. Additional sequence motifs from a library are annealed to the 12-mer until the desired length of the XTEN gene 504 is achieved. The XTEN gene is cloned into a stuffer vector. The vector optionally encodes a Flag sequence 506 followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites 507 and, in this case, a single GH gene (encoding hGH in this example) 508, resulting in the gene encoding a GHXTEN comprising a single GH 500. A non-exhaustive list of the XTEN names for polynucleotides encoding XTEN and precursor sequences is provided in Table 7.
TABLE 7
DNA sequences of XTEN and precursor sequences
XTEN SEQ ID
Name NO: DNA Nucleotide Sequence
AE48 107 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGC
GGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTC
CAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCT
AM48 108 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCCGGGC
ACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTC
CAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCT
AE144 109 GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACTTCTGAAAGCGCT
ACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCA
GGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACCTCTACTGAACCT
TCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCA
GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
AF144 110 GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTG
AATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGG
TTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACCAGCGAATCCCCG
TCTGGCACCGCACCAGGTTCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGT
ACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACTCCGGAAAGCG
GCTCCGCATCTCCAGGTTCTACTAGCTCTACTGCTGAATCTCCTGGTCCAGGTAC
CTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCT
TCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCACCA
AE288 111 GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACC
TCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT
ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCA
ACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCT
ACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT
TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCT
ACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
AE576 112 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCT
ACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT
TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA
ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT
CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCA
ACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACC
GTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC
AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACC
TTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACC
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTC
TCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACC
AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCC
AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACC
AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTC
TCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA
AGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGC
AACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
AF576 113 GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCACTAGCTCTACCG
CAGAATCTCCGGGCCCAGGTTCTACTAGCGAATCCCCTTCTGGTACCGCTCCAG
GTTCTACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGC
AGAATCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGT
TCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAAT
CTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTC
TACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCT
TCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTA
CCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCGAATCTTC
TACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACT
AGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGC
ACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTA
GCGAATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTGAAAGCGGCTCCGC
TTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACTAGC
TCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCA
TCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCG
AATCCCCGTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTCTGCTT
CTCCAGGTACTTCTACCCCGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCG
AATCTCCTTCTGGTACCGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGC
TCCAGGTTCTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTTCTACTAGCTCT
ACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCT
CCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAAT
CTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACC
AGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAATCT
CCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCA
GGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTACTTCTCCGAGCGGTG
AATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAGG
TACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTTCCACTAGCTCTACTGCT
GAATCTCCTGGCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT
CTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTTCTACTAGCTCTACTGCAG
AATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTA
CTTCTACCCCTGAAAGCGGTTCTGCATCTCCA
AE624 114 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGC
GGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTC
CAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCT
CTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCC
AGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC
AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGC
TACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTC
TCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAACC
GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGA
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACC
TTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCC
AGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC
AACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCC
AGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACC
GTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCC
AGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTC
TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCC
AGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCC
AGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACC
GTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC
AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACC
GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGA
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAAAGCGC
AACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC
AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC
AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA
AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTC
TCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
AM875 115 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAA
GGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAA
AGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAG
GTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAG
CGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGT
AGCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT
ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACC
CCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT
ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT
ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT
ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACC
CCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT
ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCC
GAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT
ACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCT
GGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGT
AGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG
CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTAC
CTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCGTCTGA
GGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAG
CCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACT
TCTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCA
AGCGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGAAAGCGCTACTCCTGA
GTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCT
CCTGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCC
CTAGCGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAGCGGTACCGCTTCTTC
CTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTAGCCCG
TCTGCATCTACCGGTACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAA
ACTCCAGGTACTTCTGAAAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCG
GCTACTTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTACTGCAGAATCTCCG
GGCCCAGGTTCTACTAGCTCTACTGCAGAATCTCCGGGTCCAGGTACTTCTCCTA
GCGGCGAATCTTCTACCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAA
CTCCAGGTAGCGAACCTGCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTG
AACCTTCTGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCGCAGAATCTCCTG
GTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCG
AATCTCCTTCTGGCACTGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCG
CTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCG
AACCTTCTGAAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCT
CCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACC
CCAGGTACCTCTGAAAGCGCAACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGT
TCTCCTACCTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCC
CAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCAC
CAGCTCTACTGGTTCTCCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCC
AGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACC
GTCCGAAGGTAGCGCACCA
AE864 116 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCT
ACTCCTGAGTCTGGTCCAGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACT
TCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCA
ACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCT
CCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCA
ACCCCGGAATCCGGCCCAGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACC
GTCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACC
AGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACC
TTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACC
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTC
TCCTACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACC
AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCC
AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACC
AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTC
TCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA
AGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGC
AACCCCGGAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC
AGGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCC
AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACC
AGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTC
TCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGA
AGGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGC
TACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCC
AGGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTAC
TTCTGGTTCTGAAACCCCAGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCC
AGGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGAACC
TTCCGAAGGCAGCGCACCAGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCC
AGGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCTGAATCTGGCCCAGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
AF864 117 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGCG
AATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG
TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGC
GGTTCCGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTT
CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATCCCCGTC
TGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCT
ACTAGCGAATCTCCGTCTGGCACTGCTCCAGGTACTTCTCCTAGCGGTGAATCTT
CTACCGCTCCAGGTACTTCCCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTAC
TAGCTCTACTGCAGAATCTCCGGGCCCAGGTACCTCTCCTAGCGGTGAATCTTCT
ACCGCTCCAGGTACTTCTCCGAGCGGTGAATCTTCTACCGCTCCAGGTTCTACTA
GCTCTACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGCTCTG
CATCTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCCAGGTTCTACTAG
CGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACT
GCACCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCAGGTTCTACCAGCT
CTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCAT
CTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTACTTCTCCGAG
CGGTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCCGGGC
CCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACTCCTG
AAAGCGGTTCTGCATCTCCAGGTTCCACTAGCTCTACCGCAGAATCTCCGGGCC
CAGGTTCTACTAGCTCTACTGCTGAATCTCCTGGCCCAGGTTCTACTAGCTCTAC
TGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAATCTCCTGGTCCA
GGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCAGGTTCTACTAGCGAATCTC
CTTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACCAG
GTACCTCTACCCCTGAAAGCGGTCCXXXXXXXXXXXXTGCAAGCGCAAGCGGC
GCGCCAAGCACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACCGCTCCAGGT
TCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTT
CTGGTACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTTC
TACCAGCGAATCCCCGTCTGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCT
GGTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACT
TCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTT
CTACTGCTCCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTC
CCCGAGCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTC
CGCTTCTCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACT
AGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCT
ACCGCACCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCT
ACCCCGGAAAGCGGCTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCC
GCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTCTA
CCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGAATCTCC
GGGTCCAGGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGC
GAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTCTACCG
CACCAGGTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCGAG
CGGTGAATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTCT
CCAGGTACCTCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCG
GCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACCGCACC
AGGTTCTACTAGCTCTACTGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACT
GCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGCACCA
GGTTCTAGCCCTTCTGCTTCCACCGGTACCGGCCCAGGTAGCTCTACTCCGTCTG
GTGCAACTGGCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCA
XXXX was inserted in two areas where no sequence
information is available.
AG864 118 GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAGCCCGTCTGCTT
CTACTGGTACTGGTCCAGGTTCTAGCCCTTCTGCTTCCACTGGTACTGGTCCAGG
TACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGT
GCTACCGGCTCTCCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTG
CTTCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCAGCGGTACCG
CATCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGTTCTCCAGGTAC
TCCTGGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCT
ACTGGTTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTACCC
CGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAAC
CGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTACCCCG
GGTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCG
GCTCTCCAGGTTCTAACCCTTCTGCATCCACCGGTACCGGCCCAGGTTCTAGCCC
TTCTGCTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGCTACCGGC
TCCCCAGGTAGCTCTACTCCTTCTGGTGCAACTGGCTCTCCAGGTGCATCTCCGG
GCACTAGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTC
TCCAGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTACTCCTGGCAGC
GGTACCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGGTTCTCC
AGGTGCTTCTCCGGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCCCCGGGCACT
AGCTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAG
GTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTGCATCTCCGGGCACTAG
CTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGT
GCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTAGCTCTACTCCGTCTGGTG
CAACCGGTTCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGC
ATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGTACCCCGGGCAGCGGTACCGC
ATCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTAGC
TCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACTCCGTCTGGTGCAA
CCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCTTC
CCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCCCCGGGTACCAGCTCTAC
CGGTTCTCCAGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCAGGTGCTTCT
CCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTCCGGGCACTAGCTCTACTG
GTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCC
TGGTACCAGCTCTACTGGTTCTCCAGGTACCCCTGGTAGCGGTACTGCTTCTTCC
TCTCCAGGTAGCTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACCCCGGGTA
GCGGTACCGCATCTTCTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGTTC
TCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCT
TCTGGTGCTACTGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCCC
CAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGTCCAGGTTCTAGCCCGTCTGC
ATCTACTGGTACTGGTCCAGGTGCATCCCCGGGCACTAGCTCTACCGGTTCTCCA
GGTACTCCTGGTAGCGGTACTGCTTCTTCTTCTCCAGGTAGCTCTACTCCTTCTG
GTGCTACTGGTTCTCCAGGTTCTAGCCCTTCTGCATCCACCGGTACCGGCCCAGG
TTCTAGCCCGTCTGCTTCTACCGGTACTGGTCCAGGTGCTTCTCCGGGTACTAGC
TCTACTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTACTGGTTCTCCAGGTA
GCTCTACTCCGTCTGGTGCAACCGGCTCTCCAGGTTCTAGCCCTTCTGCATCTAC
CGGTACTGGTCCAGGTGCATCCCCTGGTACCAGCTCTACCGGTTCTCCAGGTTCT
AGCCCTTCTGCTTCTACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACCGCA
TCTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAGGTAGCT
CTACTCCTTCTGGTGCTACTGGCTCCCCAGGTGCATCCCCTGGCACCAGCTCTAC
CGGTTCTCCA
AM923 119 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCCGGGC
ACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTC
CAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTACTTCTACTGAACC
GTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC
AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTAC
CGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCC
AGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCGAATCC
CCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAG
GTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCGGCAACCT
CCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAG
GTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTGAACCTT
CTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAG
GTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACCGT
CCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAG
GTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGAACCTT
CCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAACCTTC
CGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCCGAGGGCAGCGCACCAG
GTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTACTTCTACTGAACCTTC
CGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGG
TAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCGTCTGG
TGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGT
AGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCTCTACCGAACCGTCCG
AGGGTAGCGCACCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTCCGA
CTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTA
CTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAGCGCAAGCGGCGCGC
CAAGCACGGGAGGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCC
CGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAACTT
CTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCTAC
TAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAGCGGTGAATCTTCT
ACTGCACCAGGTACCCCTGGCAGCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTA
CCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCGGTAC
CGGCCCAGGTAGCGAACCGGCAACCTCCGGCTCTGAAACTCCAGGTACTTCTGA
AAGCGCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTACTTCCGGCTCTGA
AACCCCAGGTTCCACCAGCTCTACTGCAGAATCTCCGGGCCCAGGTTCTACTAG
CTCTACTGCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTCTACC
GCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAAACTCCAGGTAGCGAACCT
GCAACCTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTTCTGAGGGCAGC
GCACCAGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTC
CGGAAAGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGC
ACCAGGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTCTACTGA
ACCTTCCGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAGCGC
ACCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCT
GCTTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTC
CAGGTAGCGAACCTGCTACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCG
CAACTCCGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTACCTCCACTGAGG
AAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGC
TTCCACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCA
GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCG
TCTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
AE912 120 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGGTAGC
GGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTC
CAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCCCGGCTGGCT
CTCCTACCTCTACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCC
AGGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC
AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGC
TACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCGGCAGGCTC
TCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTTCTACCGAACC
GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGA
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACC
TTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCC
AGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTGAAAGCGC
AACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCC
AGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACTGAACC
GTCTGAAGGTAGCGCACCAGGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCC
AGGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCCTGCTGGCTC
TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCC
AGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTCTGAAAGCGC
TACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCC
AGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCGAACC
GTCCGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCC
AGGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTCTACCGAACC
GTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGA
AGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTGAAAGCGC
AACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC
AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC
AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA
AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGGCAGGCTC
TCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTGAAAGCGC
AACTCCTGAGTCTGGCCCAGGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCC
AGGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC
AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCTGGCTC
TCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCC
AGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGA
AGGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCGAACC
TTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCC
AGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAAGCGC
TACCCCGGAATCTGGCCCAGGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTTCTACTGAACCTTCCGAAGGCAGCGCACC
AGGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCC
AGGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
AM1318 121 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAA
GGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAA
AGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAG
GTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTACTCCTGAAAG
CGGTTCCGCTTCTCCAGGTACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGT
AGCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT
ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCGCTACC
CCGGAGTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT
ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTCCT
ACCTCCACCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT
ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCGCTACC
CCTGAGTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT
ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAACCGTCC
GAGGGCAGCGCACCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT
ACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCTACTTCT
GGTTCTGAAACCCCAGGTAGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGT
AGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCGGTACTG
CTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTAC
CTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCGTCTGA
GGGTAGCGCTCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAG
CCCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACT
TCTACTGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCAGGTCCA
GAACCAACGGGGCCGGCCCCAAGCGGAGGTAGCGAACCGGCAACCTCCGGCTC
TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCC
GGCAGGTTCTCCGACTTCCACTGAGGAAGGTACTTCTGAAAGCGCTACTCCTGA
GTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACTCCTGA
GTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGAATCT
CCTGGCCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTACTTCCC
CTAGCGGTGAATCTTCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCTGGCAC
CGCTCCAGGTTCTACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT
AGCGGCGAATCTTCTACCGCACCAGGTACTTCTACCGAACCTTCCGAGGGCAGC
GCACCAGGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAA
AGCGCTACTCCTGAATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTCTGAA
ACCCCAGGTACCTCTGAAAGCGCTACTCCGGAATCTGGTCCAGGTACTTCTGAA
AGCGCTACTCCGGAATCCGGTCCAGGTACCTCTACTGAACCTTCTGAGGGCAGC
GCTCCAGGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACT
GAACCGTCCGAAGGTAGCGCACCAGGTACCTCCCCTAGCGGCGAATCTTCTACT
GCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTACCTCCCCTA
GCGGTGAATCTTCTACCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTAGCG
CACCAGGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCG
AACCGTCCGAGGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTACCG
GCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGGCTCTCCAGGTAGCTCTACTCC
GTCTGGTGCAACCGGCTCCCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCT
CCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTGCATCCCCGGGT
ACTAGCTCTACCGGTTCTCCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGG
AGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTACC
GCTGAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAG
GTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTCTACTGAACCGT
CTGAGGGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG
GTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGGTAGCTCTACTCCTTCTGG
TGCTACCGGCTCTCCAGGTGCTTCTCCGGGTACTAGCTCTACCGGTTCTCCAGGT
ACTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTCTCCTAGCGGTGAAT
CTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTAC
TTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCGAACCGGCTACTTCTGG
CTCTGAGACTCCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCAGGTTC
TACCAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTACCAGCGAATCCCCTTCT
GGCACCGCACCAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGC
CCGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTGAAAGCGCAACCCCG
GAGTCCGGCCCAGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCAGGTAGC
CCTGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAAAGCGCAACCCCT
GAATCCGGCCCAGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCAGGTAGC
TCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTCCTGGTACTAGCTCTA
CCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGGTTCTAC
TAGCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCCCCTAGCGGTGAATCTTCT
ACTGCTCCAGGTTCTACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTAGCTCT
ACCCCTTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGGGTACCAGCTCTACC
GGTTCTCCAGGTACTCCGGGTAGCGGTACCGCTTCTTCCTCTCCAGGTAGCCCTG
CTGGCTCTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTCCGACTTCTAC
TGAGGAAGGTACTTCTACCGAACCTTCCGAAGGTAGCGCTCCA
BC864 122 GGTACTTCCACCGAACCATCCGAACCAGGTAGCGCAGGTACTTCCACCGAACCA
TCCGAACCTGGCAGCGCAGGTAGCGAACCGGCAACCTCTGGTACTGAACCATCA
GGTAGCGGCGCATCCGAGCCTACCTCTACTGAACCAGGTAGCGAACCGGCTACC
TCCGGTACTGAGCCATCAGGTAGCGAACCGGCAACTTCCGGTACTGAACCATCA
GGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCATCTGAG
CCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAGCGCA
GGTAGCGAACCAGCTACTTCTGGCACTGAACCATCAGGTACTTCTACTGAACCA
TCCGAACCAGGTAGCGCAGGTAGCGAACCTGCTACCTCTGGTACTGAGCCATCA
GGTAGCGAACCGGCTACCTCTGGTACTGAACCATCAGGTACTTCTACCGAACCA
TCCGAGCCTGGTAGCGCAGGTACTTCTACCGAACCATCCGAGCCAGGCAGCGCA
GGTAGCGAACCGGCAACCTCTGGCACTGAGCCATCAGGTAGCGAACCAGCAAC
TTCTGGTACTGAACCATCAGGTACTAGCGAGCCATCTACTTCCGAACCAGGTGC
AGGTAGCGGCGCATCCGAACCTACTTCCACTGAACCAGGTACTAGCGAGCCATC
CACCTCTGAACCAGGTGCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATC
AGGTAGCGAACCGGCTACCTCTGGTACTGAACCATCAGGTACTTCTACCGAACC
ATCCGAGCCTGGTAGCGCAGGTACTTCTACCGAACCATCCGAGCCAGGCAGCGC
AGGTAGCGGTGCATCCGAGCCGACCTCTACTGAACCAGGTAGCGAACCAGCAA
CTTCTGGCACTGAGCCATCAGGTAGCGAACCAGCTACCTCTGGTACTGAACCAT
CAGGTAGCGAACCGGCTACTTCCGGCACTGAACCATCAGGTAGCGAACCAGCA
ACCTCCGGTACTGAACCATCAGGTACTTCCACTGAACCATCCGAACCGGGTAGC
GCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCATCT
GAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAGC
GCAGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGTAGCGGCGCATCT
GAACCAACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGAGCCAGGCAGC
GCAGGTAGCGGCGCATCTGAACCAACCTCTACTGAACCAGGTAGCGAACCAGC
AACTTCTGGTACTGAACCATCAGGTAGCGGCGCATCTGAGCCTACTTCCACTGA
ACCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCATC
TGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAG
CGCAGGTAGCGAACCGGCAACTTCCGGCACTGAACCATCAGGTAGCGGTGCATC
TGAGCCGACCTCTACTGAACCAGGTACTTCTACTGAACCATCTGAGCCGGGCAG
CGCAGGTAGCGAACCAGCTACTTCTGGCACTGAACCATCAGGTACTTCTACTGA
ACCATCCGAACCAGGTAGCGCAGGTAGCGAACCTGCTACCTCTGGTACTGAGCC
ATCAGGTACTTCTACTGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGA
ACCATCTGAACCTGGTAGCGCAGGTACTTCCACTGAACCATCCGAACCAGGTAG
CGCAGGTACTTCTACTGAACCATCCGAGCCGGGTAGCGCAGGTACTTCCACTGA
ACCATCTGAACCTGGTAGCGCAGGTACTTCCACTGAACCATCCGAACCAGGTAG
CGCAGGTACTAGCGAACCATCCACCTCCGAACCAGGCGCAGGTAGCGGTGCATC
TGAACCGACTTCTACTGAACCAGGTACTTCCACTGAACCATCTGAGCCAGGTAG
CGCAGGTACTTCCACCGAACCATCCGAACCAGGTAGCGCAGGTACTTCCACCGA
ACCATCCGAACCTGGCAGCGCAGGTAGCGAACCGGCAACCTCTGGTACTGAACC
ATCAGGTAGCGGTGCATCCGAGCCGACCTCTACTGAACCAGGTAGCGAACCAGC
AACTTCTGGCACTGAGCCATCAGGTAGCGAACCAGCTACCTCTGGTACTGAACC
ATCAGGTAGCGAACCGGCAACCTCTGGCACTGAGCCATCAGGTAGCGAACCAG
CAACTTCTGGTACTGAACCATCAGGTACTAGCGAGCCATCTACTTCCGAACCAG
GTGCAGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGTAGCGGCGCAT
CTGAACCAACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGAGCCAGGCA
GCGCAGGTAGCGAACCTGCAACCTCCGGCACTGAGCCATCAGGTAGCGGCGCA
TCTGAACCAACCTCTACTGAACCAGGTACTTCCACCGAACCATCTGAGCCAGGC
AGCGCA
BD864 123 GGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTAGTGAATCCGCA
ACTAGCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGAGACTTCCACTGAAGCA
GGTACTAGCGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACTGCTAC
CTCTGGCTCCGAGACTGCAGGTAGCGAAACTGCAACCTCTGGCTCTGAAACTGC
AGGTACTTCCACTGAAGCAAGTGAAGGCTCCGCATCAGGTACTTCCACCGAAGC
AAGCGAAGGCTCCGCATCAGGTACTAGTGAGTCCGCAACTAGCGAATCCGGTGC
AGGTAGCGAAACCGCTACCTCTGGTTCCGAAACTGCAGGTACTTCTACCGAGGC
TAGCGAAGGTTCTGCATCAGGTAGCACTGCTGGTTCCGAGACTTCTACTGAAGC
AGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGC
TACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGC
AGGTACTAGCGAGTCCGCTACTAGCGAATCTGGCGCAGGTACTTCCACTGAAGC
TAGTGAAGGTTCTGCATCAGGTAGCGAAACTGCTACTTCTGGTTCCGAAACTGC
AGGTAGCGAAACCGCTACCTCTGGTTCCGAAACTGCAGGTACTTCTACCGAGGC
TAGCGAAGGTTCTGCATCAGGTAGCACTGCTGGTTCCGAGACTTCTACTGAAGC
AGGTACTAGCGAGTCCGCTACTAGCGAATCTGGCGCAGGTACTTCCACTGAAGC
TAGTGAAGGTTCTGCATCAGGTAGCGAAACTGCTACTTCTGGTTCCGAAACTGC
AGGTAGCACTGCTGGCTCCGAGACTTCTACCGAAGCAGGTAGCACTGCAGGTTC
CGAAACTTCCACTGAAGCAGGTAGCGAAACTGCTACCTCTGGCTCTGAGACTGC
AGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGC
TACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGC
AGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCCGC
TACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACTGC
AGGTAGCGAAACCGCTACCTCTGGTTCCGAAACTGCAGGTACTTCTACCGAGGC
TAGCGAAGGTTCTGCATCAGGTAGCACTGCTGGTTCCGAGACTTCTACTGAAGC
AGGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTAGTGAATCCGC
AACTAGCGAATCTGGCGCAGGTAGCACTGCAGGCTCTGAGACTTCCACTGAAGC
AGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGCACTGCAGGTTC
TGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCTCTGCATC
AGGTAGCACTGCTGGTTCCGAAACCTCTACCGAAGCAGGTAGCACTGCAGGTTC
TGAAACCTCCACTGAAGCAGGTACTTCCACTGAGGCTAGTGAAGGCTCTGCATC
AGGTAGCACTGCAGGTTCTGAGACTTCCACCGAAGCAGGTAGCGAAACTGCTAC
TTCTGGTTCCGAAACTGCAGGTACTTCCACTGAAGCTAGTGAAGGTTCCGCATC
AGGTACTAGTGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCAA
CCTCCGGTTCTGAAACTGCAGGTACTAGCGAATCCGCAACCAGCGAATCTGGCG
CAGGTACTAGTGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACCGCA
ACCTCCGGTTCTGAAACTGCAGGTACTAGCGAATCCGCAACCAGCGAATCTGGC
GCAGGTAGCGAAACTGCTACTTCCGGCTCTGAGACTGCAGGTACTTCCACCGAA
GCAAGCGAAGGTTCCGCATCAGGTACTTCCACCGAGGCTAGTGAAGGCTCTGCA
TCAGGTAGCACTGCTGGCTCCGAGACTTCTACCGAAGCAGGTAGCACTGCAGGT
TCCGAAACTTCCACTGAAGCAGGTAGCGAAACTGCTACCTCTGGCTCTGAGACT
GCAGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATCC
GCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGACT
GCAGGTAGCGAAACTGCTACTTCCGGCTCCGAGACTGCAGGTAGCGAAACTGCT
ACTTCTGGCTCCGAAACTGCAGGTACTTCTACTGAGGCTAGTGAAGGTTCCGCA
TCAGGTACTAGCGAGTCCGCAACCAGCGAATCCGGCGCAGGTAGCGAAACTGC
TACCTCTGGCTCCGAGACTGCAGGTAGCGAAACTGCAACCTCTGGCTCTGAAAC
TGCAGGTACTAGCGAATCTGCTACTAGCGAATCCGGCGCAGGTACTAGCGAATC
CGCTACCAGCGAATCCGGCGCAGGTAGCGAAACTGCAACCTCTGGTTCCGAGAC
TGCA
One may clone the library of XTEN-encoding genes into one or more expression vectors known in the art. To facilitate the identification of well-expressing library members, one can construct the library as fusion to a reporter protein. Non-limiting examples of suitable reporter genes are green fluorescent protein, luciferace, alkaline phosphatase, and beta-galactosidase. By screening, one can identify short XTEN sequences that can be expressed in high concentration in the host organism of choice. Subsequently, one can generate a library of random XTEN dimers and repeat the screen for high level of expression. Subsequently, one can screen the resulting constructs for a number of properties such as level of expression, protease stability, or binding to antiserum.
One aspect of the invention is to provide polynucleotide sequences encoding the components of the fusion protein wherein the creation of the sequence has undergone codon optimization. Of particular interest is codon optimization with the goal of improving expression of the polypeptide compositions and to improve the genetic stability of the encoding gene in the production hosts. For example, codon optimization is of particular importance for XTEN sequences that are rich in glycine or that have very repetitive amino acid sequences. Codon optimization is performed using computer programs (Gustafsson, C., et al. (2004) Trends Biotechnol, 22: 346-53), some of which minimize ribosomal pausing (Coda Genomics Inc.). In one embodiment, one can perform codon optimization by constructing codon libraries where all members of the library encode the same amino acid sequence but where codon usage is varied. Such libraries can be screened for highly expressing and genetically stable members that are particularly suitable for the large-scale production of XTEN-containing products. When designing XTEN sequences one can consider a number of properties. One can minimize the repetitiveness in the encoding DNA sequences. In addition, one can avoid or minimize the use of codons that are rarely used by the production host (e.g. the AGG and AGA arginine codons and one leucine codon in E. coli). In the case of E. coli, two glycine codons, GGA and GGG, are rarely used in highly expressed proteins. Thus codon optimization of the gene encoding XTEN sequences can be very desirable. DNA sequences that have a high level of glycine tend to have a high GC content that can lead to instability or low expression levels. Thus, when possible, it is preferred to choose codons such that the GC-content of XTEN-encoding sequence is suitable for the production organism that will be used to manufacture the XTEN.
Optionally, the full-length XTEN-encoding gene comprises one or more sequencing islands. In this context, sequencing islands are short-stretch sequences that are distinct from the XTEN library construct sequences and that include a restriction site not present or expected to be present in the full-length XTEN-encoding gene. In one embodiment, a sequencing island is the sequence
(SEQ ID NO: 124)
5′-AGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGT-3′.
In another embodiment, a sequencing island is the sequence
(SEQ ID NO: 125)
5′-AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGT-3′.
As an alternative, one can construct codon libraries where all members of the library encode the same amino acid sequence but where codon usage for the respective amino acids in the sequence is varied. Such libraries can be screened for highly expressing and genetically stable members that are particularly suitable for the large-scale production of XTEN-containing products.
Optionally, one can sequence clones in the library to eliminate isolates that contain undesirable sequences. The initial library of short XTEN sequences allows some variation in amino acid sequence. For instance one can randomize some codons such that a number of hydrophilic amino acids can occur in a particular position. During the process of iterative multimerization one can screen the resulting library members for other characteristics like solubility or protease resistance in addition to a screen for high-level expression.
Once the gene that encodes the XTEN of desired length and properties is selected, it is genetically fused to the nucleotides encoding the N- and/or the C-terminus of the GH gene(s) by cloning it into the construct adjacent and in frame with the gene coding for GH or, optionally, adjacent to a spacer sequence. The invention provides various permutations of the foregoing, depending on the GHXTEN to be encoded. For example, a gene encoding a GHXTEN fusion protein comprising a GH and two XTEN, such as embodied by formula VI, as depicted above, the gene would have polynucleotides encoding GH, encoding two XTEN, which can be identical or different in composition and sequence length. In one non-limiting embodiment of the foregoing, the GH polynucleotides would encode human growth hormone and the polynucleotides encoding the N-terminus XTEN would encode AE912 and the polynucleotides encoding the C-terminus XTEN would encode AE144. The step of cloning the GH genes into the XTEN construct can occur through a ligation or multimerization step. As shown in FIG. 2, the constructs encoding GHXTEN fusion proteins can be designed in different configurations of the components XTEN 202, GH 203, and spacer sequences 204. In one embodiment, as illustrated in FIG. 2A, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′) GH 203 and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2B, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′) GH 203, spacer sequence 204, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2C, the construct 201 encodes a monomeric GHXTEN comprising polynucleotide sequences complementary to, or those that encode components in the following order (5′ to 3′): two molecules of GH 203 and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2D, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): two molecules of GH 203, spacer sequence 204, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2E, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): GH 203, spacer sequence 204, a second molecule of GH 203, and XTEN 202, or the reverse order. In another embodiment, as illustrated in FIG. 2F, the construct comprises polynucleotide sequences complementary to, or those that encode a monomeric polypeptide of components in the following order (5′ to 3′): GH 203, XTEN 202, GH 203, and a second XTEN 202, or the reverse sequence. The spacer polynucleotides can optionally comprise sequences encoding cleavage sequences. As will be apparent to those of skill in the art, other permutations of the foregoing are possible.
The invention also encompasses polynucleotides comprising XTEN-encoding polynucleotide variants that have a high percentage of sequence identity to (a) a polynucleotide sequence from Table 7, or (b) sequences that are complementary to the polynucleotides of (a). A polynucleotide with a high percentage of sequence identity is one that has at least about an 80% nucleic acid sequence identity, alternatively at least about 81%, alternatively at least about 82%, alternatively at least about 83%, alternatively at least about 84%, alternatively at least about 85%, alternatively at least about 86%, alternatively at least about 87%, alternatively at least about 88%, alternatively at least about 89%, alternatively at least about 90%, alternatively at least about 91%, alternatively at least about 92%, alternatively at least about 93%, alternatively at least about 94%, alternatively at least about 95%, alternatively at least about 96%, alternatively at least about 97%, alternatively at least about 98%, and alternatively at least about 99% nucleic acid sequence identity to (a) or (b) of the foregoing, or that can hybridize with the target polynucleotide or its complement under stringent conditions.
Homology, sequence similarity or sequence identity of nucleotide or amino acid sequences may also be determined conventionally by using known software or computer programs such as the BestFit or Gap pairwise comparison programs (GCG Wisconsin Package, Genetics Computer Group, 575 Science Drive, Madison, Wis. 53711). BestFit uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics. 1981. 2: 482-489), to find the best segment of identity or similarity between two sequences. Gap performs global alignments: all of one sequence with all of another similar sequence using the method of Needleman and Wunsch, (Journal of Molecular Biology. 1970. 48:443-453). When using a sequence alignment program such as BestFit, to determine the degree of sequence homology, similarity or identity, the default setting may be used, or an appropriate scoring matrix may be selected to optimize identity, similarity or homology scores.
Nucleic acid sequences that are “complementary” are those that are capable of base-pairing according to the standard Watson-Crick complementarity rules. As used herein, the term “complementary sequences” means nucleic acid sequences that are substantially complementary, as may be assessed by the same nucleotide comparison set forth above, or as defined as being capable of hybridizing to the polynucleotides that encode the GHXTEN sequences under stringent conditions, such as those described herein.
The resulting polynucleotides encoding the GHXTEN chimeric fusion proteins can then be individually cloned into an expression vector. The nucleic acid sequence is inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan. Such techniques are well known in the art and well described in the scientific and patent literature.
Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The invention provides for the use of plasmid vectors containing replication and control sequences that are compatible with and recognized by the host cell, and are operably linked to the GHXTEN gene for controlled expression of the GHXTEN fusion proteins. The vector ordinarily carries a replication site, as well as sequences that encode proteins that are capable of providing phenotypic selection in transformed cells. Such vector sequences are well known for a variety of bacteria, yeast, and viruses. Useful expression vectors that can be used include, for example, segments of chromosomal, non-chromosomal and synthetic DNA sequences. “Expression vector” refers to a DNA construct containing a DNA sequence that is operably linked to a suitable control sequence capable of effecting the expression of the DNA encoding the fusion protein in a suitable host. Such control sequences include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences that control termination of transcription and translation. Other suitable vectors include, but are not limited to, derivatives of SV40 and pcDNA and known bacterial plasmids such as col EI, pCR1, pBR322, pMal-C2, pET, pGEX as described by Smith, et al., Gene 57:31-40 (1988), pMB9 and derivatives thereof, plasmids such as RP4, phage DNAs such as the numerous derivatives of phage I such as NM98 9, as well as other phage DNA such as M13 and filamentous single stranded phage DNA; yeast plasmids such as the 2 micron plasmid or derivatives of the 2m plasmid, as well as centomeric and integrative yeast shuttle vectors; vectors useful in eukaryotic cells such as vectors useful in insect or mammalian cells; vectors derived from combinations of plasmids and phage DNAs, such as plasmids that have been modified to employ phage DNA or the expression control sequences; and the like. The requirements are that the vectors are replicable and viable in the host cell of choice. Low- or high-copy number vectors may be used as desired.
Promoters suitable for use in expression vectors with prokaryotic hosts include the β-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)], all would be operably linked to the DNA encoding GHXTEN polypeptides. Promoters for use in bacterial systems can also contain a Shine-Dalgarno (S.D.) sequence, operably linked to the DNA encoding GHXTEN polypeptides.
The invention contemplates use of other expression systems including, for example, a baculovirus expression system with both non-fusion transfer vectors, such as, but not limited to pVL941 Summers, et al., Virology 84:390-402 (1978)), pVL1393 (Invitrogen), pVL1392 (Summers, et al., Virology 84:390-402 (1978) and Invitrogen) and pBlueBacIII (Invitrogen), and fusion transfer vectors such as, but not limited to, pAc7 00 (Summers, et al., Virology 84:390-402 (1978)), pAc701 and pAc70-2 (same as pAc700, with different reading frames), pAc360 Invitrogen) and pBlueBacHisA, B, C (; Invitrogen) can be used.
Mammalian expression vectors can comprise an origin of replication, a suitable promoter and enhancer, and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences. DNA sequences derived from the SV40 splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Mammalian expression vectors contemplated for use in the invention include vectors with inducible promoters, such as the dihydrofolate reductase promoters, any expression vector with a DHFR expression cassette or a DHFR/methotrexate co-amplification vector such as pED (Randal J. Kaufman, 1991, Randal J. Kaufman, Current Protocols in Molecular Biology, 16,12 (1991)). Alternatively a glutamine synthetase/methionine sulfoximine co-amplification vector, such as pEE14 (Celltech). A vector that directs episomal expression under the control of the Epstein Barr Virus (EBV) or nuclear antigen (EBNA) can be used such as pREP4 (Invitrogen), pCEP4 (Invitrogen), pMEP4 (Invitrogen), pREP8 (Invitrogen), pREP9 (Invitrogen), and pEBVHis (Invitrogen).
Selectable mammalian expression vectors for use in the invention include, but are not limited to, pRc/CMV (Invitrogen), pRc/RSV (Invitrogen) and the like. Vaccinia virus mammalian expression vectors (see, for example, Randall J. Kaufman, Current Protocols in Molecular Biology 16.12 (Frederick M. Ausubel, et al., eds. Wiley 1991) that can be used in the present invention include, but are not limited to, pSC11, pMJ601 pTKgptFISand the like.
Yeast expression systems that can also be used in the present invention include, but are not limited to, the non-fusion pYES2 vector (Invitrogen), the fusion pYESHisA, B, C (Invitrogen), pRS vectors and the like.
In addition, the expression vector containing the chimeric GHXTEN fusion protein-encoding polynucleotide molecule may include drug selection markers. Such markers aid in cloning and in the selection or identification of vectors containing chimeric DNA molecules. For example, genes that confer resistance to neomycin, puromycin, hygromycin, dihydrofolate reductase (DHFR) inhibitor, guanine phosphoribosyl transferase (GPT), zeocin, and histidinol are useful selectable markers. Alternatively, enzymes such as herpes simplex virus thymidine kinase (tk) or chloramphenicol acetyltransferase (CAT) may be employed. Immunologic markers also can be employed. Any known selectable marker may be employed so long as it is capable of being expressed simultaneously with the nucleic acid encoding a gene product. Further examples of selectable markers are well known to one of skill in the art and include reporters such as enhanced green fluorescent protein (EGFP), beta-galactosidase (β-gal) or chloramphenicol acetyltransferase (CAT).
In one embodiment, the polynucleotide encoding a GHXTEN fusion protein composition is fused C-terminally to an N-terminal signal sequence appropriate for the expression host system. Signal sequences are typically proteolytically removed from the protein during the translocation and secretion process, generating a defined N-terminus. A wide variety of signal sequences have been described for most expression systems, including bacterial, yeast, insect, and mammalian systems. A non-limiting list of preferred examples for each expression system follows herein. Preferred signal sequences are OmpA, PhoA, and DsbA for E. coli expression. Signal peptides preferred for yeast expression are ppL-alpha, DEX4, invertase signal peptide, acid phosphatase signal peptide, CPY, or INU1. For insect cell expression the preferred signal sequences are sexta adipokinetic hormone precursor, CP1, CP2, CP3, CP4, TPA, PAP, or gp67. For mammalian expression the preferred signal sequences are IL2L, SV40, IgG kappa and IgG lambda.
In another embodiment, a leader sequence, potentially comprising a well-expressed, independent protein domain, can be fused to the N-terminus of the GHXTEN sequence, separated by a protease cleavage site. While any leader peptide sequence which does not inhibit cleavage at the designed proteolytic site can be used, sequences in preferred embodiments will comprise stable, well-expressed sequences such that expression and folding of the overall composition is not significantly adversely affected, and preferably expression, solubility, and/or folding efficiency are significantly improved. A wide variety of suitable leader sequences have been described in the literature. A non-limiting list of suitable sequences includes maltose binding protein, cellulose binding domain, glutathione S-transferase, 6×His tag (SEQ ID NO: 126), FLAG tag, hemaglutinin tag, and green fluorescent protein. The leader sequence can also be further improved by codon optimization, especially in the second codon position following the ATG start codon, by methods well described in the literature and hereinabove.
Various in vitro enzymatic methods for cleaving proteins at specific sites are known. Such methods include use of enterokinase (DDDK (SEQ ID NO: 127)), Factor Xa (IDGR (SEQ ID NO: 128)), thrombin (LVPRGS (SEQ ID NO: 129)), PreScission™ (LEVLFQGP (SEQ ID NO: 130)), TEV protease (EQLYFQG (SEQ ID NO: 131)), 3C protease (ETLFQGP (SEQ ID NO: 132)), Sortase A (LPETG (SEQ ID NO: 133)), Granzyme B (D/X, N/X, M/N or SA), inteins, SUMO, DAPase (TAGZyme™), Aeromonas aminopeptidase, Aminopeptidase M, and carboxypeptidases A and B. Additional methods are disclosed in Arnau, et al., Protein Expression and Purification 48: 1-13 (2006).
In other cases, the invention provides constructs and methods of making constructs comprising an polynucleotide sequence optimized for expression that encodes at least about 20 to about 60 amino acids with XTEN characteristics that can be included at the N-terminus of an XTEN carrier encoding sequence (in other words, the polynucleotides encoding the 20-60 encoded optimized amino acids are linked in frame to polynucleotides encoding an XTEN component that is N-terminal to GH) to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. In an advantage of the foregoing, the sequence does not require subsequent cleavage, thereby reducing the number of steps to manufacture XTEN-containing compositions. As described in more detail in the Examples, the optimized N-terminal sequence has attributes of an unstructured protein, but may include nucleotide bases encoding amino acids selected for their ability to promote initiation of translation and enhanced expression. In one embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AE912. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AM923. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AE48. In another embodiment of the foregoing, the optimized polynucleotide encodes an XTEN sequence with at least about 90% sequence identity to AM48. In one embodiment, the optimized polynucleotide NTS comprises a sequence that exhibits at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, sequence identity to a sequence or its complement selected from
AE 48:
(SEQ ID NO: 134)
5′-
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCCGGG
TAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAA
CCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCA-3′
and
AM 48:
(SEQ ID NO: 135)
5′-
ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATCCCC
GGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCTA
CCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCA-3′
In another embodiment, the protease site of the leader sequence construct is chosen such that it is recognized by an in vivo protease. In this embodiment, the protein is purified from the expression system while retaining the leader by avoiding contact with an appropriate protease. The full-length construct is then injected into a patient. Upon injection, the construct comes into contact with the protease specific for the cleavage site and is cleaved by the protease. In the case where the uncleaved protein is substantially less active than the cleaved form, this method has the beneficial effect of allowing higher initial doses while avoiding toxicity, as the active form is generated slowly in vivo. Some non-limiting examples of in vivo proteases which are useful for this application include tissue kallikrein, plasma kallikrein, trypsin, pepsin, chymotrypsin, thrombin, and matrix metalloproteinases, or the proteases of Table 6.
In this manner, a chimeric DNA molecule coding for a monomeric GHXTEN fusion protein is generated within the construct. Optionally, this chimeric DNA molecule may be transferred or cloned into another construct that is a more appropriate expression vector. At this point, a host cell capable of expressing the chimeric DNA molecule can be transformed with the chimeric DNA molecule. The vectors containing the DNA segments of interest can be transferred into the host cell by well-known methods, depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment, lipofection, or electroporation may be used for other cellular hosts. Other methods used to transform mammalian cells include the use of polybrene, protoplast fusion, liposomes, electroporation, and microinjection. See, generally, Sambrook, et al., supra.
The transformation may occur with or without the utilization of a carrier, such as an expression vector. Then, the transformed host cell is cultured under conditions suitable for expression of the chimeric DNA molecule encoding of GHXTEN.
The present invention also provides a host cell for expressing the monomeric fusion protein compositions disclosed herein. Examples of suitable eukaryotic host cells include, but are not limited to mammalian cells, such as VERO cells, HELA cells such as ATCC No. CCL2, CHO cell lines, COS cells, WI38 cells, BHK cells, HepG2 cells, 3T3 cells, A549 cells, PC12 cells, K562 cells, 293 cells, Sf9 cells and CvI cells. Examples of suitable non-mammalian eukaryotic cells include eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published 31 Oct. 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 Jan. 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).
Other suitable cells that can be used in the present invention include, but are not limited to, prokaryotic host cells strains such as Escherichia coli, (e.g., strain DH5-α), Bacillus subtilis, Salmonella typhimurium, or strains of the genera of Pseudomonas, Streptomyces and Staphylococcus. Non-limiting examples of suitable prokaryotes include those from the genera: Actinoplanes; Archaeoglobus; Bdellovibrio; Borrelia; Chloroflexus; Enterococcus; Escherichia; Lactobacillus; Listeria; Oceanobacillus; Paracoccus; Pseudomonas; Staphylococcus; Streptococcus; Streptomyces; Thermoplasma; and Vibrio. Non-limiting examples of specific strains include: Archaeoglobus fulgidus; Bdellovibrio bacteriovorus; Borrelia burgdorferi; Chloroflexus aurantiacus; Enterococcus faecalis; Enterococcus faecium; Lactobacillus johnsonii; Lactobacillus plantarum; Lactococcus lactis; Listeria innocua; Listeria monocytogenes; Oceanobacillus iheyensis; Paracoccus zeaxanthinifaciens; Pseudomonas mevalonii; Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus haemolyticus; Streptococcus agalactiae; Streptomyces griseolosporeus; Streptococcus mutans; Streptococcus pneumoniae; Streptococcus pyogenes; Thermoplasma acidophilum; Thermoplasma volcanium; Vibrio cholerae; Vibrio parahaemolyticus; and Vibrio vulnificus.
Host cells containing the polynucleotides of interest can be cultured in conventional nutrient media (e.g., Ham's nutrient mixture) modified as appropriate for activating promoters, selecting transformants or amplifying genes. The culture conditions, such as temperature, pH and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. For compositions secreted by the host cells, supernatant from centrifugation is separated and retained for further purification. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents, all of which are well known to those skilled in the art. Embodiments that involve cell lysis may entail use of a buffer that contains protease inhibitors that limit degradation after expression of the chimeric DNA molecule. Suitable protease inhibitors include, but are not limited to leupeptin, pepstatin or aprotinin. The supernatant then may be precipitated in successively increasing concentrations of saturated ammonium sulfate.
Gene expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.
Gene expression, alternatively, may be measured by immunological of fluorescent methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids or the detection of selectable markers, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal Conveniently, the antibodies may be prepared against a native sequence GH polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to GH and encoding a specific antibody epitope. Examples of selectable markers are well known to one of skill in the art and include reporters such as enhanced green fluorescent protein (EGFP), beta-galactosidase (β-gal) or chloramphenicol acetyltransferase (CAT).
Expressed GHXTEN polypeptide product(s) may be purified via methods known in the art or by methods disclosed herein. Procedures such as gel filtration, affinity purification, salt fractionation, ion exchange chromatography, size exclusion chromatography, hydroxyapatite adsorption chromatography, hydrophobic interaction chromatography and gel electrophoresis may be used; each tailored to recover and purify the fusion protein produced by the respective host cells. Some expressed GHXTEN may require refolding during isolation and purification. Methods of purification are described in Robert K. Scopes, Protein Purification: Principles and Practice, Charles R. Castor (ed.), Springer-Verlag 1994, and Sambrook, et al., supra. Multi-step purification separations are also described in Baron, et al., Crit. Rev. Biotechnol. 10:179-90 (1990) and Below, et al., J. Chromatogr. A. 679:67-83 (1994).
VIII). Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising GHXTEN. In one embodiment, the pharmaceutical composition comprises the GHXTEN fusion protein and at least one pharmaceutically acceptable carrier. GHXTEN polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the polypeptide is combined in admixture with a pharmaceutically acceptable carrier vehicle, such as aqueous solutions or buffers, pharmaceutically acceptable suspensions and emulsions. Examples of non-aqueous solvents include propyl ethylene glycol, polyethylene glycol and vegetable oils. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers, as described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980), in the form of lyophilized formulations or aqueous solutions.
The pharmaceutical compositions can be administered orally, intranasally, parenterally or by inhalation therapy, and may take the form of tablets, lozenges, granules, capsules, pills, ampoules, suppositories or aerosol form. They may also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or nonaqueous diluents, syrups, granulates or powders. In addition, the pharmaceutical compositions can also contain other pharmaceutically active compounds or a plurality of compounds of the invention.
More particularly, the present pharmaceutical compositions may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, subcutaneous by infusion pump, intramuscular, intravenous and intradermal), intravitreal, and pulmonary. It will also be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated.
In one embodiment, the pharmaceutical composition is administered subcutaneously. In this embodiment, the composition may be supplied as a lyophilized powder to be reconstituted prior to administration. The composition may also be supplied in a liquid form, which can be administered directly to a patient. In one embodiment, the composition is supplied as a liquid in a pre-filled syringe such that a patient can easily self-administer the composition.
Extended release formulations useful in the present invention may be oral formulations comprising a matrix and a coating composition. Suitable matrix materials may include waxes (e.g., camauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and polyethylene glycol). Other suitable matrix tabletting materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose, with other carriers, and fillers. Tablets may also contain granulates, coated powders, or pellets. Tablets may also be multi-layered. Multi-layered tablets are especially preferred when the active ingredients have markedly different pharmacokinetic profiles. Optionally, the finished tablet may be coated or uncoated.
The coating composition may comprise an insoluble matrix polymer and/or a water soluble material. Water soluble materials can be polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, or monomeric materials such as sugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts (e.g., sodium chloride, potassium chloride and the like), organic acids (e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof. Optionally, an enteric polymer may be incorporated into the coating composition. Suitable enteric polymers include hydroxypropyl methyl cellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups. The coating composition may be plasticised by adding suitable plasticisers such as, for example, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutylsebacate, and castor oil. The coating composition may also include a filler, which can be an insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, or polacrilin potassium. The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Solvents such as water, lower alcohol, lower chlorinated hydrocarbons, ketones, or mixtures thereof may be used.
The compositions of the invention may be formulated using a variety of excipients. Suitable excipients include microcrystalline cellulose (e.g. Avicel PH102, Avicel PH101), polymethacrylate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (such as Eudragit RS-30D), hydroxypropyl methylcellulose (Methocel K100M, Premium CR Methocel K100M, Methocel E5, Opadry®), magnesium stearate, talc, triethyl citrate, aqueous ethylcellulose dispersion (Surelease®), and protamine sulfate. The slow release agent may also comprise a carrier, which can comprise, for example, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Pharmaceutically acceptable salts can also be used in these slow release agents, for example, mineral salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as the salts of organic acids such as acetates, proprionates, malonates, or benzoates. The composition may also contain liquids, such as water, saline, glycerol, and ethanol, as well as substances such as wetting agents, emulsifying agents, or pH buffering agents. Liposomes may also be used as a carrier.
In another embodiment, the compositions of the present invention are encapsulated in liposomes, which have demonstrated utility in delivering beneficial active agents in a controlled manner over prolonged periods of time. Liposomes are closed bilayer membranes containing an entrapped aqueous volume. Liposomes may also be unilamellar vesicles possessing a single membrane bilayer or multilamellar vesicles with multiple membrane bilayers, each separated from the next by an aqueous layer. The structure of the resulting membrane bilayer is such that the hydrophobic (non-polar) tails of the lipid are oriented toward the center of the bilayer while the hydrophilic (polar) heads orient towards the aqueous phase. In one embodiment, the liposome may be coated with a flexible water soluble polymer that avoids uptake by the organs of the mononuclear phagocyte system, primarily the liver and spleen. Suitable hydrophilic polymers for surrounding the liposomes include, without limitation, PEG, polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxethylacrylate, hydroxymethylcellulose hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and hydrophilic peptide sequences as described in U.S. Pat. Nos. 6,316,024; 6,126,966; 6,056,973; 6,043,094, the contents of which are incorporated by reference in their entirety.
Liposomes may be comprised of any lipid or lipid combination known in the art. For example, the vesicle-forming lipids may be naturally-occurring or synthetic lipids, including phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phasphatidylglycerol, phosphatidylinositol, and sphingomyelin as disclosed in U.S. Pat. Nos. 6,056,973 and 5,874,104. The vesicle-forming lipids may also be glycolipids, cerebrosides, or cationic lipids, such as 1,2-dioleyloxy-3-(trimethylamino) propane (DOTAP); N-[1-(2,3,-ditetradecyloxy)propyl-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N-[1[(2,3,-dioleyloxy)propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE); N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3[N-(N′,N′-dimethylaminoethane) carbamoly] cholesterol (DC-Chol); or dimethyldioctadecylammonium (DDAB) also as disclosed in U.S. Pat. No. 6,056,973. Cholesterol may also be present in the proper range to impart stability to the vesicle as disclosed in U.S. Pat. Nos. 5,916,588 and 5,874,104.
Additional liposomal technologies are described in U.S. Pat. Nos. 6,759,057; 6,406,713; 6,352,716; 6,316,024; 6,294,191; 6,126,966; 6,056,973; 6,043,094; 5,965,156; 5,916,588; 5,874,104; 5,215,680; and 4,684,479, the contents of which are incorporated herein by reference. These describe liposomes and lipid-coated microbubbles, and methods for their manufacture. Thus, one skilled in the art, considering both the disclosure of this invention and the disclosures of these other patents could produce a liposome for the extended release of the polypeptides of the present invention.
For liquid formulations, a desired property is that the formulation be supplied in a form that can pass through a 25, 28, 30, 31, 32 gauge needle for intravenous, intramuscular, intraarticular, or subcutaneous administration.
Administration via transdermal formulations can be performed using methods also known in the art, including those described generally in, e.g., U.S. Pat. Nos. 5,186,938 and 6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89/09051, incorporated herein by reference in their entireties. A transdermal patch is a particularly useful embodiment with polypeptides having absorption problems. Patches can be made to control the release of skin-permeable active ingredients over a 12 hour, 24 hour, 3 day, and 7 day period. In one example, a 2-fold daily excess of a polypeptide of the present invention is placed in a non-volatile fluid. The compositions of the invention are provided in the form of a viscous, non-volatile liquid. The penetration through skin of specific formulations may be measures by standard methods in the art (for example, Franz et al., J. Invest. Derm. 64:194-195 (1975)). Examples of suitable patches are passive transfer skin patches, iontophoretic skin patches, or patches with microneedles such as Nicoderm.
In other embodiments, the composition may be delivered via intranasal, buccal, or sublingual routes to the brain to enable transfer of the active agents through the olfactory passages into the CNS and reducing the systemic administration. Devices commonly used for this route of administration are included in U.S. Pat. No. 6,715,485. Compositions delivered via this route may enable increased CNS dosing or reduced total body burden reducing systemic toxicity risks associated with certain drugs. Preparation of a pharmaceutical composition for delivery in a subdermally implantable device can be performed using methods known in the art, such as those described in, e.g., U.S. Pat. Nos. 3,992,518; 5,660,848; and 5,756,115.
Osmotic pumps may be used as slow release agents in the form of tablets, pills, capsules or implantable devices. Osmotic pumps are well known in the art and readily available to one of ordinary skill in the art from companies experienced in providing osmotic pumps for extended release drug delivery. Examples are ALZA's DUROS™; ALZA's OROS™; Osmotica Pharmaceutical's Osmodex™ system; Shire Laboratories' EnSoTrol™ system; and Alzet™. Patents that describe osmotic pump technology are U.S. Pat. Nos. 6,890,918; 6,838,093; 6,814,979; 6,713,086; 6,534,090; 6,514,532; 6,361,796; 6,352,721; 6,294,201; 6,284,276; 6,110,498; 5,573,776; 4,200,0984; and 4,088,864, the contents of which are incorporated herein by reference. One skilled in the art, considering both the disclosure of this invention and the disclosures of these other patents could produce an osmotic pump for the extended release of the polypeptides of the present invention.
Syringe pumps may also be used as slow release agents. Such devices are described in U.S. Pat. Nos. 4,976,696; 4,933,185; 5,017,378; 6,309,370; 6,254,573; 4,435,173; 4,398,908; 6,572,585; 5,298,022; 5,176,502; 5,492,534; 5,318,540; and 4,988,337, the contents of which are incorporated herein by reference. One skilled in the art, considering both the disclosure of this invention and the disclosures of these other patents could produce a syringe pump for the extended release of the compositions of the present invention. A.
IX). Pharmaceutical Kits In another aspect, the invention provides a kit to facilitate the use of the GHXTEN polypeptides. The kit comprises the pharmaceutical composition provided herein, a label identifying the pharmaceutical composition, and an instruction for storage, reconstitution and/or administration of the pharmaceutical compositions to a subject In some embodiment, the kit comprises, preferablly: (a) an amount of a GHXTEN fusion protein composition sufficient to treat a disease, condition or disorder upon administration to a subject in need thereof; and (b) an amount of a pharmaceutically acceptable carrier; together in a formulation ready for injection or for reconstitution with sterile water, buffer, or dextrose; together with a label identifying the GHXTEN drug and storage and handling conditions, and a sheet of the approved indications for the drug, instructions for the reconstitution and/or administration of the GHXTEN drug for the use for the prevention and/or treatment of a approved indication, appropriate dosage and safety information, and information identifying the lot and expiration of the drug. In another embodiment of the foregoing, the kit can comprise a second container that can carry a suitable diluent for the GHXTEN composition, which will provide the user with the appropriate concentration of GHXTEN to be delivered to the subject.
EXAMPLES Example 1 Construction of XTEN_AD36 Motif Segments The following example describes the construction of a collection of codon-optimized genes encoding motif sequences of 36 amino acids. As a first step, a stuffer vector pCW0359 was constructed based on a pET vector and that includes a T7 promoter. pCW0359 encodes a cellulose binding domain (CBD) and a TEV protease recognition site followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites. The BsaI and BbsI sites were inserted such that they generate compatible overhangs after digestion. The stuffer sequence is followed by a truncated version of the GFP gene and a His tag. The stuffer sequence contains stop codons and thus E. coli cells carrying the stuffer plasmid pCW0359 form non-fluorescent colonies. The stuffer vector pCW0359 was digested with BsaI and KpnI to remove the stuffer segment and the resulting vector fragment was isolated by agarose gel purification. The sequences were designated XTEN_AD36, reflecting the AD family of motifs. Its segments have the amino acid sequence [X]3 where X is a 12mer peptide with the sequences: GESPGGSSGSES (SEQ ID NO: 136), GSEGSSGPGESS (SEQ ID NO: 137), GSSESGSSEGGP (SEQ ID NO: 138), or GSGGEPSESGSS (SEQ ID NO: 139). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:
AD1for:
(SEQ ID NO: 140)
AGGTGAATCTCCDGGTGGYTCYAGCGGTTCYGARTC
AD1rev:
(SEQ ID NO: 141)
ACCTGAYTCRGAACCGCTRGARCCACCHGGAGATTC
AD2for:
(SEQ ID NO: 142)
AGGTAGCGAAGGTTCTTCYGGTCCDGGYGARTCYTC
AD2rev:
(SEQ ID NO: 143)
ACCTGARGAYTCRCCHGGACCRGAAGAACCTTCGCT
AD3for:
(SEQ ID NO: 144)
AGGTTCYTCYGAAAGCGGTTCTTCYGARGGYGGTCC
AD3rev:
(SEQ ID NO: 145)
ACCTGGACCRCCYTCRGAAGAACCGCTTTCRGARGA
AD4for:
(SEQ ID NO: 146)
AGGTTCYGGTGGYGAACCDTCYGARTCTGGTAGCTC
We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 147) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 148). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0401 showed green fluorescence after induction, which shows that the sequence of XTEN_AD36 had been ligated in frame with the GFP gene and that most sequences of XTEN_AD36 had good expression levels.
We screened 96 isolates from library LCW0401 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 39 clones were identified that contained correct XTEN_AD36 segments. The file names of the nucleotide and amino acid constructs for these segments are listed in Table 8.
TABLE 8
DNA and Amino Acid Sequences for 36-mer motifs
SEQ ID SEQ ID
File name Amino acid sequence NO: Nucleotide sequence NO:
LCW0401_001_GFP- GSGGEPSESGSSGESPGG 149 GGTTCTGGTGGCGAACCGTCCGAG 150
N_A01.ab1 SSGSESGESPGGSSGSES TCTGGTAGCTCAGGTGAATCTCCG
GGTGGCTCTAGCGGTTCCGAGTCA
GGTGAATCTCCTGGTGGTTCCAGC
GGTTCCGAGTCA
LCW0401_002_GFP- GSEGSSGPGESSGESPGG 151 GGTAGCGAAGGTTCTTCTGGTCCTG 152
N_B01.ab1 SSGSESGSSESGSSEGGP GCGAGTCTTCAGGTGAATCTCCTG
GTGGTTCCAGCGGTTCTGAATCAG
GTTCCTCCGAAAGCGGTTCTTCCGA
GGGCGGTCCA
LCW0401_003_GFP- GSSESGSSEGGPGSSESG 153 GGTTCCTCTGAAAGCGGTTCTTCCG 154
N_C01.ab1 SSEGGPGESPGGSSGSES AAGGTGGTCCAGGTTCCTCTGAAA
GCGGTTCTTCTGAGGGTGGTCCAG
GTGAATCTCCGGGTGGCTCCAGCG
GTTCCGAGTCA
LCW0401_004_GFP- GSGGEPSESGSSGSSESG 155 GGTTCCGGTGGCGAACCGTCTGAA 156
N_D01.ab1 SSEGGPGSGGEPSESGSS TCTGGTAGCTCAGGTTCTTCTGAAA
GCGGTTCTTCCGAGGGTGGTCCAG
GTTCTGGTGGTGAACCTTCCGAGTC
TGGTAGCTCA
LCW0401_007_GFP- GSSESGSSEGGPGSEGSS 157 GGTTCTTCCGAAAGCGGTTCTTCTG 158
N_F01.ab1 GPGESSGSEGSSGPGESS AGGGTGGTCCAGGTAGCGAAGGTT
CTTCCGGTCCAGGTGAGTCTTCAGG
TAGCGAAGGTTCTTCTGGTCCTGGT
GAATCTTCA
LCW0401_008_GFP- GSSESGSSEGGPGESPGG 159 GGTTCCTCTGAAAGCGGTTCTTCCG 160
N_G01.ab1 SSGSESGSEGSSGPGESS AGGGTGGTCCAGGTGAATCTCCAG
GTGGTTCCAGCGGTTCTGAGTCAG
GTAGCGAAGGTTCTTCTGGTCCAG
GTGAATCCTCA
LCW0401_012_GFP- GSGGEPSESGSSGSGGEP 161 GGTTCTGGTGGTGAACCGTCTGAG 162
N_H01.ab1 SESGSSGSEGSSGPGESS TCTGGTAGCTCAGGTTCCGGTGGC
GAACCATCCGAATCTGGTAGCTCA
GGTAGCGAAGGTTCTTCCGGTCCA
GGTGAGTCTTCA
LCW0401_015_GFP- GSSESGSSEGGPGSEGSS 163 GGTTCTTCCGAAAGCGGTTCTTCCG 164
N_A02.ab1 GPGESSGESPGGSSGSES AAGGCGGTCCAGGTAGCGAAGGTT
CTTCTGGTCCAGGCGAATCTTCAGG
TGAATCTCCTGGTGGCTCCAGCGGT
TCTGAGTCA
LCW0401_016_GFP- GSSESGSSEGGPGSSESG 165 GGTTCCTCCGAAAGCGGTTCTTCTG 166
N_B02.ab1 SSEGGPGSSESGSSEGGP AGGGCGGTCCAGGTTCCTCCGAAA
GCGGTTCTTCCGAGGGCGGTCCAG
GTTCTTCTGAAAGCGGTTCTTCCGA
GGGCGGTCCA
LCW0401_020_GFP- GSGGEPSESGSSGSEGSS 167 GGTTCCGGTGGCGAACCGTCCGAA 168
N_E02.ab1 GPGESSGSSESGSSEGGP TCTGGTAGCTCAGGTAGCGAAGGT
TCTTCTGGTCCAGGCGAATCTTCAG
GTTCCTCTGAAAGCGGTTCTTCTGA
GGGCGGTCCA
LCW0401_022_GFP- GSGGEPSESGSSGSSESG 169 GGTTCTGGTGGTGAACCGTCCGAA 170
N_F02.ab1 SSEGGPGSGGEPSESGSS TCTGGTAGCTCAGGTTCTTCCGAAA
GCGGTTCTTCTGAAGGTGGTCCAG
GTTCCGGTGGCGAACCTTCTGAATC
TGGTAGCTCA
LCW0401_024_GFP- GSGGEPSESGSSGSSESG 171 GGTTCTGGTGGCGAACCGTCCGAA 172
N_G02.ab1 SSEGGPGESPGGSSGSES TCTGGTAGCTCAGGTTCCTCCGAAA
GCGGTTCTTCTGAAGGTGGTCCAG
GTGAATCTCCAGGTGGTTCTAGCG
GTTCTGAATCA
LCW0401_026_GFP- GSGGEPSESGSSGESPGG 173 GGTTCTGGTGGCGAACCGTCTGAG 174
N_H02.ab1 SSGSESGSEGSSGPGESS TCTGGTAGCTCAGGTGAATCTCCTG
GTGGCTCCAGCGGTTCTGAATCAG
GTAGCGAAGGTTCTTCTGGTCCTGG
TGAATCTTCA
LCW0401_027_GFP- GSGGEPSESGSSGESPGG 175 GGTTCCGGTGGCGAACCTTCCGAA 176
N_A03.ab1 SSGSESGSGGEPSESGSS TCTGGTAGCTCAGGTGAATCTCCG
GGTGGTTCTAGCGGTTCTGAGTCA
GGTTCTGGTGGTGAACCTTCCGAGT
CTGGTAGCTCA
LCW0401_028_GFP- GSSESGSSEGGPGSSESG 177 GGTTCCTCTGAAAGCGGTTCTTCTG 178
N_B03.ab1 SSEGGPGSSESGSSEGGP AGGGCGGTCCAGGTTCTTCCGAAA
GCGGTTCTTCCGAGGGCGGTCCAG
GTTCTTCCGAAAGCGGTTCTTCTGA
AGGCGGTCCA
LCW0401_030_GFP- GESPGGSSGSESGSEGSS 179 GGTGAATCTCCGGGTGGCTCCAGC 180
N_C03.ab1 GPGESSGSEGSSGPGESS GGTTCTGAGTCAGGTAGCGAAGGT
TCTTCCGGTCCGGGTGAGTCCTCAG
GTAGCGAAGGTTCTTCCGGTCCTG
GTGAGTCTTCA
LCW0401_031_GFP- GSGGEPSESGSSGSGGEP 181 GGTTCTGGTGGCGAACCTTCCGAA 182
N_D03.ab1 SESGSSGSSESGSSEGGP TCTGGTAGCTCAGGTTCCGGTGGTG
AACCTTCTGAATCTGGTAGCTCAG
GTTCTTCTGAAAGCGGTTCTTCCGA
GGGCGGTCCA
LCW0401_033_GFP- GSGGEPSESGSSGSGGEP 183 GGTTCCGGTGGTGAACCTTCTGAAT 184
N_E03.ab1 SESGSSGSGGEPSESGSS CTGGTAGCTCAGGTTCCGGTGGCG
AACCATCCGAGTCTGGTAGCTCAG
GTTCCGGTGGTGAACCATCCGAGT
CTGGTAGCTCA
LCW0401_037_GFP- GSGGEPSESGSSGSSESG 185 GGTTCCGGTGGCGAACCTTCTGAA 186
N_F03.ab1 SSEGGPGSEGSSGPGESS TCTGGTAGCTCAGGTTCCTCCGAAA
GCGGTTCTTCTGAGGGCGGTCCAG
GTAGCGAAGGTTCTTCTGGTCCGG
GCGAGTCTTCA
LCW0401_038_GFP- GSGGEPSESGSSGSEGSS 187 GGTTCCGGTGGTGAACCGTCCGAG 188
N_G03.ab1 GPGESSGSGGEPSESGSS TCTGGTAGCTCAGGTAGCGAAGGT
TCTTCTGGTCCGGGTGAGTCTTCAG
GTTCTGGTGGCGAACCGTCCGAAT
CTGGTAGCTCA
LCW0401_039_GFP- GSGGEPSESGSSGESPGG 189 GGTTCTGGTGGCGAACCGTCCGAA 190
N_H03.ab1 SSGSESGSGGEPSESGSS TCTGGTAGCTCAGGTGAATCTCCTG
GTGGTTCCAGCGGTTCCGAGTCAG
GTTCTGGTGGCGAACCTTCCGAATC
TGGTAGCTCA
LCW0401_040_GFP- GSSESGSSEGGPGSGGEP 191 GGTTCTTCCGAAAGCGGTTCTTCCG 192
N_A04.ab1 SESGSSGSSESGSSEGGP AGGGCGGTCCAGGTTCCGGTGGTG
AACCATCTGAATCTGGTAGCTCAG
GTTCTTCTGAAAGCGGTTCTTCTGA
AGGTGGTCCA
LCW0401_042_GFP- GSEGSSGPGESSGESPGG 193 GGTAGCGAAGGTTCTTCCGGTCCT 194
N_C04.ab1 SSGSESGSEGSSGPGESS GGTGAGTCTTCAGGTGAATCTCCA
GGTGGCTCTAGCGGTTCCGAGTCA
GGTAGCGAAGGTTCTTCTGGTCCTG
GCGAGTCCTCA
LCW0401_046_GFP- GSSESGSSEGGPGSSESG 195 GGTTCCTCTGAAAGCGGTTCTTCCG 196
N_D04.ab1 SSEGGPGSSESGSSEGGP AAGGCGGTCCAGGTTCTTCCGAAA
GCGGTTCTTCTGAGGGCGGTCCAG
GTTCCTCCGAAAGCGGTTCTTCTGA
GGGTGGTCCA
LCW0401_047_GFP- GSGGEPSESGSSGESPGG 197 GGTTCTGGTGGCGAACCTTCCGAG 198
N_E04.ab1 SSGSESGESPGGSSGSES TCTGGTAGCTCAGGTGAATCTCCG
GGTGGTTCTAGCGGTTCCGAGTCA
GGTGAATCTCCGGGTGGTTCCAGC
GGTTCTGAGTCA
LCW0401_051_GFP- GSGGEPSESGSSGSEGSS 199 GGTTCTGGTGGCGAACCATCTGAG 200
N_F04.ab1 GPGESSGESPGGSSGSES TCTGGTAGCTCAGGTAGCGAAGGT
TCTTCCGGTCCAGGCGAGTCTTCAG
GTGAATCTCCTGGTGGCTCCAGCG
GTTCTGAGTCA
LCW0401_053_GFP- GESPGGSSGSESGESPGG 201 GGTGAATCTCCTGGTGGTTCCAGC 202
N_H04.ab1 SSGSESGESPGGSSGSES GGTTCCGAGTCAGGTGAATCTCCA
GGTGGCTCTAGCGGTTCCGAGTCA
GGTGAATCTCCTGGTGGTTCTAGCG
GTTCTGAATCA
LCW0401_054_GFP- GSEGSSGPGESSGSEGSS 203 GGTAGCGAAGGTTCTTCCGGTCCA 204
N_A05.ab1 GPGESSGSGGEPSESGSS GGTGAATCTTCAGGTAGCGAAGGT
TCTTCTGGTCCTGGTGAATCCTCAG
GTTCCGGTGGCGAACCATCTGAAT
CTGGTAGCTCA
LCW0401_059_GFP- GSGGEPSESGSSGSEGSS 205 GGTTCTGGTGGCGAACCATCCGAA 206
N_D05.ab1 GPGESSGESPGGSSGSES TCTGGTAGCTCAGGTAGCGAAGGT
TCTTCTGGTCCTGGCGAATCTTCAG
GTGAATCTCCAGGTGGCTCTAGCG
GTTCCGAATCA
LCW0401_060_GFP- GSGGEPSESGSSGSSESG 207 GGTTCCGGTGGTGAACCGTCCGAA 208
N_E05.ab1 SSEGGPGSGGEPSESGSS TCTGGTAGCTCAGGTTCCTCTGAAA
GCGGTTCTTCCGAGGGTGGTCCAG
GTTCCGGTGGTGAACCTTCTGAGTC
TGGTAGCTCA
LCW0401_061_GFP- GSSESGSSEGGPGSGGEP 209 GGTTCCTCTGAAAGCGGTTCTTCTG 210
N_F05.ab1 SESGSSGSEGSSGPGESS AGGGCGGTCCAGGTTCTGGTGGCG
AACCATCTGAATCTGGTAGCTCAG
GTAGCGAAGGTTCTTCCGGTCCGG
GTGAATCTTCA
LCW0401_063_GFP- GSGGEPSESGSSGSEGSS 211 GGTTCTGGTGGTGAACCGTCCGAA 212
N_H05.ab1 GPGESSGSEGSSGPGESS TCTGGTAGCTCAGGTAGCGAAGGT
TCTTCTGGTCCTGGCGAGTCTTCAG
GTAGCGAAGGTTCTTCTGGTCCTGG
TGAATCTTCA
LCW0401_066_GFP- GSGGEPSESGSSGSSESG 213 GGTTCTGGTGGCGAACCATCCGAG 214
N_B06.ab1 SSEGGPGSGGEPSESGSS TCTGGTAGCTCAGGTTCTTCCGAAA
GCGGTTCTTCCGAAGGCGGTCCAG
GTTCTGGTGGTGAACCGTCCGAAT
CTGGTAGCTCA
LCW0401_067_GFP- GSGGEPSESGSSGESPGG 215 GGTTCCGGTGGCGAACCTTCCGAA 216
N_C06.ab1 SSGSESGESPGGSSGSES TCTGGTAGCTCAGGTGAATCTCCG
GGTGGTTCTAGCGGTTCCGAATCA
GGTGAATCTCCAGGTGGTTCTAGC
GGTTCCGAATCA
LCW0401_069_GFP- GSGGEPSESGSSGSGGEP 217 GGTTCCGGTGGTGAACCATCTGAG 218
N_D06.ab1 SESGSSGESPGGSSGSES TCTGGTAGCTCAGGTTCCGGTGGC
GAACCGTCCGAGTCTGGTAGCTCA
GGTGAATCTCCGGGTGGTTCCAGC
GGTTCCGAATCA
LCW0401_070_GFP- GSEGSSGPGESSGSSESG 219 GGTAGCGAAGGTTCTTCTGGTCCG 220
N_E06.ab1 SSEGGPGSEGSSGPGESS GGCGAATCCTCAGGTTCCTCCGAA
AGCGGTTCTTCCGAAGGTGGTCCA
GGTAGCGAAGGTTCTTCCGGTCCT
GGTGAATCTTCA
LCW0401_078_GFP- GSSESGSSEGGPGESPGG 221 GGTTCCTCTGAAAGCGGTTCTTCTG 222
N_F06.ab1 SSGSESGESPGGSSGSES AAGGCGGTCCAGGTGAATCTCCGG
GTGGCTCCAGCGGTTCTGAATCAG
GTGAATCTCCTGGTGGCTCCAGCG
GTTCCGAGTCA
LCW0401_079_GFP- GSEGSSGPGESSGSEGSS 223 GGTAGCGAAGGTTCTTCTGGTCCA 224
N_G06.ab1 GPGESSGSGGEPSESGSS GGCGAGTCTTCAGGTAGCGAAGGT
TCTTCCGGTCCTGGCGAGTCTTCAG
GTTCCGGTGGCGAACCGTCCGAAT
CTGGTAGCTCA
Example 2 Construction of XTEN_AE36 Segments A codon library encoding XTEN sequences of 36 amino acid length was constructed. The XTEN sequence was designated XTEN_AE36. Its segments have the amino acid sequence [X]3 where X is a 12mer peptide with the sequence: GSPAGSPTSTEE (SEQ ID NO: 225), GSEPATSGSE TP (SEQ ID NO: 226), GTSESA TPESGP (SEQ ID NO: 227), or GTSTEPSEGSAP (SEQ ID NO: 228). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:
AE1for:
(SEQ ID NO: 229)
AGGTAGCCCDGCWGGYTCTCCDACYTCYACYGARGA
AE1rev:
(SEQ ID NO: 230)
ACCTTCYTCRGTRGARGTHGGAGARCCWGCHGGGCT
AE2for:
(SEQ ID NO: 231)
AGGTAGCGAACCKGCWACYTCYGGYTCTGARACYCC
AE2rev:
(SEQ ID NO: 232)
ACCTGGRGTYTCAGARCCRGARGTWGCMGGTTCGCT
AE3for:
(SEQ ID NO: 233)
AGGTACYTCTGAAAGCGCWACYCCKGARTCYGGYCC
AE3rev:
(SEQ ID NO: 234)
ACCTGGRCCRGAYTCMGGRGTWGCGCTTTCAGARGT
AE4for:
(SEQ ID NO: 235)
AGGTACYTCTACYGAACCKTCYGARGGYAGCGCWCC
AE4rev:
(SEQ ID NO: 236)
ACCTGGWGCGCTRCCYTCRGAMGGTTCRGTAGARGT
We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 237) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 238). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0402 showed green fluorescence after induction which shows that the sequence of XTEN_AE36 had been ligated in frame with the GFP gene and most sequences of XTEN_AE36 show good expression.
We screened 96 isolates from library LCW0402 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 37 clones were identified that contained correct XTEN_AE36 segments. The file names of the nucleotide and amino acid constructs for these segments are listed in Table 9.
TABLE 9
DNA and Amino Acid Sequences for 36-mer motifs
SEQ ID SEQ ID
File name Amino acid sequence NO: Nucleotide sequence NO:
LCW0402_002_GFP- GSPAGSPTSTEEGTSE 239 GGTAGCCCGGCAGGCTCTCCGACCT 240
N_A07.ab1 SATPESGPGTSTEPSE CTACTGAGGAAGGTACTTCTGAAAG
GSAP CGCAACCCCGGAGTCCGGCCCAGGT
ACCTCTACCGAACCGTCTGAGGGCA
GCGCACCA
LCW0402_003_GFP- GTSTEPSEGSAPGTST 241 GGTACTTCTACCGAACCGTCCGAAG 242
N_B07.ab1 EPSEGSAPGTSTEPSE GCAGCGCTCCAGGTACCTCTACTGA
GSAP ACCTTCCGAGGGCAGCGCTCCAGGT
ACCTCTACCGAACCTTCTGAAGGTA
GCGCACCA
LCW0402_004_GFP- GTSTEPSEGSAPGTSE 243 GGTACCTCTACCGAACCGTCTGAAG 244
N_C07.ab1 SATPESGPGTSESATP GTAGCGCACCAGGTACCTCTGAAAG
ESGP CGCAACTCCTGAGTCCGGTCCAGGT
ACTTCTGAAAGCGCAACCCCGGAGT
CTGGCCCA
LCW0402_005_GFP- GTSTEPSEGSAPGTSE 245 GGTACTTCTACTGAACCGTCTGAAG 246
N_D07.ab1 SATPESGPGTSESATP GTAGCGCACCAGGTACTTCTGAAAG
ESGP CGCAACCCCGGAATCCGGCCCAGGT
ACCTCTGAAAGCGCAACCCCGGAGT
CCGGCCCA
LCW0402_006_GFP- GSEPATSGSETPGTSE 247 GGTAGCGAACCGGCAACCTCCGGCT 248
N_E07.ab1 SATPESGPGSPAGSPT CTGAAACCCCAGGTACCTCTGAAAG
STEE CGCTACTCCTGAATCCGGCCCAGGT
AGCCCGGCAGGTTCTCCGACTTCCA
CTGAGGAA
LCW0402_008_GFP- GTSESATPESGPGSEP 249 GGTACTTCTGAAAGCGCAACCCCTG 250
N_F07.ab1 ATSGSETPGTSTEPSE AATCCGGTCCAGGTAGCGAACCGGC
GSAP TACTTCTGGCTCTGAGACTCCAGGT
ACTTCTACCGAACCGTCCGAAGGTA
GCGCACCA
LCW0402_009_GFP- GSPAGSPTSTEEGSPA 251 GGTAGCCCGGCTGGCTCTCCAACCT 252
N_G07.ab1 GSPTSTEEGSEPATSG CCACTGAGGAAGGTAGCCCGGCTGG
SETP CTCTCCAACCTCCACTGAAGAAGGT
AGCGAACCGGCTACCTCCGGCTCTG
AAACTCCA
LCW0402_011_GFP- GSPAGSPTSTEEGTSE 253 GGTAGCCCGGCTGGCTCTCCTACCT 254
N_A08.ab1 SATPESGPGTSTEPSE CTACTGAGGAAGGTACTTCTGAAAG
GSAP CGCTACTCCTGAGTCTGGTCCAGGT
ACCTCTACTGAACCGTCCGAAGGTA
GCGCTCCA
LCW0402_012_GFP- GSPAGSPTSTEEGSPA 255 GGTAGCCCTGCTGGCTCTCCGACTT 256
N_B08.ab1 GSPTSTEEGTSTEPSE CTACTGAGGAAGGTAGCCCGGCTGG
GSAP TTCTCCGACTTCTACTGAGGAAGGT
ACTTCTACCGAACCTTCCGAAGGTA
GCGCTCCA
LCW0402_013_GFP- GTSESATPESGPGTST 257 GGTACTTCTGAAAGCGCTACTCCGG 258
N_C08.ab1 EPSEGSAPGTSTEPSE AGTCCGGTCCAGGTACCTCTACCGA
GSAP ACCGTCCGAAGGCAGCGCTCCAGGT
ACTTCTACTGAACCTTCTGAGGGTA
GCGCTCCA
LCW0402_014_GFP- GTSTEPSEGSAPGSPA 259 GGTACCTCTACCGAACCTTCCGAAG 260
N_D08.ab1 GSPTSTEEGTSTEPSE GTAGCGCTCCAGGTAGCCCGGCAGG
GSAP TTCTCCTACTTCCACTGAGGAAGGT
ACTTCTACCGAACCTTCTGAGGGTA
GCGCACCA
LCW0402_015_GFP- GSEPATSGSETPGSPA 261 GGTAGCGAACCGGCTACTTCCGGCT 262
N_E08.ab1 GSPTSTEEGTSESATP CTGAGACTCCAGGTAGCCCTGCTGG
ESGP CTCTCCGACCTCTACCGAAGAAGGT
ACCTCTGAAAGCGCTACCCCTGAGT
CTGGCCCA
LCW0402_016_GFP- GTSTEPSEGSAPGTSE 263 GGTACTTCTACCGAACCTTCCGAGG 264
N_F08.ab1 SATPESGPGTSESATP GCAGCGCACCAGGTACTTCTGAAAG
ESGP CGCTACCCCTGAGTCCGGCCCAGGT
ACTTCTGAAAGCGCTACTCCTGAAT
CCGGTCCA
LCW0402_020_GFP- GTSTEPSEGSAPGSEP 265 GGTACTTCTACTGAACCGTCTGAAG 266
N_G08.ab1 ATSGSETPGSPAGSPT GCAGCGCACCAGGTAGCGAACCGG
STEE CTACTTCCGGTTCTGAAACCCCAGG
TAGCCCAGCAGGTTCTCCAACTTCT
ACTGAAGAA
LCW0402_023_GFP- GSPAGSPTSTEEGTSE 267 GGTAGCCCTGCTGGCTCTCCAACCT 268
N_A09.ab1 SATPESGPGSEPATSG CCACCGAAGAAGGTACCTCTGAAAG
SETP CGCAACCCCTGAATCCGGCCCAGGT
AGCGAACCGGCAACCTCCGGTTCTG
AAACCCCA
LCW0402_024_GFP- GTSESATPESGPGSPA 269 GGTACTTCTGAAAGCGCTACTCCTG 270
N_B09.ab1 GSPTSTEEGSPAGSPT AGTCCGGCCCAGGTAGCCCGGCTGG
STEE CTCTCCGACTTCCACCGAGGAAGGT
AGCCCGGCTGGCTCTCCAACTTCTA
CTGAAGAA
LCW0402_025_GFP- GTSTEPSEGSAPGTSE 271 GGTACCTCTACTGAACCTTCTGAGG 272
N_C09.ab1 SATPESGPGTSTEPSE GCAGCGCTCCAGGTACTTCTGAAAG
GSAP CGCTACCCCGGAGTCCGGTCCAGGT
ACTTCTACTGAACCGTCCGAAGGTA
GCGCACCA
LCW0402_026_GFP- GSPAGSPTSTEEGTST 273 GGTAGCCCGGCAGGCTCTCCGACTT 274
N_D09.ab1 EPSEGSAPGSEPATSG CCACCGAGGAAGGTACCTCTACTGA
SETP ACCTTCTGAGGGTAGCGCTCCAGGT
AGCGAACCGGCAACCTCTGGCTCTG
AAACCCCA
LCW0402_027_GFP- GSPAGSPTSTEEGTST 275 GGTAGCCCAGCAGGCTCTCCGACTT 276
N_E09.ab1 EPSEGSAPGTSTEPSE CCACTGAGGAAGGTACTTCTACTGA
GSAP ACCTTCCGAAGGCAGCGCACCAGGT
ACCTCTACTGAACCTTCTGAGGGCA
GCGCTCCA
LCW0402_032_GFP- GSEPATSGSETPGTSE 277 GGTAGCGAACCTGCTACCTCCGGTT 278
N_H09.ab1 SATPESGPGSPAGSPT CTGAAACCCCAGGTACCTCTGAAAG
STEE CGCAACTCCGGAGTCTGGTCCAGGT
AGCCCTGCAGGTTCTCCTACCTCCA
CTGAGGAA
LCW0402_034_GFP- GTSESATPESGPGTST 279 GGTACCTCTGAAAGCGCTACTCCGG 280
N_A10.ab1 EPSEGSAPGTSTEPSE AGTCTGGCCCAGGTACCTCTACTGA
GSAP ACCGTCTGAGGGTAGCGCTCCAGGT
ACTTCTACTGAACCGTCCGAAGGTA
GCGCACCA
LCW0402_036_GFP- GSPAGSPTSTEEGTST 281 GGTAGCCCGGCTGGTTCTCCGACTT 282
N_C10.ab1 EPSEGSAPGTSTEPSE CCACCGAGGAAGGTACCTCTACTGA
GSAP ACCTTCTGAGGGTAGCGCTCCAGGT
ACCTCTACTGAACCTTCCGAAGGCA
GCGCTCCA
LCW0402_039_GFP- GTSTEPSEGSAPGTST 283 GGTACTTCTACCGAACCGTCCGAGG 284
N_E10.ab1 EPSEGSAPGTSTEPSE GCAGCGCTCCAGGTACTTCTACTGA
GSAP ACCTTCTGAAGGCAGCGCTCCAGGT
ACTTCTACTGAACCTTCCGAAGGTA
GCGCACCA
LCW0402_040_GFP- GSEPATSGSETPGTSE 285 GGTAGCGAACCTGCAACCTCTGGCT 286
N_F10.ab1 SATPESGPGTSTEPSE CTGAAACCCCAGGTACCTCTGAAAG
GSAP CGCTACTCCTGAATCTGGCCCAGGT
ACTTCTACTGAACCGTCCGAGGGCA
GCGCACCA
LCW0402_041_GFP- GTSTEPSEGSAPGSPA 287 GGTACTTCTACCGAACCGTCCGAGG 288
N_G10.ab1 GSPTSTEEGTSTEPSE GTAGCGCACCAGGTAGCCCAGCAG
GSAP GTTCTCCTACCTCCACCGAGGAAGG
TACTTCTACCGAACCGTCCGAGGGT
AGCGCACCA
LCW0402_050_GFP- GSEPATSGSETPGTSE 289 GGTAGCGAACCGGCAACCTCCGGCT 290
N_A11.ab1 SATPESGPGSEPATSG CTGAAACTCCAGGTACTTCTGAAAG
SETP CGCTACTCCGGAATCCGGCCCAGGT
AGCGAACCGGCTACTTCCGGCTCTG
AAACCCCA
LCW0402_051_GFP- GSEPATSGSETPGTSE 291 GGTAGCGAACCGGCAACTTCCGGCT 292
N_B11.ab1 SATPESGPGSEPATSG CTGAAACCCCAGGTACTTCTGAAAG
SETP CGCTACTCCTGAGTCTGGCCCAGGT
AGCGAACCTGCTACCTCTGGCTCTG
AAACCCCA
LCW0402_059_GFP- GSEPATSGSETPGSEP 293 GGTAGCGAACCGGCAACCTCTGGCT 294
N_E11.ab1 ATSGSETPGTSTEPSE CTGAAACTCCAGGTAGCGAACCTGC
GSAP AACCTCCGGCTCTGAAACCCCAGGT
ACTTCTACTGAACCTTCTGAGGGCA
GCGCACCA
LCW0402_060_GFP- GTSESATPESGPGSEP 295 GGTACTTCTGAAAGCGCTACCCCGG 296
N_F11.ab1 ATSGSETPGSEPATSG AATCTGGCCCAGGTAGCGAACCGGC
SETP TACTTCTGGTTCTGAAACCCCAGGT
AGCGAACCGGCTACCTCCGGTTCTG
AAACTCCA
LCW0402_061_GFP- GTSTEPSEGSAPGTST 297 GGTACCTCTACTGAACCTTCCGAAG 298
N_G11.ab1 EPSEGSAPGTSESATP GCAGCGCTCCAGGTACCTCTACCGA
ESGP ACCGTCCGAGGGCAGCGCACCAGGT
ACTTCTGAAAGCGCAACCCCTGAAT
CCGGTCCA
LCW0402_065_GFP- GSEPATSGSETPGTSE 299 GGTAGCGAACCGGCAACCTCTGGCT 300
N_A12.ab1 SATPESGPGTSESATP CTGAAACCCCAGGTACCTCTGAAAG
ESGP CGCTACTCCGGAATCTGGTCCAGGT
ACTTCTGAAAGCGCTACTCCGGAAT
CCGGTCCA
LCW0402_066_GFP- GSEPATSGSETPGSEP 301 GGTAGCGAACCTGCTACCTCCGGCT 302
N_B12.ab1 ATSGSETPGTSTEPSE CTGAAACTCCAGGTAGCGAACCGGC
GSAP TACTTCCGGTTCTGAAACTCCAGGT
ACCTCTACCGAACCTTCCGAAGGCA
GCGCACCA
LCW0402_067_GFP- GSEPATSGSETPGTST 303 GGTAGCGAACCTGCTACTTCTGGTT 304
N_C12.ab1 EPSEGSAPGSEPATSG CTGAAACTCCAGGTACTTCTACCGA
SETP ACCGTCCGAGGGTAGCGCTCCAGGT
AGCGAACCTGCTACTTCTGGTTCTG
AAACTCCA
LCW0402_069_GFP- GTSTEPSEGSAPGTST 305 GGTACCTCTACCGAACCGTCCGAGG 306
N_D12.ab1 EPSEGSAPGSEPATSG GTAGCGCACCAGGTACCTCTACTGA
SETP ACCGTCTGAGGGTAGCGCTCCAGGT
AGCGAACCGGCAACCTCCGGTTCTG
AAACTCCA
LCW0402_073_GFP- GTSTEPSEGSAPGSEP 307 GGTACTTCTACTGAACCTTCCGAAG 308
N_F12.ab1 ATSGSETPGSPAGSPT GTAGCGCTCCAGGTAGCGAACCTGC
STEE TACTTCTGGTTCTGAAACCCCAGGT
AGCCCGGCTGGCTCTCCGACCTCCA
CCGAGGAA
LCW0402_074_GFP- GSEPATSGSETPGSPA 309 GGTAGCGAACCGGCTACTTCCGGCT 310
N_G12.ab1 GSPTSTEEGTSESATP CTGAGACTCCAGGTAGCCCAGCTGG
ESGP TTCTCCAACCTCTACTGAGGAAGGT
ACTTCTGAAAGCGCTACCCCTGAAT
CTGGTCCA
LCW0402_075_GFP- GTSESATPESGPGSEP 311 GGTACCTCTGAAAGCGCAACTCCTG 312
N_H12.ab1 ATSGSETPGTSESATP AGTCTGGCCCAGGTAGCGAACCTGC
ESGP TACCTCCGGCTCTGAGACTCCAGGT
ACCTCTGAAAGCGCAACCCCGGAAT
CTGGTCCA
Example 3 Construction of XTEN_AF36 Segments A codon library encoding sequences of 36 amino acid length was constructed. The sequences were designated XTEN_AF36. Its segments have the amino acid sequence [X]3 where X is a 12mer peptide with the sequence: GSTSESPSGTAP (SEQ ID NO: 313), GTSTPESGSASP (SEQ ID NO: 314), GTSPSGESSTAP (SEQ ID NO: 315), or GSTSSTAESPGP (SEQ ID NO: 316). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:
AF1for:
(SEQ ID NO: 317)
AGGTTCTACYAGCGAATCYCCKTCTGGYACYGCWCC
AF1rev:
(SEQ ID NO: 318)
ACCTGGWGCRGTRCCAGAMGGRGATTCGCTRGTAGA
AF2for:
(SEQ ID NO: 319)
AGGTACYTCTACYCCKGAAAGCGGYTCYGCWTCTCC
AF2rev:
(SEQ ID NO: 320)
ACCTGGAGAWGCRGARCCGCTTTCMGGRGTAGARGT
AF3for:
(SEQ ID NO: 321)
AGGTACYTCYCCKAGCGGYGAATCTTCTACYGCWCC
AF3rev:
(SEQ ID NO: 322)
ACCTGGWGCRGTAGAAGATTCRCCGCTMGGRGARGT
AF4for:
(SEQ ID NO: 323)
AGGTTCYACYAGCTCTACYGCWGAATCTCCKGGYCC
AF4rev:
(SEQ ID NO: 324)
ACCTGGRCCMGGAGATTCWGCRGTAGAGCTRGTRGA
We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 325) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 326). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0403 showed green fluorescence after induction which shows that the sequence of XTEN_AF36 had been ligated in frame with the GFP gene and most sequences of XTEN_AF36 show good expression.
We screened 96 isolates from library LCW0403 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 44 clones were identified that contained correct XTEN_AF36 segments. The file names of the nucleotide and amino acid constructs for these segments are listed in Table 10.
TABLE 10
DNA and Amino Acid Sequences for 36-mer motifs
SEQ ID SEQ ID
File name Amino acid sequence NO: Nucleotide sequence NO:
LCW0403_004_GFP- GTSTPESGSASPGTSP 327 GGTACTTCTACTCCGGAAAGCGGTTC 328
N_A01.ab1 SGESSTAPGTSPSGES CGCATCTCCAGGTACTTCTCCTAGCG
STAP GTGAATCTTCTACTGCTCCAGGTACC
TCTCCTAGCGGCGAATCTTCTACTGC
TCCA
LCW0403_005_GFP- GTSPSGESSTAPGSTS 329 GGTACTTCTCCGAGCGGTGAATCTTC 330
N_B01.ab1 STAESPGPGTSPSGES TACCGCACCAGGTTCTACTAGCTCTA
STAP CCGCTGAATCTCCGGGCCCAGGTACT
TCTCCGAGCGGTGAATCTTCTACTGC
TCCA
LCW0403_006_GFP- GSTSSTAESPGPGTSP 331 GGTTCCACCAGCTCTACTGCTGAATC 332
N_C01.ab1 SGESSTAPGTSTPESG TCCTGGTCCAGGTACCTCTCCTAGCG
SASP GTGAATCTTCTACTGCTCCAGGTACT
TCTACTCCTGAAAGCGGCTCTGCTTC
TCCA
LCW0403_007_GFP- GSTSSTAESPGPGSTS 333 GGTTCTACCAGCTCTACTGCAGAATC 334
N_D01.ab1 STAESPGPGTSPSGES TCCTGGCCCAGGTTCCACCAGCTCTA
STAP CCGCAGAATCTCCGGGTCCAGGTACT
TCCCCTAGCGGTGAATCTTCTACCGC
ACCA
LCW0403_008_GFP- GSTSSTAESPGPGTSP 335 GGTTCTACTAGCTCTACTGCTGAATC 336
N_E01.ab1 SGESSTAPGTSTPESG TCCTGGCCCAGGTACTTCTCCTAGCG
SASP GTGAATCTTCTACCGCTCCAGGTACC
TCTACTCCGGAAAGCGGTTCTGCATC
TCCA
LCW0403_010_GFP- GSTSSTAESPGPGTST 337 GGTTCTACCAGCTCTACCGCAGAATC 338
N_F01.ab1 PESGSASPGSTSESPS TCCTGGTCCAGGTACCTCTACTCCGG
GTAP AAAGCGGCTCTGCATCTCCAGGTTCT
ACTAGCGAATCTCCTTCTGGCACTGC
ACCA
LCW0403_011_GFP- GSTSSTAESPGPGTST 339 GGTTCTACTAGCTCTACTGCAGAATC 340
N_G01.ab1 PESGSASPGTSTPESG TCCTGGCCCAGGTACCTCTACTCCGG
SASP AAAGCGGCTCTGCATCTCCAGGTACT
TCTACCCCTGAAAGCGGTTCTGCATC
TCCA
LCW0403_012_GFP- GSTSESPSGTAPGTSP 341 GGTTCTACCAGCGAATCTCCTTCTGG 342
N_H01.ab1 SGESSTAPGSTSESPS CACCGCTCCAGGTACCTCTCCTAGCG
GTAP GCGAATCTTCTACCGCTCCAGGTTCT
ACTAGCGAATCTCCTTCTGGCACTGC
ACCA
LCW0403_013_GFP- GSTSSTAESPGPGSTS 343 GGTTCCACCAGCTCTACTGCAGAATC 344
N_A02.ab1 STAESPGPGTSPSGES TCCGGGCCCAGGTTCTACTAGCTCTA
STAP CTGCAGAATCTCCGGGTCCAGGTACT
TCTCCTAGCGGCGAATCTTCTACCGC
TCCA
LCW0403_014_GFP- GSTSSTAESPGPGTST 345 GGTTCCACTAGCTCTACTGCAGAATC 346
N_B02.ab1 PESGSASPGSTSESPS TCCTGGCCCAGGTACCTCTACCCCTG
GTAP AAAGCGGCTCTGCATCTCCAGGTTCT
ACCAGCGAATCCCCGTCTGGCACCGC
ACCA
LCW0403_015_GFP- GSTSSTAESPGPGSTS 347 GGTTCTACTAGCTCTACTGCTGAATC 348
N_C02.ab1 STAESPGPGTSPSGES TCCGGGTCCAGGTTCTACCAGCTCTA
STAP CTGCTGAATCTCCTGGTCCAGGTACC
TCCCCGAGCGGTGAATCTTCTACTGC
ACCA
LCW0403_017_GFP- GSTSSTAESPGPGSTS 349 GGTTCTACCAGCTCTACCGCTGAATC 350
N_D02.ab1 ESPSGTAPGSTSSTAE TCCTGGCCCAGGTTCTACCAGCGAAT
SPGP CCCCGTCTGGCACCGCACCAGGTTCT
ACTAGCTCTACCGCTGAATCTCCGGG
TCCA
LCW0403_018_GFP- GSTSSTAESPGPGSTS 351 GGTTCTACCAGCTCTACCGCAGAATC 352
N_E02.ab1 STAESPGPGSTSSTAE TCCTGGCCCAGGTTCCACTAGCTCTA
SPGP CCGCTGAATCTCCTGGTCCAGGTTCT
ACTAGCTCTACCGCTGAATCTCCTGG
TCCA
LCW0403_019_GFP- GSTSESPSGTAPGSTS 353 GGTTCTACTAGCGAATCCCCTTCTGG 354
N_F02.ab1 STAESPGPGSTSSTAE TACTGCTCCAGGTTCCACTAGCTCTA
SPGP CCGCTGAATCTCCTGGCCCAGGTTCC
ACTAGCTCTACTGCAGAATCTCCTGG
TCCA
LCW0403_023_GFP- GSTSESPSGTAPGSTS 355 GGTTCTACTAGCGAATCTCCTTCTGG 356
N_H02.ab1 ESPSGTAPGSTSESPS TACCGCTCCAGGTTCTACCAGCGAAT
GTAP CCCCGTCTGGTACTGCTCCAGGTTCT
ACCAGCGAATCTCCTTCTGGTACTGC
ACCA
LCW0403_024_GFP- GSTSSTAESPGPGSTS 357 GGTTCCACCAGCTCTACTGCTGAATC 358
N_A03.ab1 STAESPGPGSTSSTAE TCCTGGCCCAGGTTCTACCAGCTCTA
SPGP CTGCTGAATCTCCGGGCCCAGGTTCC
ACCAGCTCTACCGCTGAATCTCCGGG
TCCA
LCW0403_025_GFP- GSTSSTAESPGPGSTS 359 GGTTCCACTAGCTCTACCGCAGAATC 360
N_B03.ab1 STAESPGPGTSPSGES TCCTGGTCCAGGTTCTACTAGCTCTA
STAP CTGCTGAATCTCCGGGTCCAGGTACC
TCCCCTAGCGGCGAATCTTCTACCGC
TCCA
LCW0403_028_GFP- GSSPSASTGTGPGSST 361 GGTTCTAGCCCTTCTGCTTCCACCGG 362
N_D03.ab1 PSGATGSPGSSTPSGA TACCGGCCCAGGTAGCTCTACTCCGT
TGSP CTGGTGCAACTGGCTCTCCAGGTAGC
TCTACTCCGTCTGGTGCAACCGGCTC
CCCA
LCW0403_029_GFP- GTSPSGESSTAPGTST 363 GGTACTTCCCCTAGCGGTGAATCTTC 364
N_E03.ab1 PESGSASPGSTSSTAE TACTGCTCCAGGTACCTCTACTCCGG
SPGP AAAGCGGCTCCGCATCTCCAGGTTCT
ACTAGCTCTACTGCTGAATCTCCTGG
TCCA
LCW0403_030_GFP- GSTSSTAESPGPGSTS 365 GGTTCTACTAGCTCTACCGCTGAATC 366
N_F03.ab1 STAESPGPGTSTPESG TCCGGGTCCAGGTTCTACCAGCTCTA
SASP CTGCAGAATCTCCTGGCCCAGGTACT
TCTACTCCGGAAAGCGGTTCCGCTTC
TCCA
LCW0403_031_GFP- GTSPSGESSTAPGSTS 367 GGTACTTCTCCTAGCGGTGAATCTTC 368
N_G03.ab1 STAESPGPGTSTPESG TACCGCTCCAGGTTCTACCAGCTCTA
SASP CTGCTGAATCTCCTGGCCCAGGTACT
TCTACCCCGGAAAGCGGCTCCGCTTC
TCCA
LCW0403_033_GFP- GSTSESPSGTAPGSTS 369 GGTTCTACTAGCGAATCCCCTTCTGG 370
N_H03.ab1 STAESPGPGSTSSTAE TACTGCACCAGGTTCTACCAGCTCTA
SPGP CTGCTGAATCTCCGGGCCCAGGTTCC
ACCAGCTCTACCGCAGAATCTCCTGG
TCCA
LCW0403_035_GFP- GSTSSTAESPGPGSTS 371 GGTTCCACCAGCTCTACCGCTGAATC 372
N_A04.ab1 ESPSGTAPGSTSSTAE TCCGGGCCCAGGTTCTACCAGCGAAT
SPGP CCCCTTCTGGCACTGCACCAGGTTCT
ACTAGCTCTACCGCAGAATCTCCGGG
CCCA
LCW0403_036_GFP- GSTSSTAESPGPGTSP 373 GGTTCTACCAGCTCTACTGCTGAATC 374
N_B04.ab1 SGESSTAPGTSTPESG TCCGGGTCCAGGTACTTCCCCGAGCG
SASP GTGAATCTTCTACTGCACCAGGTACT
TCTACTCCGGAAAGCGGTTCCGCTTC
TCCA
LCW0403_039_GFP- GSTSESPSGTAPGSTS 375 GGTTCTACCAGCGAATCTCCTTCTGG 376
N_C04.ab1 ESPSGTAPGTSPSGES CACCGCTCCAGGTTCTACTAGCGAAT
STAP CCCCGTCTGGTACCGCACCAGGTACT
TCTCCTAGCGGCGAATCTTCTACCGC
ACCA
LCW0403_041_GFP- GSTSESPSGTAPGSTS 377 GGTTCTACCAGCGAATCCCCTTCTGG 378
N_D04.ab1 ESPSGTAPGTSTPESG TACTGCTCCAGGTTCTACCAGCGAAT
SASP CCCCTTCTGGCACCGCACCAGGTACT
TCTACCCCTGAAAGCGGCTCCGCTTC
TCCA
LCW0403_044_GFP- GTSTPESGSASPGSTS 379 GGTACCTCTACTCCTGAAAGCGGTTC 380
N_E04.ab1 STAESPGPGSTSSTAE TGCATCTCCAGGTTCCACTAGCTCTA
SPGP CCGCAGAATCTCCGGGCCCAGGTTCT
ACTAGCTCTACTGCTGAATCTCCTGG
CCCA
LCW0403_046_GFP- GSTSESPSGTAPGSTS 381 GGTTCTACCAGCGAATCCCCTTCTGG 382
N_F04.ab1 ESPSGTAPGTSPSGES CACTGCACCAGGTTCTACTAGCGAAT
STAP CCCCTTCTGGTACCGCACCAGGTACT
TCTCCGAGCGGCGAATCTTCTACTGC
TCCA
LCW0403_047_GFP- GSTSSTAESPGPGSTS 383 GGTTCTACTAGCTCTACCGCTGAATC 384
N_G04.ab1 STAESPGPGSTSESPS TCCTGGCCCAGGTTCCACTAGCTCTA
GTAP CCGCAGAATCTCCGGGCCCAGGTTCT
ACTAGCGAATCCCCTTCTGGTACCGC
TCCA
LCW0403_049_GFP- GSTSSTAESPGPGSTS 385 GGTTCCACCAGCTCTACTGCAGAATC 386
N_H04.ab1 STAESPGPGTSTPESG TCCTGGCCCAGGTTCTACTAGCTCTA
SASP CCGCAGAATCTCCTGGTCCAGGTACC
TCTACTCCTGAAAGCGGTTCCGCATC
TCCA
LCW0403_051_GFP- GSTSSTAESPGPGSTS 387 GGTTCTACTAGCTCTACTGCTGAATC 388
N_A05.ab1 STAESPGPGSTSESPS TCCGGGCCCAGGTTCTACTAGCTCTA
GTAP CCGCTGAATCTCCGGGTCCAGGTTCT
ACTAGCGAATCTCCTTCTGGTACCGC
TCCA
LCW0403_053_GFP- GTSPSGESSTAPGSTS 389 GGTACCTCCCCGAGCGGTGAATCTTC 390
N_B05.ab1 ESPSGTAPGSTSSTAE TACTGCACCAGGTTCTACTAGCGAAT
SPGP CCCCTTCTGGTACTGCTCCAGGTTCC
ACCAGCTCTACTGCAGAATCTCCGGG
TCCA
LCW0403_054_GFP- GSTSESPSGTAPGTSP 391 GGTTCTACTAGCGAATCCCCGTCTGG 392
N_C05.ab1 SGESSTAPGSTSSTAE TACTGCTCCAGGTACTTCCCCTAGCG
SPGP GTGAATCTTCTACTGCTCCAGGTTCT
ACCAGCTCTACCGCAGAATCTCCGGG
TCCA
LCW0403_057_GFP- GSTSSTAESPGPGSTS 393 GGTTCTACCAGCTCTACCGCTGAATC 394
N_D05.ab1 ESPSGTAPGTSPSGES TCCTGGCCCAGGTTCTACTAGCGAAT
STAP CTCCGTCTGGCACCGCACCAGGTACT
TCCCCTAGCGGTGAATCTTCTACTGC
ACCA
LCW0403_058_GFP- GSTSESPSGTAPGSTS 395 GGTTCTACTAGCGAATCTCCTTCTGG 396
N_E05.ab1 ESPSGTAPGTSTPESG CACTGCACCAGGTTCTACCAGCGAAT
SASP CTCCGTCTGGCACTGCACCAGGTACC
TCTACCCCTGAAAGCGGTTCCGCTTC
TCCA
LCW0403_060_GFP- GTSTPESGSASPGSTS 397 GGTACCTCTACTCCGGAAAGCGGTTC 398
N_F05.ab1 ESPSGTAPGSTSSTAE CGCATCTCCAGGTTCTACCAGCGAAT
SPGP CCCCGTCTGGCACCGCACCAGGTTCT
ACTAGCTCTACTGCTGAATCTCCGGG
CCCA
LCW0403_063_GFP- GSTSSTAESPGPGTSP 399 GGTTCTACTAGCTCTACTGCAGAATC 400
N_G05.ab1 SGESSTAPGTSPSGES TCCGGGCCCAGGTACCTCTCCTAGCG
STAP GTGAATCTTCTACCGCTCCAGGTACT
TCTCCGAGCGGTGAATCTTCTACCGC
TCCA
LCW0403_064_GFP- GTSPSGESSTAPGTSP 401 GGTACCTCCCCTAGCGGCGAATCTTC 402
N_H05.ab1 SGESSTAPGTSPSGES TACTGCTCCAGGTACCTCTCCTAGCG
STAP GCGAATCTTCTACCGCTCCAGGTACC
TCCCCTAGCGGTGAATCTTCTACCGC
ACCA
LCW0403_065_GFP- GSTSSTAESPGPGTST 403 GGTTCCACTAGCTCTACTGCTGAATC 404
N_A06.ab1 PESGSASPGSTSESPS TCCTGGCCCAGGTACTTCTACTCCGG
GTAP AAAGCGGTTCCGCTTCTCCAGGTTCT
ACTAGCGAATCTCCGTCTGGCACCGC
ACCA
LCW0403_066_GFP- GSTSESPSGTAPGTSP 405 GGTTCTACTAGCGAATCTCCGTCTGG 406
N_B06.ab1 SGESSTAPGTSPSGES CACTGCTCCAGGTACTTCTCCTAGCG
STAP GTGAATCTTCTACCGCTCCAGGTACT
TCCCCTAGCGGCGAATCTTCTACCGC
TCCA
LCW0403_067_GFP- GSTSESPSGTAPGTST 407 GGTTCTACTAGCGAATCTCCTTCTGG 408
N_C06.ab1 PESGSASPGSTSSTAE TACCGCTCCAGGTACTTCTACCCCTG
SPGP AAAGCGGCTCCGCTTCTCCAGGTTCC
ACTAGCTCTACCGCTGAATCTCCGGG
TCCA
LCW0403_068_GFP- GSTSSTAESPGPGSTS 409 GGTTCCACTAGCTCTACTGCTGAATC 410
N_D06.ab1 STAESPGPGSTSESPS TCCTGGCCCAGGTTCTACCAGCTCTA
GTAP CCGCTGAATCTCCTGGCCCAGGTTCT
ACCAGCGAATCTCCGTCTGGCACCGC
ACCA
LCW0403_069_GFP- GSTSESPSGTAPGTST 411 GGTTCTACTAGCGAATCCCCGTCTGG 412
N_E06.ab1 PESGSASPGTSTPESG TACCGCACCAGGTACTTCTACCCCGG
SASP AAAGCGGCTCTGCTTCTCCAGGTACT
TCTACCCCGGAAAGCGGCTCCGCATC
TCCA
LCW0403_070_GFP- GSTSESPSGTAPGTST 413 GGTTCTACTAGCGAATCCCCGTCTGG 414
N_F06.ab1 PESGSASPGTSTPESG TACTGCTCCAGGTACTTCTACTCCTG
SASP AAAGCGGTTCCGCTTCTCCAGGTACC
TCTACTCCGGAAAGCGGTTCTGCATC
TCCA
Example 4 Construction of XTEN_AG36 Segments A codon library encoding sequences of 36 amino acid length was constructed. The sequences were designated XTEN_AG36. Its segments have the amino acid sequence [X]3 where X is a 12mer peptide with the sequence: GTPGSGTASSSP (SEQ ID NO: 415), GSSTPSGATGSP (SEQ ID NO: 416), GSSPSASTGTGP (SEQ ID NO: 417), or GASPGTSSTGSP (SEQ ID NO: 418). The insert was obtained by annealing the following pairs of phosphorylated synthetic oligonucleotide pairs:
AG1for:
(SEQ ID NO: 419)
AGGTACYCCKGGYAGCGGTACYGCWTCTTCYTCTCC
AG1rev:
(SEQ ID NO: 420)
ACCTGGAGARGAAGAWGCRGTACCGCTRCCMGGRGT
AG2for:
(SEQ ID NO: 421)
AGGTAGCTCTACYCCKTCTGGTGCWACYGGYTCYCC
AG2rev:
(SEQ ID NO: 422)
ACCTGGRGARCCRGTWGCACCAGAMGGRGTAGAGCT
AG3for:
(SEQ ID NO: 423)
AGGTTCTAGCCCKTCTGCWTCYACYGGTACYGGYCC
AG3rev:
(SEQ ID NO: 424)
ACCTGGRCCRGTACCRGTRGAWGCAGAMGGGCTAGA
AG4for:
(SEQ ID NO: 425)
AGGTGCWTCYCCKGGYACYAGCTCTACYGGTTCTCC
AG4rev:
(SEQ ID NO: 426)
ACCTGGAGAACCRGTAGAGCTRGTRCCMGGRGAWGC
We also annealed the phosphorylated oligonucleotide 3KpnIstopperFor: AGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 427) and the non-phosphorylated oligonucleotide pr_3KpnIstopperRev: CCTCGAGTGAAGACGA (SEQ ID NO: 428). The annealed oligonucleotide pairs were ligated, which resulted in a mixture of products with varying length that represents the varying number of 12mer repeats ligated to one BbsI/KpnI segment. The products corresponding to the length of 36 amino acids were isolated from the mixture by preparative agarose gel electrophoresis and ligated into the BsaI/KpnI digested stuffer vector pCW0359. Most of the clones in the resulting library designated LCW0404 showed green fluorescence after induction which shows that the sequence of XTEN_AG36 had been ligated in frame with the GFP gene and most sequences of XTEN_AG36 show good expression.
We screened 96 isolates from library LCW0404 for high level of fluorescence by stamping them onto agar plate containing IPTG. The same isolates were evaluated by PCR and 48 isolates were identified that contained segments with 36 amino acids as well as strong fluorescence. These isolates were sequenced and 44 clones were identified that contained correct XTEN_AG36 segments. The file names of the nucleotide and amino acid constructs for these segments are listed in Table 11.
TABLE 11
DNA and Amino Acid Sequences for 36-mer motifs
SEQ ID SEQ ID
File name Amino acid sequence NO: Nucleotide sequence NO:
LCW0404_001_GFP- GASPGTSSTGSPGTPG 429 GGTGCATCCCCGGGCACTAGCTCTAC 430
N_A07.ab1 SGTASSSPGSSTPSGA CGGTTCTCCAGGTACTCCTGGTAGCG
TGSP GTACTGCTTCTTCTTCTCCAGGTAGCT
CTACTCCTTCTGGTGCTACTGGTTCTC
CA
LCW0404_003_GFP- GSSTPSGATGSPGSSP 431 GGTAGCTCTACCCCTTCTGGTGCTACC 432
N_B07.ab1 SASTGTGPGSSTPSGA GGCTCTCCAGGTTCTAGCCCGTCTGCT
TGSP TCTACCGGTACCGGTCCAGGTAGCTCT
ACCCCTTCTGGTGCTACTGGTTCTCCA
LCW0404_006_GFP- GASPGTSSTGSPGSSP 433 GGTGCATCTCCGGGTACTAGCTCTACC 434
N_C07.ab1 SASTGTGPGSSTPSGA GGTTCTCCAGGTTCTAGCCCTTCTGCT
TGSP TCCACTGGTACCGGCCCAGGTAGCTC
TACCCCGTCTGGTGCTACTGGTTCCCCA
LCW0404_007_GFP- GTPGSGTASSSPGSST 435 GGTACTCCGGGCAGCGGTACTGCTTC 436
N_D07.ab1 PSGATGSPGASPGTSS TTCCTCTCCAGGTAGCTCTACCCCTTC
TGSP TGGTGCAACTGGTTCCCCAGGTGCAT
CCCCTGGTACTAGCTCTACCGGTTCTC
CA
LCW0404_009_GFP- GTPGSGTASSSPGASP 437 GGTACCCCTGGCAGCGGTACTGCTTCT 438
N_E07.ab1 GTSSTGSPGSRPSAST TCTTCTCCAGGTGCTTCCCCTGGTACC
GTGP AGCTCTACCGGTTCTCCAGGTTCTAGA
CCTTCTGCATCCACCGGTACTGGTCCA
LCW0404_011_GFP- GASPGTSSTGSPGSST 439 GGTGCATCTCCTGGTACCAGCTCTACC 440
N_F07.ab1 PSGATGSPGASPGTSS GGTTCTCCAGGTAGCTCTACTCCTTCT
TGSP GGTGCTACTGGCTCTCCAGGTGCTTCC
CCGGGTACCAGCTCTACCGGTTCTCCA
LCW0404_012_GFP- GTPGSGTASSSPGSST 441 GGTACCCCGGGCAGCGGTACCGCATC 442
N_G07.ab1 PSGATGSPGSSTPSGA TTCCTCTCCAGGTAGCTCTACCCCGTC
TGSP TGGTGCTACCGGTTCCCCAGGTAGCTC
TACCCCGTCTGGTGCAACCGGCTCCCCA
LCW0404_014_GFP- GASPGTSSTGSPGASP 443 GGTGCATCTCCGGGCACTAGCTCTACT 444
N_H07.ab1 GTSSTGSPGASPGTSS GGTTCTCCAGGTGCATCCCCTGGCACT
TGSP AGCTCTACTGGTTCTCCAGGTGCTTCT
CCTGGTACCAGCTCTACTGGTTCTCCA
LCW0404_015_GFP- GSSTPSGATGSPGSSP 445 GGTAGCTCTACTCCGTCTGGTGCAACC 446
N_A08.ab1 SASTGTGPGASPGTSS GGCTCCCCAGGTTCTAGCCCGTCTGCT
TGSP TCCACTGGTACTGGCCCAGGTGCTTCC
CCGGGCACCAGCTCTACTGGTTCTCCA
LCW0404_016_GFP- GSSTPSGATGSPGSST 447 GGTAGCTCTACTCCTTCTGGTGCTACC 448
N_B08.ab1 PSGATGSPGTPGSGT GGTTCCCCAGGTAGCTCTACTCCTTCT
ASSSP GGTGCTACTGGTTCCCCAGGTACTCCG
GGCAGCGGTACTGCTTCTTCCTCTCCA
LCW0404_017_GFP- GSSTPSGATGSPGSST 449 GGTAGCTCTACTCCGTCTGGTGCAACC 450
N_C08.ab1 PSGATGSPGASPGTSS GGTTCCCCAGGTAGCTCTACTCCTTCT
TGSP GGTGCTACTGGCTCCCCAGGTGCATC
CCCTGGCACCAGCTCTACCGGTTCTCCA
LCW0404_018_GFP- GTPGSGTASSSPGSSP 451 GGTACTCCTGGTAGCGGTACCGCATC 452
N_D08.ab1 SASTGTGPGSSTPSGA TTCCTCTCCAGGTTCTAGCCCTTCTGC
TGSP ATCTACCGGTACCGGTCCAGGTAGCT
CTACTCCTTCTGGTGCTACTGGCTCTC
CA
LCW0404_023_GFP- GASPGTSSTGSPGSSP 453 GGTGCTTCCCCGGGCACTAGCTCTACC 454
N_F08.ab1 SASTGTGPGTPGSGT GGTTCTCCAGGTTCTAGCCCTTCTGCA
ASSSP TCTACTGGTACTGGCCCAGGTACTCCG
GGCAGCGGTACTGCTTCTTCCTCTCCA
LCW0404_025_GFP- GSSTPSGATGSPGSST 455 GGTAGCTCTACTCCGTCTGGTGCTACC 456
N_G08.ab1 PSGATGSPGASPGTSS GGCTCTCCAGGTAGCTCTACCCCTTCT
TGSP GGTGCAACCGGCTCCCCAGGTGCTTC
TCCGGGTACCAGCTCTACTGGTTCTCCA
LCW0404_029_GFP- GTPGSGTASSSPGSST 457 GGTACCCCTGGCAGCGGTACCGCTTC 458
N_A09.ab1 PSGATGSPGSSPSAST TTCCTCTCCAGGTAGCTCTACCCCGTC
GTGP TGGTGCTACTGGCTCTCCAGGTTCTAG
CCCGTCTGCATCTACCGGTACCGGCCCA
LCW0404_030_GFP- GSSTPSGATGSPGTPG 459 GGTAGCTCTACTCCTTCTGGTGCAACC 460
N_B09.ab1 SGTASSSPGTPGSGTA GGCTCCCCAGGTACCCCGGGCAGCGG
SSSP TACCGCATCTTCCTCTCCAGGTACTCC
GGGTAGCGGTACTGCTTCTTCTTCTCCA
LCW0404_031_GFP- GTPGSGTASSSPGSST 461 GGTACCCCGGGTAGCGGTACTGCTTC 462
N_C09.ab1 PSGATGSPGASPGTSS TTCCTCTCCAGGTAGCTCTACCCCTTC
TGSP TGGTGCAACCGGCTCTCCAGGTGCTTC
TCCGGGCACCAGCTCTACCGGTTCTCCA
LCW0404_034_GFP- GSSTPSGATGSPGSST 463 GGTAGCTCTACCCCGTCTGGTGCTACC 464
N_D09.ab1 PSGATGSPGASPGTSS GGCTCTCCAGGTAGCTCTACCCCGTCT
TGSP GGTGCAACCGGCTCCCCAGGTGCATC
CCCGGGTACTAGCTCTACCGGTTCTCCA
LCW0404_035_GFP- GASPGTSSTGSPGTPG 465 GGTGCTTCTCCGGGCACCAGCTCTACT 466
N_E09.ab1 SGTASSSPGSSTPSGA GGTTCTCCAGGTACCCCGGGCAGCGG
TGSP TACCGCATCTTCTTCTCCAGGTAGCTC
TACTCCTTCTGGTGCAACTGGTTCTCCA
LCW0404_036_GFP- GSSPSASTGTGPGSST 467 GGTTCTAGCCCGTCTGCTTCCACCGGT 468
N_F09.ab1 PSGATGSPGTPGSGT ACTGGCCCAGGTAGCTCTACCCCGTCT
ASSSP GGTGCAACTGGTTCCCCAGGTACCCC
TGGTAGCGGTACCGCTTCTTCTTCTCCA
LCW0404_037_GFP- GASPGTSSTGSPGSSP 469 GGTGCTTCTCCGGGCACCAGCTCTACT 470
N_G09.ab1 SASTGTGPGSSTPSGA GGTTCTCCAGGTTCTAGCCCTTCTGCA
TGSP TCCACCGGTACCGGTCCAGGTAGCTC
TACCCCTTCTGGTGCAACCGGCTCTCCA
LCW0404_040_GFP- GASPGTSSTGSPGSST 471 GGTGCATCCCCGGGCACCAGCTCTAC 472
N_H09.ab1 PSGATGSPGSSTPSGA CGGTTCTCCAGGTAGCTCTACCCCGTC
TGSP TGGTGCTACCGGCTCTCCAGGTAGCTC
TACCCCGTCTGGTGCTACTGGCTCTCCA
LCW0404_041_GFP- GTPGSGTASSSPGSST 473 GGTACCCCTGGTAGCGGTACTGCTTCT 474
N_A10.ab1 PSGATGSPGTPGSGT TCCTCTCCAGGTAGCTCTACTCCGTCT
ASSSP GGTGCTACCGGTTCTCCAGGTACCCC
GGGTAGCGGTACCGCATCTTCTTCTCCA
LCW0404_043_GFP- GSSPSASTGTGPGSST 475 GGTTCTAGCCCTTCTGCTTCCACCGGT 476
N_C10.ab1 PSGATGSPGSSTPSGA ACTGGCCCAGGTAGCTCTACCCCTTCT
TGSP GGTGCTACCGGCTCCCCAGGTAGCTC
TACTCCTTCTGGTGCAACTGGCTCTCCA
LCW0404_045_GFP- GASPGTSSTGSPGSSP 477 GGTGCTTCTCCTGGCACCAGCTCTACT 478
N_D10.ab1 SASTGTGPGSSPSAST GGTTCTCCAGGTTCTAGCCCTTCTGCT
GTGP TCTACCGGTACTGGTCCAGGTTCTAGC
CCTTCTGCATCCACTGGTACTGGTCCA
LCW0404_047_GFP- GTPGSGTASSSPGASP 479 GGTACTCCTGGCAGCGGTACCGCTTCT 480
N_F10.ab1 GTSSTGSPGASPGTSS TCTTCTCCAGGTGCTTCTCCTGGTACT
TGSP AGCTCTACTGGTTCTCCAGGTGCTTCT
CCGGGCACTAGCTCTACTGGTTCTCCA
LCW0404_048_GFP- GSSTPSGATGSPGASP 481 GGTAGCTCTACCCCGTCTGGTGCTACC 482
N_G10.ab1 GTSSTGSPGSSTPSGA GGTTCCCCAGGTGCTTCTCCTGGTACT
TGSP AGCTCTACCGGTTCTCCAGGTAGCTCT
ACCCCGTCTGGTGCTACTGGCTCTCCA
LCW0404_049_GFP- GSSTPSGATGSPGTPG 483 GGTAGCTCTACCCCGTCTGGTGCTACT 484
N_H10.ab1 SGTASSSPGSSTPSGA GGTTCTCCAGGTACTCCGGGCAGCGG
TGSP TACTGCTTCTTCCTCTCCAGGTAGCTC
TACCCCTTCTGGTGCTACTGGCTCTCCA
LCW0404_050_GFP- GASPGTSSTGSPGSSP 485 GGTGCATCTCCTGGTACCAGCTCTACT 486
N_A11.ab1 SASTGTGPGSSTPSGA GGTTCTCCAGGTTCTAGCCCTTCTGCT
TGSP TCTACCGGTACCGGTCCAGGTAGCTCT
ACTCCTTCTGGTGCTACCGGTTCTCCA
LCW0404_051_GFP- GSSTPSGATGSPGSST 487 GGTAGCTCTACCCCGTCTGGTGCTACT 488
N_B11.ab1 PSGATGSPGSSTPSGA GGCTCTCCAGGTAGCTCTACTCCTTCT
TGSP GGTGCTACTGGTTCCCCAGGTAGCTCT
ACCCCGTCTGGTGCAACTGGCTCTCCA
LCW0404_052_GFP- GASPGTSSTGSPGTPG 489 GGTGCATCCCCGGGTACCAGCTCTAC 490
N_C11.ab1 SGTASSSPGASPGTSS CGGTTCTCCAGGTACTCCTGGCAGCG
TGSP GTACTGCATCTTCCTCTCCAGGTGCTT
CTCCGGGCACCAGCTCTACTGGTTCTC
CA
LCW0404_053_GFP- GSSTPSGATGSPGSSP 491 GGTAGCTCTACTCCTTCTGGTGCAACT 492
N_D11.ab1 SASTGTGPGASPGTSS GGTTCTCCAGGTTCTAGCCCGTCTGCA
TGSP TCCACTGGTACCGGTCCAGGTGCTTCC
CCTGGCACCAGCTCTACCGGTTCTCCA
LCW0404_057_GFP- GASPGTSSTGSPGSST 493 GGTGCATCTCCTGGTACTAGCTCTACT 494
N_E11.ab1 PSGATGSPGSSPSAST GGTTCTCCAGGTAGCTCTACTCCGTCT
GTGP GGTGCAACCGGCTCTCCAGGTTCTAG
CCCTTCTGCATCTACCGGTACTGGTCCA
LCW0404_060_GFP- GTPGSGTASSSPGSST 495 GGTACTCCTGGCAGCGGTACCGCATC 496
N_F11.ab1 PSGATGSPGASPGTSS TTCCTCTCCAGGTAGCTCTACTCCGTC
TGSP TGGTGCAACTGGTTCCCCAGGTGCTTC
TCCGGGTACCAGCTCTACCGGTTCTCCA
LCW0404_062_GFP- GSSTPSGATGSPGTPG 497 GGTAGCTCTACCCCGTCTGGTGCAAC 498
N_G11.ab1 SGTASSSPGSSTPSGA CGGCTCCCCAGGTACTCCTGGTAGCG
TGSP GTACCGCTTCTTCTTCTCCAGGTAGCT
CTACTCCGTCTGGTGCTACCGGCTCCC
CA
LCW0404_066_GFP- GSSPSASTGTGPGSSP 499 GGTTCTAGCCCTTCTGCATCCACCGGT 500
N_H11.ab1 SASTGTGPGASPGTSS ACCGGCCCAGGTTCTAGCCCGTCTGCT
TGSP TCTACCGGTACTGGTCCAGGTGCTTCT
CCGGGTACTAGCTCTACTGGTTCTCCA
LCW0404_067_GFP- GTPGSGTASSSPGSST 501 GGTACCCCGGGTAGCGGTACCGCTTC 502
N_A12.ab1 PSGATGSPGSNPSAST TTCTTCTCCAGGTAGCTCTACTCCGTC
GTGP TGGTGCTACCGGCTCTCCAGGTTCTAA
CCCTTCTGCATCCACCGGTACCGGCCCA
LCW0404_068_GFP- GSSPSASTGTGPGSST 503 GGTTCTAGCCCTTCTGCATCTACTGGT 504
N_B12.ab1 PSGATGSPGASPGTSS ACTGGCCCAGGTAGCTCTACTCCTTCT
TGSP GGTGCTACCGGCTCTCCAGGTGCTTCT
CCGGGTACTAGCTCTACCGGTTCTCCA
LCW0404_069_GFP- GSSTPSGATGSPGASP 505 GGTAGCTCTACCCCTTCTGGTGCAACC 506
N_C12.ab1 GTSSTGSPGTPGSGTA GGCTCTCCAGGTGCATCCCCGGGTAC
SSSP CAGCTCTACCGGTTCTCCAGGTACTCC
GGGTAGCGGTACCGCTTCTTCCTCTCCA
LCW0404_070_GFP- GSSTPSGATGSPGSST 507 GGTAGCTCTACTCCGTCTGGTGCAACC 508
N_D12.ab1 PSGATGSPGSSTPSGA GGTTCCCCAGGTAGCTCTACCCCTTCT
TGSP GGTGCAACCGGCTCCCCAGGTAGCTC
TACCCCTTCTGGTGCAACTGGCTCTCCA
LCW0404_073_GFP- GASPGTSSTGSPGTPG 509 GGTGCTTCTCCTGGCACTAGCTCTACC 510
N_E12.ab1 SGTASSSPGSSTPSGA GGTTCTCCAGGTACCCCTGGTAGCGG
TGSP TACCGCATCTTCCTCTCCAGGTAGCTC
TACTCCTTCTGGTGCTACTGGTTCCCCA
LCW0404_075_GFP- GSSTPSGATGSPGSSP 511 GGTAGCTCTACCCCGTCTGGTGCTACT 512
N_F12.ab1 SASTGTGPGSSPSAST GGCTCCCCAGGTTCTAGCCCTTCTGCA
GTGP TCCACCGGTACCGGTCCAGGTTCTAG
CCCGTCTGCATCTACTGGTACTGGTCCA
LCW0404_080_GFP- GASPGTSSTGSPGSSP 513 GGTGCTTCCCCGGGCACCAGCTCTACT 514
N_G12.ab1 SASTGTGPGSSPSAST GGTTCTCCAGGTTCTAGCCCGTCTGCT
GTGP TCTACTGGTACTGGTCCAGGTTCTAGC
CCTTCTGCTTCCACTGGTACTGGTCCA
LCW0404_081_GFP- GASPGTSSTGSPGSSP 515 GGTGCTTCCCCGGGTACCAGCTCTACC 516
N_H12.ab1 SASTGTGPGTPGSGT GGTTCTCCAGGTTCTAGCCCTTCTGCT
ASSSP TCTACCGGTACCGGTCCAGGTACCCCT
GGCAGCGGTACCGCATCTTCCTCTCCA
Example 5 Construction of XTEN_AE864 XTEN_AE864 was constructed from serial dimerization of XTEN_AE36 to AE72, 144, 288, 576 and 864. A collection of XTEN_AE72 segments was constructed from 37 different segments of XTEN_AE36. Cultures of E. coli harboring all 37 different 36-amino acid segments were mixed and plasmid was isolated. This plasmid pool was digested with BsaI/NcoI to generate the small fragment as the insert. The same plasmid pool was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated resulting in a doubling of the length and the ligation mixture was transformed into BL21Gold(DE3) cells to obtain colonies of XTEN_AE72.
This library of XTEN_AE72 segments was designated LCW0406. All clones from LCW0406 were combined and dimerized again using the same process as described above yielding library LCW0410 of XTEN_AE144. All clones from LCW0410 were combined and dimerized again using the same process as described above yielding library LCW0414 of XTEN_AE288. Two isolates LCW0414.001 and LCW0414.002 were randomly picked from the library and sequenced to verify the identities. All clones from LCW0414 were combined and dimerized again using the same process as described above yielding library LCW0418 of XTEN_AE576. We screened 96 isolates from library LCW0418 for high level of GFP fluorescence. 8 isolates with right sizes of inserts by PCR and strong fluorescence were sequenced and 2 isolates (LCW0418.018 and LCW0418.052) were chosen for future use based on sequencing and expression data.
The specific clone pCW0432 of XTEN_AE864 was constructed by combining LCW0418.018 of XTEN_AE576 and LCW0414.002 of XTEN_AE288 using the same dimerization process as described above.
Example 6 Construction of XTEN_AM144 A collection of XTEN_AM144 segments was constructed starting from 37 different segments of XTEN_AE36, 44 segments of XTEN_AF36, and 44 segments of XTEN_AG36.
Cultures of E. coli harboring all 125 different 36-amino acid segments were mixed and plasmid was isolated. This plasmid pool was digested with BsaI/NcoI to generate the small fragment as the insert. The same plasmid pool was digested with BbsI/NcoI to generate the large fragment as the vector. The insert and vector fragments were ligated resulting in a doubling of the length and the ligation mixture was transformed into BL21Gold(DE3) cells to obtain colonies of XTEN_AM72.
This library of XTEN_AM72 segments was designated LCW0461. All clones from LCW0461 were combined and dimerized again using the same process as described above yielding library LCW0462. 1512 Isolates from library LCW0462 were screened for protein expression. Individual colonies were transferred into 96 well plates and cultured overnight as starter cultures. These starter cultures were diluted into fresh autoinduction medium and cultured for 20-30 h. Expression was measured using a fluorescence plate reader with excitation at 395 nm and emission at 510 nm. 192 isolates showed high level expression and were submitted to DNA sequencing. Most clones in library LCW0462 showed good expression and similar physicochemical properties suggesting that most combinations of XTEN_AM36 segments yield useful XTEN sequences. 30 isolates from LCW0462 were chosen as a preferred collection of XTEN_AM144 segments for the construction of multifunctional proteins that contain multiple XTEN segments. The file names of the nucleotide and amino acid constructs for these segments are listed in Table 12.
TABLE 12
DNA and amino acid sequences for AM144 segments
SEQ ID SEQ ID
Clone Sequence Trimmed NO: Protein Sequence NO:
LCW462_r1 GGTACCCCGGGCAGCGGTACCGC 517 GTPGSGTASSSPGSSTPS 518
ATCTTCCTCTCCAGGTAGCTCTAC GATGSPGSSTPSGATGS
CCCGTCTGGTGCTACCGGTTCCC PGSPAGSPTSTEEGTSES
CAGGTAGCTCTACCCCGTCTGGT ATPESGPGTSTEPSEGS
GCAACCGGCTCCCCAGGTAGCCC APGSSPSASTGTGPGSS
GGCTGGCTCTCCTACCTCTACTG PSASTGTGPGASPGTSS
AGGAAGGTACTTCTGAAAGCGCT TGSPGTSTEPSEGSAPG
ACTCCTGAGTCTGGTCCAGGTAC TSTEPSEGSAPGSEPATS
CTCTACTGAACCGTCCGAAGGTA GSETP
GCGCTCCAGGTTCTAGCCCTTCT
GCATCCACCGGTACCGGCCCAGG
TTCTAGCCCGTCTGCTTCTACCGG
TACTGGTCCAGGTGCTTCTCCGG
GTACTAGCTCTACTGGTTCTCCA
GGTACCTCTACCGAACCGTCCGA
GGGTAGCGCACCAGGTACCTCTA
CTGAACCGTCTGAGGGTAGCGCT
CCAGGTAGCGAACCGGCAACCTC
CGGTTCTGAAACTCCA
LCW462_r5 GGTTCTACCAGCGAATCCCCTTC 519 GSTSESPSGTAPGSTSES 520
TGGCACTGCACCAGGTTCTACTA PSGTAPGTSPSGESSTAP
GCGAATCCCCTTCTGGTACCGCA GTSTEPSEGSAPGTSTEP
CCAGGTACTTCTCCGAGCGGCGA SEGSAPGTSESATPESG
ATCTTCTACTGCTCCAGGTACCTC PGASPGTSSTGSPGSSTP
TACTGAACCTTCCGAAGGCAGCG SGATGSPGASPGTSSTG
CTCCAGGTACCTCTACCGAACCG SPGSTSESPSGTAPGSTS
TCCGAGGGCAGCGCACCAGGTAC ESPSGTAPGTSTPESGS
TTCTGAAAGCGCAACCCCTGAAT ASP
CCGGTCCAGGTGCATCTCCTGGT
ACCAGCTCTACCGGTTCTCCAGG
TAGCTCTACTCCTTCTGGTGCTAC
TGGCTCTCCAGGTGCTTCCCCGG
GTACCAGCTCTACCGGTTCTCCA
GGTTCTACTAGCGAATCTCCTTCT
GGCACTGCACCAGGTTCTACCAG
CGAATCTCCGTCTGGCACTGCAC
CAGGTACCTCTACCCCTGAAAGC
GGTTCCGCTTCTCCA
LCW462_r9 GGTACTTCTACCGAACCTTCCGA 521 GTSTEPSEGSAPGTSES 522
GGGCAGCGCACCAGGTACTTCTG ATPESGPGTSESATPES
AAAGCGCTACCCCTGAGTCCGGC GPGTSTEPSEGSAPGTS
CCAGGTACTTCTGAAAGCGCTAC ESATPESGPGTSTEPSEG
TCCTGAATCCGGTCCAGGTACCT SAPGTSTEPSEGSAPGS
CTACTGAACCTTCTGAGGGCAGC EPATSGSETPGSPAGSP
GCTCCAGGTACTTCTGAAAGCGC TSTEEGASPGTSSTGSP
TACCCCGGAGTCCGGTCCAGGTA GSSPSASTGTGPGSSPS
CTTCTACTGAACCGTCCGAAGGT ASTGTGP
AGCGCACCAGGTACTTCTACTGA
ACCTTCCGAAGGTAGCGCTCCAG
GTAGCGAACCTGCTACTTCTGGT
TCTGAAACCCCAGGTAGCCCGGC
TGGCTCTCCGACCTCCACCGAGG
AAGGTGCTTCTCCTGGCACCAGC
TCTACTGGTTCTCCAGGTTCTAGC
CCTTCTGCTTCTACCGGTACTGGT
CCAGGTTCTAGCCCTTCTGCATCC
ACTGGTACTGGTCCA
LCW462_r10 GGTAGCGAACCGGCAACCTCTGG 523 GSEPATSGSETPGTSES 524
CTCTGAAACCCCAGGTACCTCTG ATPESGPGTSESATPES
AAAGCGCTACTCCGGAATCTGGT GPGSTSESPSGTAPGSTS
CCAGGTACTTCTGAAAGCGCTAC ESPSGTAPGTSPSGESST
TCCGGAATCCGGTCCAGGTTCTA APGASPGTSSTGSPGSS
CCAGCGAATCTCCTTCTGGCACC PSASTGTGPGSSTPSGA
GCTCCAGGTTCTACTAGCGAATC TGSPGSSTPSGATGSPG
CCCGTCTGGTACCGCACCAGGTA SSTPSGATGSPGASPGT
CTTCTCCTAGCGGCGAATCTTCTA SSTGSP
CCGCACCAGGTGCATCTCCGGGT
ACTAGCTCTACCGGTTCTCCAGG
TTCTAGCCCTTCTGCTTCCACTGG
TACCGGCCCAGGTAGCTCTACCC
CGTCTGGTGCTACTGGTTCCCCA
GGTAGCTCTACTCCGTCTGGTGC
AACCGGTTCCCCAGGTAGCTCTA
CTCCTTCTGGTGCTACTGGCTCCC
CAGGTGCATCCCCTGGCACCAGC
TCTACCGGTTCTCCA
LCW462_r15 GGTGCTTCTCCGGGCACCAGCTC 525 GASPGTSSTGSPGSSPS 526
TACTGGTTCTCCAGGTTCTAGCCC ASTGTGPGSSTPSGATG
TTCTGCATCCACCGGTACCGGTC SPGTSESATPESGPGSEP
CAGGTAGCTCTACCCCTTCTGGT ATSGSETPGSEPATSGS
GCAACCGGCTCTCCAGGTACTTC ETPGTSESATPESGPGTS
TGAAAGCGCTACCCCGGAATCTG TEPSEGSAPGTSTEPSEG
GCCCAGGTAGCGAACCGGCTACT SAPGTSTEPSEGSAPGT
TCTGGTTCTGAAACCCCAGGTAG STEPSEGSAPGSEPATS
CGAACCGGCTACCTCCGGTTCTG GSETP
AAACTCCAGGTACTTCTGAAAGC
GCTACTCCGGAGTCCGGTCCAGG
TACCTCTACCGAACCGTCCGAAG
GCAGCGCTCCAGGTACTTCTACT
GAACCTTCTGAGGGTAGCGCTCC
AGGTACCTCTACCGAACCGTCCG
AGGGTAGCGCACCAGGTACCTCT
ACTGAACCGTCTGAGGGTAGCGC
TCCAGGTAGCGAACCGGCAACCT
CCGGTTCTGAAACTCCA
LCW462_r16 GGTACCTCTACCGAACCTTCCGA 527 GTSTEPSEGSAPGSPAG 528
AGGTAGCGCTCCAGGTAGCCCGG SPTSTEEGTSTEPSEGSA
CAGGTTCTCCTACTTCCACTGAG PGTSESATPESGPGSEP
GAAGGTACTTCTACCGAACCTTC ATSGSETPGTSESATPES
TGAGGGTAGCGCACCAGGTACCT GPGSPAGSPTSTEEGTS
CTGAAAGCGCAACTCCTGAGTCT ESATPESGPGTSTEPSEG
GGCCCAGGTAGCGAACCTGCTAC SAPGSEPATSGSETPGT
CTCCGGCTCTGAGACTCCAGGTA STEPSEGSAPGSEPATS
CCTCTGAAAGCGCAACCCCGGAA GSETP
TCTGGTCCAGGTAGCCCGGCTGG
CTCTCCTACCTCTACTGAGGAAG
GTACTTCTGAAAGCGCTACTCCT
GAGTCTGGTCCAGGTACCTCTAC
TGAACCGTCCGAAGGTAGCGCTC
CAGGTAGCGAACCTGCTACTTCT
GGTTCTGAAACTCCAGGTACTTC
TACCGAACCGTCCGAGGGTAGCG
CTCCAGGTAGCGAACCTGCTACT
TCTGGTTCTGAAACTCCA
LCW462_r20 GGTACTTCTACCGAACCGTCCGA 529 GTSTEPSEGSAPGTSTEP 530
AGGCAGCGCTCCAGGTACCTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCCGAGGGCAGCGCT PGTSTEPSEGSAPGTSTE
CCAGGTACCTCTACCGAACCTTC PSEGSAPGTSTEPSEGS
TGAAGGTAGCGCACCAGGTACTT APGTSTEPSEGSAPGTS
CTACCGAACCGTCCGAAGGCAGC ESATPESGPGTSESATPE
GCTCCAGGTACCTCTACTGAACC SGPGTSTEPSEGSAPGS
TTCCGAGGGCAGCGCTCCAGGTA EPATSGSETPGSPAGSP
CCTCTACCGAACCTTCTGAAGGT TSTEE
AGCGCACCAGGTACTTCTACCGA
ACCTTCCGAGGGCAGCGCACCAG
GTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGA
AAGCGCTACTCCTGAATCCGGTC
CAGGTACTTCTACTGAACCTTCC
GAAGGTAGCGCTCCAGGTAGCGA
ACCTGCTACTTCTGGTTCTGAAA
CCCCAGGTAGCCCGGCTGGCTCT
CCGACCTCCACCGAGGAA
LCW462_r23 GGTACTTCTACCGAACCGTCCGA 531 GTSTEPSEGSAPGTSTEP 532
GGGCAGCGCTCCAGGTACTTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCTGAAGGCAGCGCT PGSTSESPSGTAPGSTSE
CCAGGTACTTCTACTGAACCTTC SPSGTAPGTSTPESGSAS
CGAAGGTAGCGCACCAGGTTCTA PGSEPATSGSETPGTSES
CCAGCGAATCCCCTTCTGGTACT ATPESGPGTSTEPSEGS
GCTCCAGGTTCTACCAGCGAATC APGTSTEPSEGSAPGTS
CCCTTCTGGCACCGCACCAGGTA ESATPESGPGTSESATPE
CTTCTACCCCTGAAAGCGGCTCC SGP
GCTTCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAG
GTACCTCTGAAAGCGCTACTCCT
GAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCAC
CAGGTACTTCTACTGAACCGTCT
GAAGGTAGCGCACCAGGTACTTC
TGAAAGCGCAACCCCGGAATCCG
GCCCAGGTACCTCTGAAAGCGCA
ACCCCGGAGTCCGGCCCA
LCW462_r24 GGTAGCTCTACCCCTTCTGGTGCT 533 GSSTPSGATGSPGSSPS 534
ACCGGCTCTCCAGGTTCTAGCCC ASTGTGPGSSTPSGATG
GTCTGCTTCTACCGGTACCGGTC SPGSPAGSPTSTEEGSPA
CAGGTAGCTCTACCCCTTCTGGT GSPTSTEEGTSTEPSEGS
GCTACTGGTTCTCCAGGTAGCCC APGASPGTSSTGSPGSS
TGCTGGCTCTCCGACTTCTACTGA PSASTGTGPGTPGSGTA
GGAAGGTAGCCCGGCTGGTTCTC SSSPGSTSSTAESPGPGT
CGACTTCTACTGAGGAAGGTACT SPSGESSTAPGTSTPESG
TCTACCGAACCTTCCGAAGGTAG SASP
CGCTCCAGGTGCTTCCCCGGGCA
CTAGCTCTACCGGTTCTCCAGGTT
CTAGCCCTTCTGCATCTACTGGTA
CTGGCCCAGGTACTCCGGGCAGC
GGTACTGCTTCTTCCTCTCCAGGT
TCTACTAGCTCTACTGCTGAATCT
CCTGGCCCAGGTACTTCTCCTAG
CGGTGAATCTTCTACCGCTCCAG
GTACCTCTACTCCGGAAAGCGGT
TCTGCATCTCCA
LCW462_r27 GGTACCTCTACTGAACCTTCTGA 535 GTSTEPSEGSAPGTSES 536
GGGCAGCGCTCCAGGTACTTCTG ATPESGPGTSTEPSEGS
AAAGCGCTACCCCGGAGTCCGGT APGTSTEPSEGSAPGTS
CCAGGTACTTCTACTGAACCGTC ESATPESGPGTSESATPE
CGAAGGTAGCGCACCAGGTACTT SGPGTPGSGTASSSPGA
CTACTGAACCGTCTGAAGGTAGC SPGTSSTGSPGASPGTSS
GCACCAGGTACTTCTGAAAGCGC TGSPGSPAGSPTSTEEG
AACCCCGGAATCCGGCCCAGGTA SPAGSPTSTEEGTSTEPS
CCTCTGAAAGCGCAACCCCGGAG EGSAP
TCCGGCCCAGGTACTCCTGGCAG
CGGTACCGCTTCTTCTTCTCCAGG
TGCTTCTCCTGGTACTAGCTCTAC
TGGTTCTCCAGGTGCTTCTCCGG
GCACTAGCTCTACTGGTTCTCCA
GGTAGCCCTGCTGGCTCTCCGAC
TTCTACTGAGGAAGGTAGCCCGG
CTGGTTCTCCGACTTCTACTGAG
GAAGGTACTTCTACCGAACCTTC
CGAAGGTAGCGCTCCA
LCW462_r28 GGTAGCCCAGCAGGCTCTCCGAC 537 GSPAGSPTSTEEGTSTEP 538
TTCCACTGAGGAAGGTACTTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCCGAAGGCAGCGCA PGTSTEPSEGSAPGTSES
CCAGGTACCTCTACTGAACCTTC ATPESGPGTSESATPES
TGAGGGCAGCGCTCCAGGTACCT GPGTPGSGTASSSPGSS
CTACCGAACCGTCTGAAGGTAGC TPSGATGSPGASPGTSS
GCACCAGGTACCTCTGAAAGCGC TGSPGTSTEPSEGSAPG
AACTCCTGAGTCCGGTCCAGGTA TSESATPESGPGTSTEPS
CTTCTGAAAGCGCAACCCCGGAG EGSAP
TCTGGCCCAGGTACCCCGGGTAG
CGGTACTGCTTCTTCCTCTCCAGG
TAGCTCTACCCCTTCTGGTGCAA
CCGGCTCTCCAGGTGCTTCTCCG
GGCACCAGCTCTACCGGTTCTCC
AGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTACTTCT
GAAAGCGCTACCCCGGAGTCCGG
TCCAGGTACTTCTACTGAACCGT
CCGAAGGTAGCGCACCA
LCW462_r38 GGTAGCGAACCGGCAACCTCCGG 539 GSEPATSGSETPGTSES 540
CTCTGAAACTCCAGGTACTTCTG ATPESGPGSEPATSGSE
AAAGCGCTACTCCGGAATCCGGC TPGSSTPSGATGSPGTP
CCAGGTAGCGAACCGGCTACTTC GSGTASSSPGSSTPSGA
CGGCTCTGAAACCCCAGGTAGCT TGSPGASPGTSSTGSPG
CTACCCCGTCTGGTGCAACCGGC SSTPSGATGSPGASPGT
TCCCCAGGTACTCCTGGTAGCGG SSTGSPGSEPATSGSETP
TACCGCTTCTTCTTCTCCAGGTAG GTSTEPSEGSAPGSEPA
CTCTACTCCGTCTGGTGCTACCG TSGSETP
GCTCCCCAGGTGCATCTCCTGGT
ACCAGCTCTACCGGTTCTCCAGG
TAGCTCTACTCCTTCTGGTGCTAC
TGGCTCTCCAGGTGCTTCCCCGG
GTACCAGCTCTACCGGTTCTCCA
GGTAGCGAACCTGCTACTTCTGG
TTCTGAAACTCCAGGTACTTCTA
CCGAACCGTCCGAGGGTAGCGCT
CCAGGTAGCGAACCTGCTACTTC
TGGTTCTGAAACTCCA
LCW462_r39 GGTACCTCTACTGAACCTTCCGA 541 GTSTEPSEGSAPGTSTEP 542
AGGCAGCGCTCCAGGTACCTCTA SEGSAPGTSESATPESG
CCGAACCGTCCGAGGGCAGCGCA PGSPAGSPTSTEEGSPA
CCAGGTACTTCTGAAAGCGCAAC GSPTSTEEGTSTEPSEGS
CCCTGAATCCGGTCCAGGTAGCC APGSPAGSPTSTEEGTS
CTGCTGGCTCTCCGACTTCTACTG TEPSEGSAPGTSTEPSEG
AGGAAGGTAGCCCGGCTGGTTCT SAPGASPGTSSTGSPGS
CCGACTTCTACTGAGGAAGGTAC SPSASTGTGPGSSPSAST
TTCTACCGAACCTTCCGAAGGTA GTGP
GCGCTCCAGGTAGCCCGGCTGGT
TCTCCGACTTCCACCGAGGAAGG
TACCTCTACTGAACCTTCTGAGG
GTAGCGCTCCAGGTACCTCTACT
GAACCTTCCGAAGGCAGCGCTCC
AGGTGCTTCCCCGGGCACCAGCT
CTACTGGTTCTCCAGGTTCTAGCC
CGTCTGCTTCTACTGGTACTGGTC
CAGGTTCTAGCCCTTCTGCTTCCA
CTGGTACTGGTCCA
LCW462_r41 GGTAGCTCTACCCCGTCTGGTGC 543 GSSTPSGATGSPGASPG 544
TACCGGTTCCCCAGGTGCTTCTCC TSSTGSPGSSTPSGATGS
TGGTACTAGCTCTACCGGTTCTCC PGSPAGSPTSTEEGTSES
AGGTAGCTCTACCCCGTCTGGTG ATPESGPGSEPATSGSE
CTACTGGCTCTCCAGGTAGCCCT TPGASPGTSSTGSPGSST
GCTGGCTCTCCAACCTCCACCGA PSGATGSPGSSPSASTG
AGAAGGTACCTCTGAAAGCGCAA TGPGSTSESPSGTAPGS
CCCCTGAATCCGGCCCAGGTAGC TSESPSGTAPGTSTPESG
GAACCGGCAACCTCCGGTTCTGA SASP
AACCCCAGGTGCATCTCCTGGTA
CTAGCTCTACTGGTTCTCCAGGT
AGCTCTACTCCGTCTGGTGCAAC
CGGCTCTCCAGGTTCTAGCCCTTC
TGCATCTACCGGTACTGGTCCAG
GTTCTACCAGCGAATCCCCTTCT
GGTACTGCTCCAGGTTCTACCAG
CGAATCCCCTTCTGGCACCGCAC
CAGGTACTTCTACCCCTGAAAGC
GGCTCCGCTTCTCCA
LCW462_r42 GGTTCTACCAGCGAATCTCCTTCT 545 GSTSESPSGTAPGSTSES 546
GGCACCGCTCCAGGTTCTACTAG PSGTAPGTSPSGESSTAP
CGAATCCCCGTCTGGTACCGCAC GTSESATPESGPGTSTEP
CAGGTACTTCTCCTAGCGGCGAA SEGSAPGTSTEPSEGSA
TCTTCTACCGCACCAGGTACCTCT PGTSTEPSEGSAPGTSES
GAAAGCGCTACTCCGGAGTCTGG ATPESGPGTSTEPSEGS
CCCAGGTACCTCTACTGAACCGT APGSSTPSGATGSPGAS
CTGAGGGTAGCGCTCCAGGTACT PGTSSTGSPGSSTPSGAT
TCTACTGAACCGTCCGAAGGTAG GSP
CGCACCAGGTACCTCTACTGAAC
CTTCTGAGGGCAGCGCTCCAGGT
ACTTCTGAAAGCGCTACCCCGGA
GTCCGGTCCAGGTACTTCTACTG
AACCGTCCGAAGGTAGCGCACCA
GGTAGCTCTACCCCGTCTGGTGC
TACCGGTTCCCCAGGTGCTTCTCC
TGGTACTAGCTCTACCGGTTCTCC
AGGTAGCTCTACCCCGTCTGGTG
CTACTGGCTCTCCA
LCW462_r43 GGTTCTACTAGCTCTACTGCAGA 547 GSTSSTAESPGPGTSPSG 548
ATCTCCGGGCCCAGGTACCTCTC ESSTAPGTSPSGESSTAP
CTAGCGGTGAATCTTCTACCGCT GSTSSTAESPGPGSTSST
CCAGGTACTTCTCCGAGCGGTGA AESPGPGTSTPESGSASP
ATCTTCTACCGCTCCAGGTTCTAC GTSPSGESSTAPGSTSST
TAGCTCTACCGCTGAATCTCCGG AESPGPGTSTPESGSASP
GTCCAGGTTCTACCAGCTCTACT GSTSSTAESPGPGSTSES
GCAGAATCTCCTGGCCCAGGTAC PSGTAPGTSPSGESSTAP
TTCTACTCCGGAAAGCGGTTCCG
CTTCTCCAGGTACTTCTCCTAGCG
GTGAATCTTCTACCGCTCCAGGT
TCTACCAGCTCTACTGCTGAATCT
CCTGGCCCAGGTACTTCTACCCC
GGAAAGCGGCTCCGCTTCTCCAG
GTTCTACCAGCTCTACCGCTGAA
TCTCCTGGCCCAGGTTCTACTAG
CGAATCTCCGTCTGGCACCGCAC
CAGGTACTTCCCCTAGCGGTGAA
TCTTCTACTGCACCA
LCW462_r45 GGTACCTCTACTCCGGAAAGCGG 549 GTSTPESGSASPGSTSES 550
TTCCGCATCTCCAGGTTCTACCA PSGTAPGSTSSTAESPGP
GCGAATCCCCGTCTGGCACCGCA GTSTEPSEGSAPGTSTEP
CCAGGTTCTACTAGCTCTACTGCT SEGSAPGTSESATPESG
GAATCTCCGGGCCCAGGTACCTC PGTSESATPESGPGTSTE
TACTGAACCTTCCGAAGGCAGCG PSEGSAPGTSTEPSEGS
CTCCAGGTACCTCTACCGAACCG APGTSESATPESGPGTS
TCCGAGGGCAGCGCACCAGGTAC TEPSEGSAPGTSTEPSEG
TTCTGAAAGCGCAACCCCTGAAT SAP
CCGGTCCAGGTACCTCTGAAAGC
GCTACTCCGGAGTCTGGCCCAGG
TACCTCTACTGAACCGTCTGAGG
GTAGCGCTCCAGGTACTTCTACT
GAACCGTCCGAAGGTAGCGCACC
AGGTACTTCTGAAAGCGCTACTC
CGGAGTCCGGTCCAGGTACCTCT
ACCGAACCGTCCGAAGGCAGCGC
TCCAGGTACTTCTACTGAACCTTC
TGAGGGTAGCGCTCCC
LCW462_r47 GGTACCTCTACCGAACCGTCCGA 551 GTSTEPSEGSAPGTSTEP 552
GGGTAGCGCACCAGGTACCTCTA SEGSAPGSEPATSGSET
CTGAACCGTCTGAGGGTAGCGCT PGTSTEPSEGSAPGTSES
CCAGGTAGCGAACCGGCAACCTC ATPESGPGTSESATPES
CGGTTCTGAAACTCCAGGTACTT GPGASPGTSSTGSPGSS
CTACTGAACCGTCTGAAGGTAGC PSASTGTGPGSSTPSGA
GCACCAGGTACTTCTGAAAGCGC TGSPGSSTPSGATGSPG
AACCCCGGAATCCGGCCCAGGTA SSTPSGATGSPGASPGT
CCTCTGAAAGCGCAACCCCGGAG SSTGSP
TCCGGCCCAGGTGCATCTCCGGG
TACTAGCTCTACCGGTTCTCCAG
GTTCTAGCCCTTCTGCTTCCACTG
GTACCGGCCCAGGTAGCTCTACC
CCGTCTGGTGCTACTGGTTCCCC
AGGTAGCTCTACTCCGTCTGGTG
CAACCGGTTCCCCAGGTAGCTCT
ACTCCTTCTGGTGCTACTGGCTCC
CCAGGTGCATCCCCTGGCACCAG
CTCTACCGGTTCTCCA
LCW462_r54 GGTAGCGAACCGGCAACCTCTGG 553 GSEPATSGSETPGSEPA 554
CTCTGAAACTCCAGGTAGCGAAC TSGSETPGTSTEPSEGSA
CTGCAACCTCCGGCTCTGAAACC PGSEPATSGSETPGTSES
CCAGGTACTTCTACTGAACCTTCT ATPESGPGTSTEPSEGS
GAGGGCAGCGCACCAGGTAGCG APGSSTPSGATGSPGSS
AACCTGCAACCTCTGGCTCTGAA TPSGATGSPGASPGTSS
ACCCCAGGTACCTCTGAAAGCGC TGSPGSSTPSGATGSPG
TACTCCTGAATCTGGCCCAGGTA ASPGTSSTGSPGSSTPSG
CTTCTACTGAACCGTCCGAGGGC ATGSP
AGCGCACCAGGTAGCTCTACTCC
GTCTGGTGCTACCGGCTCTCCAG
GTAGCTCTACCCCTTCTGGTGCA
ACCGGCTCCCCAGGTGCTTCTCC
GGGTACCAGCTCTACTGGTTCTC
CAGGTAGCTCTACCCCGTCTGGT
GCTACCGGTTCCCCAGGTGCTTC
TCCTGGTACTAGCTCTACCGGTTC
TCCAGGTAGCTCTACCCCGTCTG
GTGCTACTGGCTCTCCA
LCW462_r55 GGTACTTCTACCGAACCGTCCGA 555 GTSTEPSEGSAPGTSTEP 556
GGGCAGCGCTCCAGGTACTTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCTGAAGGCAGCGCT PGTSESATPESGPGTSTE
CCAGGTACTTCTACTGAACCTTC PSEGSAPGTSTEPSEGS
CGAAGGTAGCGCACCAGGTACTT APGSTSESPSGTAPGTSP
CTGAAAGCGCTACTCCGGAGTCC SGESSTAPGTSPSGESST
GGTCCAGGTACCTCTACCGAACC APGSPAGSPTSTEEGTS
GTCCGAAGGCAGCGCTCCAGGTA ESATPESGPGTSTEPSEG
CTTCTACTGAACCTTCTGAGGGT SAP
AGCGCTCCAGGTTCTACTAGCGA
ATCTCCGTCTGGCACTGCTCCAG
GTACTTCTCCTAGCGGTGAATCTT
CTACCGCTCCAGGTACTTCCCCT
AGCGGCGAATCTTCTACCGCTCC
AGGTAGCCCGGCTGGCTCTCCTA
CCTCTACTGAGGAAGGTACTTCT
GAAAGCGCTACTCCTGAGTCTGG
TCCAGGTACCTCTACTGAACCGT
CCGAAGGTAGCGCTCCA
LCW462_r57 GGTACTTCTACTGAACCTTCCGA 557 GTSTEPSEGSAPGSEPA 558
AGGTAGCGCTCCAGGTAGCGAAC TSGSETPGSPAGSPTSTE
CTGCTACTTCTGGTTCTGAAACCC EGSPAGSPTSTEEGTSES
CAGGTAGCCCGGCTGGCTCTCCG ATPESGPGTSTEPSEGS
ACCTCCACCGAGGAAGGTAGCCC APGTSTEPSEGSAPGTS
GGCAGGCTCTCCGACCTCTACTG TEPSEGSAPGTSESATPE
AGGAAGGTACTTCTGAAAGCGCA SGPGSSTPSGATGSPGS
ACCCCGGAGTCCGGCCCAGGTAC SPSASTGTGPGASPGTS
CTCTACCGAACCGTCTGAGGGCA STGSP
GCGCACCAGGTACCTCTACTGAA
CCTTCCGAAGGCAGCGCTCCAGG
TACCTCTACCGAACCGTCCGAGG
GCAGCGCACCAGGTACTTCTGAA
AGCGCAACCCCTGAATCCGGTCC
AGGTAGCTCTACTCCGTCTGGTG
CAACCGGCTCCCCAGGTTCTAGC
CCGTCTGCTTCCACTGGTACTGG
CCCAGGTGCTTCCCCGGGCACCA
GCTCTACTGGTTCTCCA
LCW462_r61 GGTAGCGAACCGGCTACTTCCGG 559 GSEPATSGSETPGSPAG 560
CTCTGAGACTCCAGGTAGCCCTG SPTSTEEGTSESATPESG
CTGGCTCTCCGACCTCTACCGAA PGTSTEPSEGSAPGTSTE
GAAGGTACCTCTGAAAGCGCTAC PSEGSAPGTSESATPES
CCCTGAGTCTGGCCCAGGTACCT GPGTSTPESGSASPGSTS
CTACTGAACCTTCCGAAGGCAGC ESPSGTAPGSTSSTAESP
GCTCCAGGTACCTCTACCGAACC GPGTSESATPESGPGTS
GTCCGAGGGCAGCGCACCAGGTA TEPSEGSAPGTSTEPSEG
CTTCTGAAAGCGCAACCCCTGAA SAP
TCCGGTCCAGGTACCTCTACTCC
GGAAAGCGGTTCCGCATCTCCAG
GTTCTACCAGCGAATCCCCGTCT
GGCACCGCACCAGGTTCTACTAG
CTCTACTGCTGAATCTCCGGGCC
CAGGTACTTCTGAAAGCGCTACT
CCGGAGTCCGGTCCAGGTACCTC
TACCGAACCGTCCGAAGGCAGCG
CTCCAGGTACTTCTACTGAACCTT
CTGAGGGTAGCGCTCCA
LCW462_r64 GGTACTTCTACCGAACCGTCCGA 561 GTSTEPSEGSAPGTSTEP 562
GGGCAGCGCTCCAGGTACTTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCTGAAGGCAGCGCT PGTSTEPSEGSAPGTSES
CCAGGTACTTCTACTGAACCTTC ATPESGPGTSESATPES
CGAAGGTAGCGCACCAGGTACCT GPGTPGSGTASSSPGSS
CTACCGAACCGTCTGAAGGTAGC TPSGATGSPGASPGTSS
GCACCAGGTACCTCTGAAAGCGC TGSPGSTSSTAESPGPG
AACTCCTGAGTCCGGTCCAGGTA TSPSGESSTAPGTSTPES
CTTCTGAAAGCGCAACCCCGGAG GSASP
TCTGGCCCAGGTACTCCTGGCAG
CGGTACCGCATCTTCCTCTCCAG
GTAGCTCTACTCCGTCTGGTGCA
ACTGGTTCCCCAGGTGCTTCTCC
GGGTACCAGCTCTACCGGTTCTC
CAGGTTCCACCAGCTCTACTGCT
GAATCTCCTGGTCCAGGTACCTC
TCCTAGCGGTGAATCTTCTACTG
CTCCAGGTACTTCTACTCCTGAA
AGCGGCTCTGCTTCTCCA
LCW462_r67 GGTAGCCCGGCAGGCTCTCCGAC 563 GSPAGSPTSTEEGTSES 564
CTCTACTGAGGAAGGTACTTCTG ATPESGPGTSTEPSEGS
AAAGCGCAACCCCGGAGTCCGGC APGTSESATPESGPGSE
CCAGGTACCTCTACCGAACCGTC PATSGSETPGTSTEPSEG
TGAGGGCAGCGCACCAGGTACTT SAPGSPAGSPTSTEEGT
CTGAAAGCGCAACCCCTGAATCC STEPSEGSAPGTSTEPSE
GGTCCAGGTAGCGAACCGGCTAC GSAPGTSTEPSEGSAPG
TTCTGGCTCTGAGACTCCAGGTA TSTEPSEGSAPGTSTEPS
CTTCTACCGAACCGTCCGAAGGT EGSAP
AGCGCACCAGGTAGCCCGGCTGG
TTCTCCGACTTCCACCGAGGAAG
GTACCTCTACTGAACCTTCTGAG
GGTAGCGCTCCAGGTACCTCTAC
TGAACCTTCCGAAGGCAGCGCTC
CAGGTACTTCTACCGAACCGTCC
GAGGGCAGCGCTCCAGGTACTTC
TACTGAACCTTCTGAAGGCAGCG
CTCCAGGTACTTCTACTGAACCTT
CCGAAGGTAGCGCACCA
LCW462_r69 GGTACTTCTCCGAGCGGTGAATC 565 GTSPSGESSTAPGSTSST 566
TTCTACCGCACCAGGTTCTACTA AESPGPGTSPSGESSTAP
GCTCTACCGCTGAATCTCCGGGC GTSESATPESGPGTSTEP
CCAGGTACTTCTCCGAGCGGTGA SEGSAPGTSTEPSEGSA
ATCTTCTACTGCTCCAGGTACCTC PGSSPSASTGTGPGSSTP
TGAAAGCGCTACTCCGGAGTCTG SGATGSPGASPGTSSTG
GCCCAGGTACCTCTACTGAACCG SPGTSTPESGSASPGTSP
TCTGAGGGTAGCGCTCCAGGTAC SGESSTAPGTSPSGESST
TTCTACTGAACCGTCCGAAGGTA AP
GCGCACCAGGTTCTAGCCCTTCT
GCATCTACTGGTACTGGCCCAGG
TAGCTCTACTCCTTCTGGTGCTAC
CGGCTCTCCAGGTGCTTCTCCGG
GTACTAGCTCTACCGGTTCTCCA
GGTACTTCTACTCCGGAAAGCGG
TTCCGCATCTCCAGGTACTTCTCC
TAGCGGTGAATCTTCTACTGCTC
CAGGTACCTCTCCTAGCGGCGAA
TCTTCTACTGCTCCA
LCW462_r70 GGTACCTCTGAAAGCGCTACTCC 567 GTSESATPESGPGTSTEP 568
GGAGTCTGGCCCAGGTACCTCTA SEGSAPGTSTEPSEGSA
CTGAACCGTCTGAGGGTAGCGCT PGSPAGSPTSTEEGSPA
CCAGGTACTTCTACTGAACCGTC GSPTSTEEGTSTEPSEGS
CGAAGGTAGCGCACCAGGTAGCC APGSSPSASTGTGPGSS
CTGCTGGCTCTCCGACTTCTACTG TPSGATGSPGSSTPSGA
AGGAAGGTAGCCCGGCTGGTTCT TGSPGSEPATSGSETPG
CCGACTTCTACTGAGGAAGGTAC TSESATPESGPGSEPATS
TTCTACCGAACCTTCCGAAGGTA GSETP
GCGCTCCAGGTTCTAGCCCTTCT
GCTTCCACCGGTACTGGCCCAGG
TAGCTCTACCCCTTCTGGTGCTAC
CGGCTCCCCAGGTAGCTCTACTC
CTTCTGGTGCAACTGGCTCTCCA
GGTAGCGAACCGGCAACTTCCGG
CTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCTGGC
CCAGGTAGCGAACCTGCTACCTC
TGGCTCTGAAACCCCA
LCW462_r72 GGTACTTCTACCGAACCGTCCGA 569 GTSTEPSEGSAPGTSTEP 570
AGGCAGCGCTCCAGGTACCTCTA SEGSAPGTSTEPSEGSA
CTGAACCTTCCGAGGGCAGCGCT PGSSTPSGATGSPGASP
CCAGGTACCTCTACCGAACCTTC GTSSTGSPGSSTPSGAT
TGAAGGTAGCGCACCAGGTAGCT GSPGTSESATPESGPGS
CTACCCCGTCTGGTGCTACCGGT EPATSGSETPGTSTEPSE
TCCCCAGGTGCTTCTCCTGGTACT GSAPGSTSESPSGTAPG
AGCTCTACCGGTTCTCCAGGTAG STSESPSGTAPGTSTPES
CTCTACCCCGTCTGGTGCTACTG GSASP
GCTCTCCAGGTACTTCTGAAAGC
GCAACCCCTGAATCCGGTCCAGG
TAGCGAACCGGCTACTTCTGGCT
CTGAGACTCCAGGTACTTCTACC
GAACCGTCCGAAGGTAGCGCACC
AGGTTCTACTAGCGAATCTCCTT
CTGGCACTGCACCAGGTTCTACC
AGCGAATCTCCGTCTGGCACTGC
ACCAGGTACCTCTACCCCTGAAA
GCGGTTCCGCTTCTCCA
LCW462_r73 GGTACCTCTACTCCTGAAAGCGG 571 GTSTPESGSASPGSTSST 572
TTCTGCATCTCCAGGTTCCACTAG AESPGPGSTSSTAESPGP
CTCTACCGCAGAATCTCCGGGCC GSSPSASTGTGPGSSTPS
CAGGTTCTACTAGCTCTACTGCT GATGSPGASPGTSSTGS
GAATCTCCTGGCCCAGGTTCTAG PGSEPATSGSETPGTSES
CCCTTCTGCATCTACTGGTACTGG ATPESGPGSPAGSPTST
CCCAGGTAGCTCTACTCCTTCTG EEGSTSESPSGTAPGSTS
GTGCTACCGGCTCTCCAGGTGCT ESPSGTAPGTSTPESGS
TCTCCGGGTACTAGCTCTACCGG ASP
TTCTCCAGGTAGCGAACCGGCAA
CCTCCGGCTCTGAAACCCCAGGT
ACCTCTGAAAGCGCTACTCCTGA
ATCCGGCCCAGGTAGCCCGGCAG
GTTCTCCGACTTCCACTGAGGAA
GGTTCTACTAGCGAATCTCCTTCT
GGCACTGCACCAGGTTCTACCAG
CGAATCTCCGTCTGGCACTGCAC
CAGGTACCTCTACCCCTGAAAGC
GGTTCCGCTTCTCCC
LCW462_r78 GGTAGCCCGGCTGGCTCTCCTAC 573 GSPAGSPTSTEEGTSES 574
CTCTACTGAGGAAGGTACTTCTG ATPESGPGTSTEPSEGS
AAAGCGCTACTCCTGAGTCTGGT APGSTSESPSGTAPGSTS
CCAGGTACCTCTACTGAACCGTC ESPSGTAPGTSPSGESST
CGAAGGTAGCGCTCCAGGTTCTA APGTSTEPSEGSAPGSP
CCAGCGAATCTCCTTCTGGCACC AGSPTSTEEGTSTEPSE
GCTCCAGGTTCTACTAGCGAATC GSAPGSEPATSGSETPG
CCCGTCTGGTACCGCACCAGGTA TSESATPESGPGTSTEPS
CTTCTCCTAGCGGCGAATCTTCTA EGSAP
CCGCACCAGGTACCTCTACCGAA
CCTTCCGAAGGTAGCGCTCCAGG
TAGCCCGGCAGGTTCTCCTACTT
CCACTGAGGAAGGTACTTCTACC
GAACCTTCTGAGGGTAGCGCACC
AGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCT
GAAAGCGCTACTCCTGAATCTGG
CCCAGGTACTTCTACTGAACCGT
CCGAGGGCAGCGCACCA
LCW462_r79 GGTACCTCTACCGAACCTTCCGA 575 GTSTEPSEGSAPGSPAG 576
AGGTAGCGCTCCAGGTAGCCCGG SPTSTEEGTSTEPSEGSA
CAGGTTCTCCTACTTCCACTGAG PGTSPSGESSTAPGTSPS
GAAGGTACTTCTACCGAACCTTC GESSTAPGTSPSGESST
TGAGGGTAGCGCACCAGGTACCT APGSTSESPSGTAPGSTS
CCCCTAGCGGCGAATCTTCTACT ESPSGTAPGTSTPESGS
GCTCCAGGTACCTCTCCTAGCGG ASPGSEPATSGSETPGT
CGAATCTTCTACCGCTCCAGGTA SESATPESGPGTSTEPSE
CCTCCCCTAGCGGTGAATCTTCT GSAP
ACCGCACCAGGTTCTACCAGCGA
ATCCCCTTCTGGTACTGCTCCAG
GTTCTACCAGCGAATCCCCTTCT
GGCACCGCACCAGGTACTTCTAC
CCCTGAAAGCGGCTCCGCTTCTC
CAGGTAGCGAACCTGCAACCTCT
GGCTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCG
TCCGAGGGCAGCGCACCA
LCW462_r87 GGTAGCGAACCGGCAACCTCTGG 577 GSEPATSGSETPGTSES 578
CTCTGAAACCCCAGGTACCTCTG ATPESGPGTSESATPES
AAAGCGCTACTCCGGAATCTGGT GPGTSPSGESSTAPGSTS
CCAGGTACTTCTGAAAGCGCTAC STAESPGPGTSPSGESST
TCCGGAATCCGGTCCAGGTACTT APGSTSESPSGTAPGTSP
CTCCGAGCGGTGAATCTTCTACC SGESSTAPGSTSSTAESP
GCACCAGGTTCTACTAGCTCTAC GPGSSTPSGATGSPGSS
CGCTGAATCTCCGGGCCCAGGTA TPSGATGSPGSSTPSGA
CTTCTCCGAGCGGTGAATCTTCT NWLS
ACTGCTCCAGGTTCTACTAGCGA
ATCCCCGTCTGGTACTGCTCCAG
GTACTTCCCCTAGCGGTGAATCT
TCTACTGCTCCAGGTTCTACCAG
CTCTACCGCAGAATCTCCGGGTC
CAGGTAGCTCTACTCCGTCTGGT
GCAACCGGTTCCCCAGGTAGCTC
TACCCCTTCTGGTGCAACCGGCT
CCCCAGGTAGCTCTACCCCTTCT
GGTGCAAACTGGCTCTCC
LCW462_r88 GGTAGCCCTGCTGGCTCTCCGAC 579 GSPAGSPTSTEEGSPAG 580
TTCTACTGAGGAAGGTAGCCCGG SPTSTEEGTSTEPSEGSA
CTGGTTCTCCGACTTCTACTGAG PGTSTEPSEGSAPGTSTE
GAAGGTACTTCTACCGAACCTTC PSEGSAPGTSESATPES
CGAAGGTAGCGCTCCAGGTACCT GPGASPGTSSTGSPGSS
CTACTGAACCTTCCGAAGGCAGC TPSGATGSPGASPGTSS
GCTCCAGGTACCTCTACCGAACC TGSPGSSTPSGATGSPG
GTCCGAGGGCAGCGCACCAGGTA TPGSGTASSSPGSSTPSG
CTTCTGAAAGCGCAACCCCTGAA ATGSP
TCCGGTCCAGGTGCATCTCCTGG
TACCAGCTCTACCGGTTCTCCAG
GTAGCTCTACTCCTTCTGGTGCTA
CTGGCTCTCCAGGTGCTTCCCCG
GGTACCAGCTCTACCGGTTCTCC
AGGTAGCTCTACCCCGTCTGGTG
CTACTGGTTCTCCAGGTACTCCG
GGCAGCGGTACTGCTTCTTCCTCT
CCAGGTAGCTCTACCCCTTCTGG
TGCTACTGGCTCTCCA
LCW462_r89 GGTAGCTCTACCCCGTCTGGTGC 581 GSSTPSGATGSPGTPGS 582
TACTGGTTCTCCAGGTACTCCGG GTASSSPGSSTPSGATG
GCAGCGGTACTGCTTCTTCCTCTC SPGSPAGSPTSTEEGTSE
CAGGTAGCTCTACCCCTTCTGGT SATPESGPGTSTEPSEGS
GCTACTGGCTCTCCAGGTAGCCC APGTSESATPESGPGSE
GGCTGGCTCTCCTACCTCTACTG PATSGSETPGTSESATPE
AGGAAGGTACTTCTGAAAGCGCT SGPGTSTEPSEGSAPGT
ACTCCTGAGTCTGGTCCAGGTAC SESATPESGPGTSESATP
CTCTACTGAACCGTCCGAAGGTA ESGP
GCGCTCCAGGTACCTCTGAAAGC
GCAACTCCTGAGTCTGGCCCAGG
TAGCGAACCTGCTACCTCCGGCT
CTGAGACTCCAGGTACCTCTGAA
AGCGCAACCCCGGAATCTGGTCC
AGGTACTTCTACTGAACCGTCTG
AAGGTAGCGCACCAGGTACTTCT
GAAAGCGCAACCCCGGAATCCG
GCCCAGGTACCTCTGAAAGCGCA
ACCCCGGAGTCCGGCCCA
Example 7 Construction of XTEN_AM288 The entire library LCW0462 was dimerized as described in Example 6 resulting in a library of XTEN_AM288 clones designated LCW0463. 1512 isolates from library LCW0463 were screened using the protocol described in Example 6. 176 highly expressing clones were sequenced and 40 preferred XTEN_AM288 segments were chosen for the construction of multifunctional proteins that contain multiple XTEN segments with 288 amino acid residues.
Example 8 Construction of XTEN_AM432 We generated a library of XTEN_AM432 segments by recombining segments from library LCW0462 of XTEN_AM144 segments and segments from library LCW0463 of XTEN_AM288 segments. This new library of XTEN_AM432 segment was designated LCW0464. Plasmid was isolated from cultures of E. coli harboring LCW0462 and LCW0463, respectively. 1512 isolates from library LCW0464 were screened using the protocol described in Example 6. 176 highly expressing clones were sequenced and 39 preferred XTEN_AM432 segment were chosen for the construction of longer XTENs and for the construction of multifunctional proteins that contain multiple XTEN segments with 432 amino acid residues.
In parallel we constructed library LMS0100 of XTEN_AM432 segments using preferred segments of XTEN_AM144 and XTEN_AM288. Screening of this library yielded 4 isolates that were selected for further construction
Example 9 Construction of XTEN_AM875 The stuffer vector pCW0359 was digested with BsaI and KpnI to remove the stuffer segment and the resulting vector fragment was isolated by agarose gel purification.
We annealed the phosphorylated oligonucleotide BsaI-AscI-KpnIforP: AGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 583) and the non-phosphorylated oligonucleotide BsaI-AscI-KpnIrev: CCTCGAGTGAAGACGAACCTCCCGTGCTTGGCGCGCCGCTTGCGCTTGC (SEQ ID NO: 584) for introducing the sequencing island A (SI-A) which encodes amino acids GASASGAPSTG (SEQ ID NO: 585) and has the restriction enzyme AscI recognition nucleotide sequence GGCGCGCC inside. The annealed oligonucleotide pairs were ligated with BsaI and KpnI digested stuffer vector pCW0359 prepared above to yield pCW0466 containing SI-A. We then generated a library of XTEN_AM443 segments by recombining 43 preferred XTEN_AM432 segments from Example 8 and SI-A segments from pCW0466 at C-terminus using the same dimerization process described in Example 5. This new library of XTEN_AM443 segments was designated LCW0479.
We generated a library of XTEN_AM875 segments by recombining segments from library LCW0479 of XTEN_AM443 segments and 43 preferred XTEN_AM432 segments from Example 8 using the same dimerization process described in Example 5. This new library of XTEN_AM875 segment was designated LCW0481.
Example 10 Construction of XTEN_AM1318 We annealed the phosphorylated oligonucleotide BsaI-FseI-KpnIforP: AGGTCCAGAACCAACGGGGCCGGCCCCAAGCGGAGGTTCGTCTTCACTCGAGGGTAC (SEQ ID NO: 586) and the non-phosphorylated oligonucleotide BsaI-FseI-KpnIrev: CCTCGAGTGAAGACGAACCTCCGCTTGGGGCCGGCCCCGTTGGTTCTGG (SEQ ID NO: 587) for introducing the sequencing island B (SI-B) which encodes amino acids GPEPTGPAPSG (SEQ ID NO: 588) and has the restriction enzyme FseI recognition nucleotide sequence GGCCGGCC inside. The annealed oligonucleotide pairs were ligated with BsaI and KpnI digested stuffer vector pCW0359 as used in Example 9 to yield pCW0467 containing SI-B. We then generated a library of XTEN_AM443 segments by recombining 43 preferred XTEN_AM432 segments from Example 8 and SI-B segments from pCW0467 at C-terminus using the same dimerization process described in Example 5. This new library of XTEN_AM443 segments was designated LCW0480.
We generated a library of XTEN_AM1318 segments by recombining segments from library LCW0480 of XTEN_AM443 segments and segments from library LCW0481 of XTEN_AM875 segments using the same dimerization process as in Example 5. This new library of XTEN_AM1318 segment was designated LCW0487.
Example 11 Construction of XTEN_AD864 Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AD864 sequences starting from segments of XTEN_AD36 listed in Example 1. These sequences were assembled as described in Example 5. Several isolates from XTEN_AD864 were evaluated and found to show good expression and excellent solubility under physiological conditions. One intermediate construct of XTEN_AD576 was sequenced. This clone was evaluated in a PK experiment in cynomolgus monkeys and a half-life of about 20 h was measured.
Example 12 Construction of XTEN_AF864 Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AF864 sequences starting from segments of XTEN_AF36 listed in Example 3. These sequences were assembled as described in Example 5. Several isolates from XTEN_AF864 were evaluated and found to show good expression and excellent solubility under physiological conditions. One intermediate construct of XTEN_AF540 was sequenced. This clone was evaluated in a PK experiment in cynomolgus monkeys and a half-life of about 20 h was measured. A full length clone of XTEN_AF864 had excellent solubility and showed half-life exceeding 60 h in cynomolgus monkeys. A second set of XTEN_AF sequences was assembled including a sequencing island as described in Example 9.
Example 13 Construction of XTEN_AG864 Using the several consecutive rounds of dimerization, we assembled a collection of XTEN_AG864 sequences starting from segments of XTEN_AD36 listed in Example 1. These sequences were assembled as described in Example 5. Several isolates from XTEN_AG864 were evaluated and found to show good expression and excellent solubility under physiological conditions. A full-length clone of XTEN_AG864 had excellent solubility and showed half-life exceeding 60 h in cynomolgus monkeys.
Example 14 Construction of N-Terminal Extensions of XTEN—Construction and Screening of 12mer Addition Libraries This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of fusion proteins without the presence of a helper domain. Historically expression of proteins with XTEN at the N-terminus was poor, yielding values that would essentially undetectable in the GFP fluorescence assay (<25% of the expression with the N-terminal CBD helper domain) To create diversity at the codon level, seven amino acid sequences were selected and prepared with a diversity of codons. Seven pairs of oligonucleotides encoding 12 amino acids with codon diversities were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of seven libraries. The resulting clones have N-terminal XTEN 12mers fused in-frame to XTEN_AM875-GFP to allow use of GFP fluorescence for screening the expression. Individual colonies from the seven created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. The number of colonies picked ranged from approximately half to a third of the theoretical diversity of the library (see Table 13).
TABLE 13
Theoretical Diversity and Sampling Numbers for 12mer Addition
Libraries. The amino acid residues with randomized codons
are underlined.
Amino Acid SEQ ID Theoretical Number
Library Motif Family Sequence NO: Diversity screened
LCW546 AE12 MASPAGSPTSTEE 589 572 2 plates (168)
LCW547 AE12 MATSESATPESGP 590 1536 5 plates (420)
LCW548 AF12 MATSPSGESSTAP 591 192 2 plates (168)
LCW549 AF12 MESTSSTAESPGP 592 384 2 plates (168)
LCW552 AG12 MASSTPSGATGSP 593 384 2 plates (168)
LCW553 AG12 MEASPGTSSTGSP 594 384 2 plates (168)
LCW554 (CBD-like) MASTPESGSSG 595 32 1 plate (84)
The saturated overnight cultures were used to inoculate fresh 500 μl cultures in auto-induction media in which they were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present (see FIG. 9 for results of expression assays). The results, graphed as box and whisker plots, indicate that while median expression levels were approximately half of the expression levels compared to the “benchmark” CBD N-terminal helper domain, the best clones from the libraries were much closer to the benchmarks, indicating that further optimization around those sequences was warranted. This is in contrast to previous XTEN versions that were <25% of the expression levels of the CBD N-terminal benchmark. The results also show that the libraries starting with amino acids MA had better expression levels than those beginning with ME. This was most apparent when looking at the best clones, which were closer to the benchmarks as they mostly start with MA. Of the 176 clones within 33% of the CBD-AM875 benchmark, 87% begin with MA, where as only 75% of the sequences in the libraries beginning with MA, a clear over representation of the clones beginning with MA at the highest level of expression. 96 of the best clones were sequenced to confirm identity and twelve sequences (see Table 14), 4 from LCW546, 4 from LCW547 and 4 from LCW552 were selected for further optimization.
TABLE 14
Advanced 12mer DNA Nucleotide Sequences
SEQ ID
Clone DNA Nucleotide Sequence NO:
LCW546_02 ATGGCTAGTCCGGCTGGCTCTCCGACCTCCACTGAGGAAGGTACTTCTACT 596
LCW546_06 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACTTCTACT 597
LCW546_07 ATGGCTAGTCCAGCAGGCTCTCCTACCTCCACCGAGGAAGGTACTTCTACT 598
LCW546_09 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTACT 599
LCW547_03 ATGGCTACATCCGAAAGCGCAACCCCTGAGTCCGGTCCAGGTACTTCTACT 600
LCW547_06 ATGGCTACATCCGAAAGCGCAACCCCTGAATCTGGTCCAGGTACTTCTACT 601
LCW547_10 ATGGCTACGTCTGAAAGCGCTACTCCGGAATCTGGTCCAGGTACTTCTACT 602
LCW547_17 ATGGCTACGTCCGAAAGCGCTACCCCTGAATCCGGTCCAGGTACTTCTACT 603
LCW552_03 ATGGCTAGTTCTACCCCGTCTGGTGCAACCGGTTCCCCAGGTACTTCTACT 604
LCW552_05 ATGGCTAGCTCCACTCCGTCTGGTGCTACCGGTTCCCCAGGTACTTCTACT 605
LCW552_10 ATGGCTAGCTCTACTCCGTCTGGTGCTACTGGTTCCCCAGGTACTTCTACT 606
LCW552_11 ATGGCTAGTTCTACCCCTTCTGGTGCTACTGGTTCTCCAGGTACTTCTACT 607
Example 15 Construction of N-Terminal Extensions of XTEN—Construction and Screening of Libraries Optimizing Codons 3 and 4 This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first two codons established (see Example supra), the third and fourth codons were randomized to determine preferences. Three libraries, based upon best clones from LCW546, LCW547 and LCW552, were designed with the third and fourth residues modified such that all combinations of allowable XTEN codons were present at these positions (see FIG. 10). In order to include all the allowable XTEN codons for each library, nine pairs of oligonucleotides encoding 12 amino acids with codon diversities of third and fourth residues were designed, annealed and ligated into the NdeI/BsaI restriction enzyme digested stuffer vector pCW0551 (Stuffer-XTEN_AM875-GFP), and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of three libraries LCW0569-571. With 24 XTEN codons the theoretical diversity of each library is 576 unique clones. A total of 504 individual colonies from the three created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media in which were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 75 clones from the screen were sequenced and retested for GFP reporter expression versus the benchmark samples (see FIG. 11). 52 clones yielded usable sequencing data and were used for subsequent analysis. The results were broken down by library and indicate that LCW546 was the superior library. The results are presented in Table 15. Surprisingly, it was discovered that base-lined fluorescence readings for the best clones were ˜900 AU, whereas the CBD N-terminal benchmark was only ˜600 AU. This indicates that this library had instituted an approximately 33% improvement over the best clones from the previous library which were approximately equal in expression to the CBD N-terminal benchmark (Example 14).
TABLE 15
Third and Fourth Codon Optimization Library Comparison
LCW569 LCW570 LCW571
N 21 15 16
Mean Fluorescence (AU) 628 491 537
SD 173 71 232
CV 28% 15% 43%
Further trends were seen in the data showing preferences for particular codons at the third and fourth position. Within the LCW569 library the glutamate codon GAA at the third position and the threonine codon ACT were associated with higher expression as seen in Table 16.
TABLE 16
Preferred Third and Fourth Codons in LCW569
3 = GAA Rest 4 = ACT Rest
N 8 13 4 17
Mean Fluorescence (AU) 749 554 744 601
SD 234 47 197 162
CV 31% 9% 26% 27%
Additionally, the retest of the top 75 clones indicated that several were now superior to the benchmark clones.
Example 16 Construction of N-Terminal Extensions of XTEN—Construction and Screening of Combinatorial 12mer and 36mer Libraries This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first two codons established (see Example supra), the N-terminus was examined in a broader context by combining the 12 selected 12mer sequences (see Example supra) at the very N-terminus followed by 125 previously constructed 36mer segments (see example supra) in a combinatorial manner. This created novel 48mers at the N-terminus of the XTEN protein and enabled the assessment of the impact of longer-range interactions at the N-terminus on expression of the longer sequences (FIG. 12). Similar to the dimerization procedures used to assemble 36mers (see Example infra), the plasmids containing the 125 selected 36mer segments were digested with restriction enzymes BbsI/NcoI and the appropriate fragment was gel-purified. The plasmid from clone AC94 (CBD-XTEN_AM875-GFP) was also digested with BsaI/NcoI and the appropriate fragments were gel-purified. These fragments were ligated together and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of the library LCW0579, which also served as the vector for further cloning 12 selected 12mers at the very N-terminus. The plasmids of LCW0579 were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. 12 pairs of oligonucleotides encoding 12 selected 12mer sequences were designed, annealed and ligated with the NdeI/EcoRI/BsaI digested LCW0579 vector, and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of the library LCW0580. With a theoretical diversity of 1500 unique clones, a total of 1512 individual colonies from the created library were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media that were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 90 clones were sequenced and retested for GFP reporter expression. 83 clones yielded usable sequencing data and were used for subsequent analysis. The sequencing data was used to determine the lead 12mer that was present in each clone and the impact of each 12mer on expression was assessed. Clones LCW546_06 and LCW546_09 stood out as being the superior N-terminus (see Table 17).
TABLE 17
Relative Performance of Clones Starting with
LCW546 06 and LCW459 09
LCW546_06 All Others LCW546_09 All Others
N 11 72 9 74
Mean 1100 752 988 775
Fluorescence
(AU)
SD 275 154 179 202
CV 25% 20% 18% 26%
The sequencing and retest also revealed several instances of independent replicates of the same sequence in the data producing similar results, thus increasing confidence in the assay. Additionally, 10 clones with 6 unique sequences were superior to the benchmark clone. They are presented in Table 18. It was noted that these were the only occurrences of these sequences and in no case did one of these sequences occur and fail to beat the bench-mark clone. These six sequences were advanced for further optimization.
TABLE 18
Combinatorial 12mer and 36mer Clones Superior to Benchmark Clone
Clone Name First 60 codons SEQ ID NO: 12mer Name 36mer Name
LCW580_51 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT 608 LCW546_06 LCW0404_040
GAGGAAGGTGCATCCCCGGGCACCAGCTCTACC
GGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCT
ACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGT
GCTACTGGCTCTCCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_81 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT 609 LCW546_06 LCW0404_040
GAGGAAGGTGCATCCCCGGGCACCAGCTCTACC
GGTTCTCCAGGTAGCTCTACCCCGTCTGGTGCT
ACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGT
GCTACTGGCTCTCCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_38 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT 610 LCW546_06 LCW0402_041
GAGGAAGGTACTTCTACCGAACCGTCCGAGGGT
AGCGCACCAGGTAGCCCAGCAGGTTCTCCTACC
TCCACCGAGGAAGGTACTTCTACCGAACCGTCC
GAGGGTAGCGCACCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_63 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 611 LCW546_09 LCW0402_020
GAGGAAGGTACTTCTACTGAACCGTCTGAAGGC
AGCGCACCAGGTAGCGAACCGGCTACTTCCGGT
TCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCA
ACTTCTACTGAAGAAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_06 ATGGCTAGTCCTGCTGGCTCTCCAACCTCCACT 612 LCW546_06 LCW0404_031
GAGGAAGGTACCCCGGGTAGCGGTACTGCTTCT
TCCTCTCCAGGTAGCTCTACCCCTTCTGGTGCAA
CCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCT
CTACCGGTTCTCCAGGTACTTCTACTGAACCGT
CTGAAGGCAGCGCA
LCW580_35 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 613 LCW546_09 LCW0402_020
GAGGAAGGTACTTCTACTGAACCGTCTGAAGGC
AGCGCACCAGGTAGCGAACCGGCTACTTCCGGT
TCTGAAACCCCAGGTAGCCCAGCAGGTTCTCCA
ACTTCTACTGAAGAAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_67 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 614 LCW546_09 LCW0403_064
GAGGAAGGTACCTCCCCTAGCGGCGAATCTTCT
ACTGCTCCAGGTACCTCTCCTAGCGGCGAATCT
TCTACCGCTCCAGGTACCTCCCCTAGCGGTGAA
TCTTCTACCGCACCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_13 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 615 LCW546_09 LCW0403_060
GAGGAAGGTACCTCTACTCCGGAAAGCGGTTCC
GCATCTCCAGGTTCTACCAGCGAATCCCCGTCT
GGCACCGCACCAGGTTCTACTAGCTCTACTGCT
GAATCTCCGGGCCCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_88 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 616 LCW546_09 LCW0403_064
GAGGAAGGTACCTCCCCTAGCGGCGAATCTTCT
ACTGCTCCAGGTACCTCTCCTAGCGGCGAATCT
TCTACCGCTCCAGGTACCTCCCCTAGCGGTGAA
TCTTCTACCGCACCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
LCW580_11 ATGGCTAGTCCTGCTGGCTCTCCGACCTCTACT 617 LCW546_09 LCW0403_060
GAGGAAGGTACCTCTACTCCGGAAAGCGGTTCC
GCATCTCCAGGTTCTACCAGCGAATCCCCGTCT
GGCACCGCACCAGGTTCTACTAGCTCTACTGCT
GAATCTCCGGGCCCAGGTACTTCTACTGAACCG
TCTGAAGGCAGCGCA
Example 17 Construction of N-Terminal Extensions of XTEN—Construction and Screening of Combinatorial 12mer and 36mer Libraries for XTEN-AM875 and XTEN-AE864 This example details a step in the optimization of the N-terminus of the XTEN protein to promote the initiation of translation to allow for expression of XTEN fusions at the N-terminus of proteins without the presence of a helper domain. With preferences for the first four codons (see Examples supra, and for the best pairing of N-terminal 12mers and 36mers (see Example supra) established, a combinatorial approach was undertaken to examine the union of these preferences. This created novel 48mers at the N-terminus of the XTEN protein and enabled the testing of the confluence of previous conclusions. Additionally, the ability of these leader sequences to be a universal solution for all XTEN proteins was assessed by placing the new 48mers in front of both XTEN-AE864 and XTEN-AM875. Instead of using all 125 clones of 36mer segment, the plasmids from 6 selected clones of 36mer segment with best GFP expression in the combinatorial library were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. The plasmids from clones AC94 (CBD-XTEN_AM875-GFP) and AC104 (CBD-XTEN_AE864-GFP) were digested with digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. These fragments were ligated together and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of the libraries LCW0585 (−XTEN_AM875-GFP) and LCW0586 (−XTEN_AE864-GFP), which could also serve as the vectors for further cloning 8 selected 12mers at the very N-terminus. The plasmids of LCW0585 and LCW0586 were digested with NdeI/EcoRI/BsaI and the appropriate fragments were gel-purified. 8 pairs of oligonucleotides encoding 8 selected 12mer sequences with best GFP expression in the previous (Generation 2) screening were designed, annealed and ligated with the NdeI/EcoRI/BsaI digested LCW0585 and LCW0586 vectors, and transformed into E. coli BL21Gold(DE3) competent cells to obtain colonies of the final libraries LCW0587 (XTEN_AM923-GFP) and LCW0588 (XTEN_AE912-GFP). With a theoretical diversity of 48 unique clones, a total of 252 individual colonies from the created libraries were picked and grown overnight to saturation in 500 μl of super broth media in a 96 deep well plate. This provided sufficient coverage to understand relative library performance and sequence preferences. The saturated overnight cultures were used to inoculate new 500 μl cultures in auto-induction media in which were grown overnight at 26° C. These expression cultures were then assayed using a fluorescence plate reader (excitation 395 nm, emission 510 nm) to determine the amount of GFP reporter present. The top 36 clones were sequenced and retested for GFP reporter expression. 36 clones yielded usable sequencing data and these 36 were used for the subsequent analysis. The sequencing data determined the 12mer, the third codon, the fourth codon and the 36mer present in the clone and revealed that many of the clones were independent replicates of the same sequence. Additionally, the retest results for these clones are close in value, indicating the screening process was robust. Preferences for certain combinations at the N-terminus were seen and were consistently yielding higher fluorescence values approximately 50% greater than the benchmark controls (see Tables 19 and 20). These date support the conclusion that the inclusion of the sequences encoding the optimized N-terminal XTEN into the fusion protein genes conferred a marked enhancement on the expression of the fusion proteins.
TABLE 19
Preferred N-terminal Combinations for XTEN-AM875
Number of
Clone Name Replicates 12mer 36mer Mean SD CV
CBD-AM875 NA NA NA 1715 418 16%
LCW587_08 7 LCW546_06_3 = GAA LCW404_40 2333 572 18%
LCW587_17 5 LCW546_09_3 = GAA LCW403_64 2172 293 10%
TABLE 20
Preferred N-terminal Combinations for XTEN-AE864
Number of
Clone Name Replicates 12mer 36mer Mean SD CV
AC82 NA NA NA 1979 679 24%
LCW588_14 8 LCW546_06_opt3 LCW404_31 2801 240 6%
LCW588_27 2 LCW546_06_opt34 LCW404_40 2839 556 15%
Notably, the preferred combination of the N-terminal for the XTEN-AM875 and the preferred combination for the XTEN-AE864 are not the same (Tables 19 and 20), indicating more complex interactions further than 150 bases from the initiation site influence expression levels. The sequences for the preferred nucleotide sequences are listed in Table 21 and the preferred clones were analyzed by SDS-PAGE to independently confirm expression (see FIG. 13). The complete sequences of XTEN_AM923 and XTEN_AE912 were selected for further analysis.
TABLE 21
Preferred DNA Nucleotide Sequences for first 48 Amino Acid Residues of
N-terminal XTEN-AM875 and XTEN-AE864
XTEN
Clone Name Modified DNA Nucleotide Sequence SEQ ID NO:
LCW587_08 AM875 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC 618
CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG
GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC
TCTCCAGGTACTTCTACTGAACCGTCTGAAGGCAGCGCA
LCW587_17 AM875 ATGGCTGAACCTGCTGGCTCTCCGACCTCTACTGAGGAAGGTACCTC 619
CCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCG
AATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTACC
GCACCAGGTACTTCTACTGAACCGTCTGAAGGCAGCGCA
LCW588_14 AE864 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGTACCCC 620
GGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTGG
TGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCAGCTCTACCGGTT
CTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG
LCW588_27 AE864 ATGGCTGAAACTGCTGGCTCTCCAACCTCCACTGAGGAAGGTGCATC 621
CCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGCTCTACCCCGTCTG
GTGCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTACTGGC
TCTCCAGGTAGCCCGGCTGGCTCTCCTACCTCTACTGAG
Example 18 Methods of Producing and Evaluating GHXTEN; XTEN-hGH as Example A general schema for producing and evaluating GHXTEN compositions is presented in FIG. 6, and forms the basis for the general description of this Example. Using the disclosed methods and those known to one of ordinary skill in the art, together with guidance provided in the illustrative examples, a skilled artesian can create and evaluate a range of GHXTEN fusion proteins comprising, XTENs, GH and variants of GH known in the art. The Example is, therefore, to be construed as merely illustrative, and not limitative of the methods in any way whatsoever; numerous variations will be apparent to the ordinarily skilled artisan. In this Example, a GHXTEN of human growth hormone linked to an XTEN of the AE family of motifs would be created.
The general scheme for producing polynucleotides encoding XTEN is presented in FIGS. 4 and 5. FIG. 5 is a schematic flowchart of representative steps in the assembly of a XTEN polynucleotide construct in one of the embodiments of the invention. Individual oligonucleotides 501 are annealed into sequence motifs 502 such as a 12 amino acid motif (“12-mer”), which is subsequently ligated with an oligo containing BbsI, and KpnI restriction sites 503. The motif libraries can be limited to specific sequence XTEN families; e.g., AD, AE, AF, AG, AM, or AQ sequences of Table 1. In this case, the motifs of the AE family would be used as the motif library, which are annealed to the 12-mer to create a “building block” length; e.g., a segment that encodes 36 amino acids. The gene encoding the XTEN sequence can be assembled by ligation and multimerization of the “building blocks” until the desired length of the XTEN gene 504 is achieved. As illustrated in FIG. 5, the XTEN length in this case is 48 amino acid residues, but longer lengths can be achieved by this process. For example, multimerization can be performed by ligation, overlap extension, PCR assembly or similar cloning techniques known in the art. The XTEN gene can be cloned into a stuffer vector. In the example illustrated in FIG. 5, the vector can encode a Flag sequence 506 followed by a stuffer sequence that is flanked by BsaI, BbsI, and KpnI sites 507 and a GH gene (e.g., hGH) 508, resulting in the gene encoding the GHXTEN 500, which, in this case encodes the fusion protein in the configuration, N- to C-terminus, XTEN-hGH.
DNA sequences encoding GH can be conveniently obtained by standard procedures known in the art from a cDNA library prepared from an appropriate cellular source, from a genomic library, or may be created synthetically (e.g., automated nucleic acid synthesis) using DNA sequences obtained from publicly available databases, patents, or literature references. A gene or polynucleotide encoding the GH portion of the protein can be then be cloned into a construct, such as those described herein, which can be a plasmid or other vector under control of appropriate transcription and translation sequences for high level protein expression in a biological system. A second gene or polynucleotide coding for the XTEN portion (in the case of FIG. 5 illustrated as an AE with 48 amino acid residues) can be genetically fused to the nucleotides encoding the N-terminus of the hGH gene by cloning it into the construct adjacent and in frame with the gene coding for the hGH, through a ligation or multimerization step. In this manner, a chimeric DNA molecule coding for (or complementary to) the XTEN-hGH GHXTEN fusion protein would be generated within the construct. Optionally, a gene encoding for a second XTEN could be inserted and ligated in-frame to the nucleotides encoding the C-terminus of the XTEN-hGH gene, resulting in a construct encoding an XTEN-hGH-XTEN fusion protein. The construct can be designed in different configurations to encode the various permutations of the fusion partners as a monomeric polypeptide. For example, the gene can be created to encode the fusion protein in the order (N- to C-terminus): hGH-XTEN; XTEN-hGH; hGH-XTEN-hGH; XTEN-hGH-XTEN; as well as multimers of the foregoing. Optionally, this chimeric DNA molecule may be transferred or cloned into another construct that is a more appropriate expression vector. At this point, a host cell capable of expressing the chimeric DNA molecule would be transformed with the chimeric DNA molecule. The vectors containing the DNA segments of interest can be transferred into an appropriate host cell by well-known methods, depending on the type of cellular host, as described supra.
Host cells containing the XTEN-GH expression vector would be cultured in conventional nutrient media modified as appropriate for activating the promoter. The culture conditions, such as temperature, pH and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. After expression of the fusion protein, cells would be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for purification of the fusion protein, as described below. For GHXTEN compositions secreted by the host cells, supernatant from centrifugation would be separated and retained for further purification.
Gene expression would be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, gene expression would be measured by immunological of fluorescent methods, such as immunohistochemical staining of cells to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal Conveniently, the antibodies may be prepared against the hGH sequence polypeptide using a synthetic peptide based on the sequences provided herein or against exogenous sequence fused to hGH and encoding a specific antibody epitope. Examples of selectable markers are well known to one of skill in the art and include reporters such as enhanced green fluorescent protein (EGFP), beta-galactosidase ((β-gal) or chloramphenicol acetyltransferase (CAT).
The XTEN-hGH polypeptide product would be purified via methods known in the art. Procedures such as gel filtration, affinity purification, salt fractionation, ion exchange chromatography, size exclusion chromatography, hydroxyapatite adsorption chromatography, hydrophobic interaction chromatography or gel electrophoresis are all techniques that may be used in the purification. Specific methods of purification are described in Robert K. Scopes, Protein Purification: Principles and Practice, Charles R. Castor, ed., Springer-Verlag 1994, and Sambrook, et al., supra. Multi-step purification separations are also described in Baron, et al., Crit. Rev. Biotechnol. 10:179-90 (1990) and Below, et al., J. Chromatogr. A. 679:67-83 (1994).
As illustrated in FIG. 6, the isolated XTEN-hGH fusion proteins would then be characterized for their chemical and activity properties. Isolated fusion protein would be characterized, e.g., for sequence, purity, apparent molecular weight, solubility and stability using standard methods known in the art. The fusion protein meeting expected standards would then be evaluated for activity, which can be measured in vitro or in vivo by measuring one of the growth hormone-associated parameters described herein, using one or more assays disclosed herein, or using the assays of the Examples or Table 34.
In addition, the XTEN-hGH fusion protein would be administered to one or more animal species to determine standard pharmacokinetic parameters, as described in Examples 30-32.
By the iterative process of producing, expressing, and recovering XTEN-hGH constructs, followed by their characterization using methods disclosed herein or others known in the art, the GHXTEN compositions comprising hGH and an XTEN can be produced and evaluated by one of ordinary skill in the art to confirm the expected properties such as enhanced solubility, enhanced stability, improved pharmacokinetics and reduced immunogenicity, leading to an overall enhanced therapeutic activity compared to the corresponding unfused hGH. For those fusion proteins not possessing the desired properties, a different sequence can be constructed, expressed, isolated and evaluated by these methods in order to obtain a composition with such properties.
Example 19 Construction of Genes and Vectors of hGH Linked to K and Y XTEN Sequences K Series GHXTEN Constructs
A pET-series vector was constructed with T7 promoter, which expresses a protein containing cellulose binding domain (CBD) at the N-terminus, followed by a Tomato Etch Virus (TEV) protease cleavage site, followed by the hGH coding sequence, and by the K288 coding sequence: CBD-K288-hGH. The K288 has the repetitive sequence (GEGGGEGGE) 32 (SEQ ID NO: 622). The CBD sequence used is shown in Swissprot file Q06851 and the purification of CBD fusion proteins is described in Ofir, K. et al. (2005) Proteomics 5:1806. The sequence of the TEV cleavage site is ENLYFQ/X (SEQ ID NO: 623); G was used in the X position. This construct was transformed into BL21(DE3)-star E.coli strain and grown under conditions promoting expression. Cells were collected and disrupted. The cellular supernatant was applied on beaded cellulose resin (Perloza 100), washed with buffer A (25 mM Tris pH=8.0) and eluted from the column with 20 mM NaOH. pH was adjusted by titrating the sample with 1M Tris buffer pH=8.0. Protein purity was estimated to be above 90%. The eluted protein was digested with purified TEV protease overnight at 4° C., and the digested sample was applied to a beaded cellulose resin (Perloza 100). The CBD was retained on the column, and the K288-hGH was found in the column flow-through. The pooled flow-through was loaded on the anion-exchange (Q-sepharose, Pharmacia), washed with buffer A (25 mM Tris pH=8.0) and eluted from the column using a shallow linear gradient of same buffer with 1M NaCl. The eluted fusion protein was pooled, dialyzed against buffer A, concentrated, and purified by size-exclusion chromatography (SEC) as the final purification. Protein purity was estimated to be above 98%. The final protein is K288-hGH. SDS PAGE analyses of samples throughout the purification process are shown in FIG. 20.
Y Series GHXTEN Contructs
The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BbsI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN destination vector. The pCBD-XTEN plasmid is a pET30 derivative from Novagen in the format of Cellulose Binding Domain (CBD)-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 576 or greater. Constructs were generated by replacing a stuffer sequence in pCBD-XTEN with the hGH-encoding fragment (FIG. 7B). The pCBD-XTEN features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_Y and encode lengths that include 36, 72, 144, 288, and 576 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pCBD-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vector yields the CBD_XTEN_hGH gene under the control of a T7 promoter. The resulting DNA sequences encoded for GH linked to XTEN of lengths of 36, 72, 144, and 288 amino acids, respectively.
Example 20 Construction of hGH-XTEN Genes and Vectors using AE and AM XTEN Sequences The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced NdeI and BbsI restriction sites that are compatible with the NdeI and BsaI sites that flank the stuffer in the XTEN destination vector. The pXTEN plasmid is a pET30 derivative from Novagen in the format of Stuffer-XTEN, where Stuffer can be either green fluorescent protein (GFP) or CBD and XTEN can be any length from 36 to 1318 amino acids or greater (FIG. 7). Constructs were generated by replacing a stuffer sequence in pXTEN with the hGH-encoding fragment. The pXTEN features a T7 promoter upstream of the stuffer sequence, and an XTEN sequence fused in-frame downstream of the stuffer sequence. The XTEN sequences employed belong to the AE or AM family of XTEN and encode lengths that include 36, 72, 144, 288, 576, 864, 875 and 1318 amino acids. The stuffer fragment was removed by restriction digest using NdeI and BsaI endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pXTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired constructs were confirmed by DNA sequencing. The final vector yields the hGH-XTEN gene under the control of a T7 promoter, and would be used to express a fusion protein with hGH at the N-terminus.
Example 21 Construction of XTEN-hGH and XTEN-hGH Genes and Vectors using AE and AM XTEN Sequences The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BbsI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the XTEN destination vector. The pCBD-XTEN plasmid is a pET30 derivative from Novagen in the format of Cellulose Binding Domain (CBD)-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 1318 or greater (FIG. 7). Constructs were generated by replacing a stuffer sequence in pCBD-XTEN with the hGH-encoding fragment. The pCBD-XTEN features a T7 promoter upstream of CBD followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_AE and XTEN_AM and encode lengths that include 36, 72, 144, 288, 576, 864, 875 and 1318 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pCBD-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vector yields the CBD_XTEN_hGH gene under the control of a T7 promoter, and would be used to express a fusion protein with hGH at the C-terminus.
Example 22 Construction of XTEN-AE_hGH_XTEN-AE Genes and Vectors The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BsaI and HindIII restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the pNTS-XTEN destination vector. The pNTS-XTEN_AE plasmid is a pET30 derivative from Novagen in the format of N-terminal XTEN expression sequence of 48 amino acids-XTEN-Stuffer, where Stuffer is green fluorescent protein (GFP) and XTEN can be any length from 36 to 576 or greater. Constructs were generated by replacing a stuffer sequence in pNTS-XTEN with the hGH-encoding fragment. The pNTS-XTEN features a T7 promoter upstream of NTS followed by an XTEN sequence fused in-frame upstream of the stuffer sequence. The XTEN sequences employed belong to family XTEN_AE and encode lengths that can include 36, 72, 144, 288, 576, 864, and 1296 amino acids. The stuffer fragment was removed by restriction digest using BbsI and HindIII endonucleases. Restriction digested hGH DNA fragment was ligated into the cleaved pNTS-XTEN vector using T4 DNA ligase and electroporated into BL21(DE3) Gold (Stratagene). In some cases, a second XTEN_AE sequence of 144 or 288 amino acids was ligated to the C-terminus of the hGH encoding gene, the steps of which are illustrated in FIG. 8. The gene encoding hGH was amplified by polymerase chain reaction (PCR), which introduced BsaI and HindIII (with additional BbsI in front of HindIII) restriction sites that are compatible with the BbsI and HindIII sites that flank the stuffer in the pNTS-XTEN destination vector. After restriction enzyme digestions, ligation and transformation, the resulting intermediate plasmid has the format of pNTS-XTEN-hGH with the BbsI/HindIII restriction sites at the C-terminus of hGH. The intermediate plasmid was further digested with BbsI and HindIII, ligated with the second XTEN_AE sequence of 144 or 288 amino acids flanked by BsaI and HindIII, placing the AE144 or the AE288 encoding sequenes at the C-terminus of the XTEN-hGH gene, and transformed into BL21(DE3)Gold. Transformants were screened by DNA miniprep and the desired construct was confirmed by DNA sequencing. The final vectors, described above, yield the genes in configurations of either NTS_XTEN_hGH or NTS_XTEN_hGH_XTEN, under the control of a T7 promoter, as shown in FIGS. 7C and 7D.
Example 23 Purification of GHXTEN_AE Constructs Protein Expression
The plasmids described above were transformed into BL21(DE3)-Gold E. coli strain (Novagen) and plated on an LB-agar plate with the appropriate antibiotics and grown overnight at 37° C. A single colony was inoculated into 5 ml of TB125 medium and grown overnight at 37° C. The next day the inoculum was transformed into a 2 L vessel with 500 ml of TB125, and grown until an OD=0.6 was reached, followed by continued growth at 26° C. for 16 hr with 0.1 mM IPTG.
Cells were collected by centrifugation and the cell pellet was resuspended in 50 ml Buffer containing 5 mM Tris pH 8.0, 100 mM NaCl. Cells were disrupted using an APV-2000 homogenizer. The pH of the lysate was then adjusted to pH 4.5 with acetic acid to precipitate contaminating host cell proteins and was subsequently clarified by centrifugation. The clarified, acid-treated lysate was then applied to a DE52 Anion exchange chromatography column and eluted with NaCl. The eluted fraction was then further acidified to pH 4.2 and applied to a MacroCapSP cation exchange chromatography column Product was eluted using sequential elution with NaCl. An additional chromatography step employing Macrocap Q was implemented to remove product-related aggregates and residual host cell impurities (e.g. endotoxin, DNA, host cell protein).
Protein purity was estimated to be above 98%. The quantity of eluted fusion protein was determined by SDS-PAGE analysis and by measurement of total protein concentration. The high quantity of eluted GHXTEN fusion protein reflects the higher degree of solubility of the fusion protein relative to hGH not linked to XTEN (see, e.g., Singh, S. M., et al. (2005) J Biosci Bioeng, 99: 303; Patra, A. K., et al. (2000) Protein Expr Purif. 18: 182), as well as the ability to remain soluble at acidified conditions that result in the precipitation of host cell protein.
Final Formulation and Storage
The buffer exchanged proteins were then concentrated using 10K MWCO Vivacell 100 centrifugal ultrafiltration unit to not less than 15 mg/ml. The concentrate was sterile filtered using a 0.22 um syringe filter. The final solution was aliquoted and stored at −80° C.
Example 24 Characterization of GHXTEN Constructs SDS-PAGE Analysis
5 μg of final purified GHXTEN proteins of GH linked to Y576 (either N- or C-terminus of Y576) was subjected to both non-reducing and reducing SDS-PAGE using NuPAGE 4-12% Bis-Tris gel from Invitrogen according to manufacturer's specifications. The resulting gel is shown in FIG. 20.
Analytical Size Exclusion Chromatography
Size exclusion chromatography analysis was performed using a TSKGel-G4000 SWXL (7.8 mm×30 cm) column. 20 ug of the purified protein at a concentration of 1 mg/ml was separated at a flowrate of 0.6 ml/min in 20 mM phosphate pH 6.8, 114 mM NaCl. Chromatogram profiles were monitored using OD214 nm and OD280 nm. Column calibration was performed using a size exclusion calibration standard from BioRad, the markers include thyroglobulin (670 kDa), bovine gamma-globulin (158 kDa), chicken ovalbumin (44 kDa), equine myoglobuin (17 kDa) and vitamin B12 (1.35 kDa). The chromatographic profiles of Y576-GH were generated and demonstrate that the apparent molecular weight of each construct is significantly larger than that expected for a globular protein, in comparison to the standard proteins run in the same assay (data not shown).
Analytical RP-HPLC
Analytical RP-HPLC chromatography analysis was performed using a C4 (7.8 mm×20 cm) column. The column was equilibrated with 100% AcetonNitrile plus 0.1% TFA in the mobile phase at a flowrate of 1 ml/min. Twenty micro gram of the purified protein, with and without denaturing, at a concentration of 0.2 mg/ml was injected separately. The protein was separated and eluted by liner gradient within 15 min from 5% to 60% of buffer containing HPLC grade H20 plus 0.1% TFA. Chromatogram profiles were monitored using OD214 nm and OD280 nm. The chromatographic profiles of native and denatured Y576-GH are shown as an overlay in FIG. 21.
Example 25 ELISA-Based Binding Assays XTEN fusions to GH were tested in a standard ELISA-based assay to evaluate their ability to bind to GH Receptor. Assays were performed using a sandwich ELISA format in which a recombinant hGH receptor (hGHR-Fc) is coated onto wells of an ELISA plate. The wells were then blocked, washed, and GHXTEN samples are then incubated in the wells at varying dilutions to allow capture of the GHXTEN. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of a polyclonal or monoclonal anti-GH or anti-XTEN antibody and streptavidin HRP. The fraction of bound protein can be calculated by comparing the colorimetric response at each serum dilution to a standard curve of unmodified GH. In a first assay comparing hGH bound to K288 compared to recombinant hGH, the results, show in FIG. 15, demonstrate the ability of GHXTEN to bind to the hGH receptor. In a second assay, two configurations of GHXTEN; AM864-hGH and hGH-AM864; compared to recombinant hGH. The results, shown in FIG. 16, indicate apparent EC50 values for native hGH of 0.0701 nM, AM864-hGH of 0.3905, and hGH-AM864 of 2.733. In a third assay, recombinant hGH was compared to AE912-hGH-AE144 in order to show the ability to reduce binding affinity by the addition of a C-terminal XTEN to the hGH component of an GHXTEN fusion protein, and the results (FIG. 18) demonstrate a decrease in binding affinity of approximately 17-fold compared to hGH.
Example 26 Effect of Heat Treatment on the Stability of hGH and GHXTEN The ability of XTEN to confer structural stability on the attached therapeutic molecule was investigated. Samples of hGH and AM864-hGH were incubated at 25° C. and 80° C., and then analyzed by gel electrophoresis and Coomassie staining FIG. 17A is an SDS-PAGE gel of the two preparations treated at 25° C. and 80° C. for 15 minutes, while FIG. 17B shows the corresponding percentage of receptor binding activity of the 80° C. sample relative to the 25° C. treatment. The results indicate that hGH denatures under the treatment conditions while the GHXTEN construct remains largely stable under the experimental conditions, retaining nearly 80% of its receptor binding activity.
Conclusions: The XTEN component of the GHXTEN fusion protein confers enhanced solubility and stability properties to the fusion protein in comparison to hGH not linked to XTEN.
Example 27 Comparative Effects of hGH and AM864-hGH on Secretion of IGF-1 The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of circulating IGF-1 in response to administered compound. FIG. 24 shows the effects of daily administration of hGH (0.071 mg/kg daily) or a single dose of AM864-hGH (5 mg/kg; equivalent to 1.1 mg/kg) on circulating IGF-1 levels in cynomolgus monkeys (n=4/group), depicted as percentage change compared to baseline. The results show enhanced activity by the GHXTEN construct, despite being dosed only once at the beginning of the experiment.
Example 28 Comparative Effects of hGH and AM864-hGH on Body Weight Gain The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of body weight gain in a hypox rat in response to administered compound. FIG. 25 shows the effects of administration of hGH or AM864-hGH at the indicated doses and dose frequency on body weight in hypox rats. The results show retention of biologic activity by the GHXTEN constructs that is equivalent in potency to comparable dosage of hGH, yet with less frequent dosing. Increased dosage of AM864-hGH led to increases in body weight gains showing enhancement of the pharmacodynamic properties of the GHXTEN compared to hGH under these conditions.
Example 29 Comparative Effects of hGH and AM864-hGH on Bone Cartilage The ability of a GHXTEN to retain pharmacologic potency was assessed using the measured parameter of increase in tibial epiphyseal plate width in hypox rats. FIG. 26 shows the comparative effects of administration of placebo, hGH, and AM864-hGH, shown in histologic cross-sections of the tibia from rats after 9 days of treatment, with the margins denoted with dotted lines. Groups are the same as shown in FIG. 26. FIG. 26A shows that the placebo group had an average cross-section width of 344±38.6 μm of the plate after 9 days. FIG. 26B shows that the hGH group (10 μg daily) had an average cross-section width of 598±8.5 μm after 9 days. FIG. 26C shows that the AM864-hGH (15 mg/kg q3d) had an average cross-section width of 944±8.5 μm after 9 days. The results show enhanced activity by the GHXTEN construct compared to hGH, despite being dosed at less frequent intervals.
Example 30 PK Analysis of GHXTEN Protein Fusions GH-Y576 and Y576h-GH (in this case indicating the N- to C-terminus order of GH and XTEN) were injected into cynomolgus monkeys in order to determine in vivo pharmacokinetic parameters. The compositions were provided in an aqueous buffer and were administered by intravenous routes into separate animals at 0.15 mg/kg dosing. Serum samples were collected at various time points following administration and analyzed for serum concentrations of the accessory proteins. Analysis was performed using a sandwich ELISA format. Rabbit polyclonal anti-XTEN (to Y-type XTEN) antibodies were coated onto wells of an ELISA plate. Serum samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti-XTEN antibody and streptavidin HRP. Serum protein concentrations were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package.
FIG. 22 shows the concentration profile of the two GH constructs following intravenous administration to cynomolgus monkeys. Following IV administration, the half-life was calculated to be 7 hours for hGH-Y576 and 10.5 hours for Y576-hGH. For reference, the published half-life of unmodified GH is well described in the literature as 10-15 minutes in adult humans (see, e.g., Hindmarch, P. C., et al., Clinical Endocrinology (2008) 30(4): 443-450). The results show that the orientation (N- versus C-terminal) of hGH relative to the XTEN did not affect the clearance of the fusion proteins, and that addition of the Y576 greatly extended the terminal half-life of the fusion protein.
Another pharmacokinetic study in cynomolgus monkeys was performed using the AM864-hGH construct. FIG. 23 shows the pharmacokinetic profile after a single dose of 5 mg/kg AM864-hGH administered subcutaneously to cynomolgus monkeys, with the derived equivalent hGH concentration shown (dashed line).
Conclusions: The XTEN component of the GHXTEN fusion protein confers enhanced pharmacokinetic properties to the fusion protein in comparison to hGH not linked to XTEN, under these conditions.
Example 31 PK Analysis of hGH XTEN Fusion Polypeptides in Rats The GHXTEN fusion proteins AE912-hGH, AM864-hGH (synonym to AM875-hGH for this and following Examples), AE912-hGH-AE144 and AE912-hGH-AE288 were evaluated in rats in order to determine in vivo pharmacokinetic parameters of the hGHXTEN polypeptides. All compositions were provided in an aqueous buffer and were administered by subcutaneous (SC) route into separate animals using 1.5 mg/kg single doses. Plasma samples were collected at various time points following administration and analyzed for concentrations of the test articles. Analysis was performed using a sandwich ELISA format. Recombinant hGHR-Fc was coated onto wells of an ELISA plate. The wells were blocked, washed and plasma samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti hGH antibody and streptavidin HRP. Concentrations of test article were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package.
FIG. 27 shows the concentration profiles of the four hGH XTEN constructs after subcutaneous administration. The calculated terminal half-life for AE912-hGH was 7.5 h, 6.8 h for AM864-hGH (synonym for AM875-hGH), 12.4 h for AE912-hGH-AE144 and 13.1 h for AE912-hGH-AE288. For comparison, unmodified hGH was run in parallel in the same experiment and showed a dramatically shorter plasma half-life.
Conclusions: The incorporation of different XTEN sequences into fusion proteins comprising hGH results in significant enhancement of pharmacokinetic parameters for all four compositions compared to unmodified hGH, as demonstrated in the rodent model under these conditions. The addition of a second XTEN protein to the C-terminus of the AE-hGH constructs results in a further enhancement of the terminal half-life compared to the constructs with a single XTEN; likely due to reduced receptor mediated clearance.
Example 32 PK Analysis of hGH XTEN Fusion Polypeptides in Cynomolgus Monkeys GHXTEN fusion proteins containing one or two XTEN molecules (AE912-hGH, AM864-hGH, and AE912-hGH-AE144) were evaluated in cynomolgus monkeys in order to determine the effect of the inclusion of a second XTEN on in vivo pharmacokinetic parameters of the hGHXTEN polypeptides. All compositions were provided in an aqueous buffer and were administered by subcutaneous (SC) route into separate animals using 1.5 mg/kg single doses. Plasma samples were collected at various time points following administration and analyzed for concentrations of the test articles. Analysis was performed using a sandwich ELISA format. Recombinant hGHR-Fc was coated onto wells of an ELISA plate. The wells were blocked, washed and plasma samples were then incubated in the wells at varying dilutions to allow capture of the compound by the coated antibodies. Wells were washed extensively, and bound protein was detected using a biotinylated preparation of the polyclonal anti hGH antibody and streptavidin HRP. Concentrations of test article were calculated at each time point by comparing the colorimetric response at each serum dilution to a standard curve. Pharmacokinetic parameters were calculated using the WinNonLin software package, and FIG. 28 shows the concentration profiles of the three hGH XTEN constructs after subcutaneous administration over the 336 h period. The average terminal half-life for the fusion proteins were 33 h for AM864-hGH, 44 h for AE912-hGH, and 110 h for the AE912-hGH-AE144 (containing two XTEN linked to the N- and C-termini of hGH).
Conclusions: The incorporation of different XTEN sequences into fusion proteins comprising hGH resulted in significant enhancement of pharmacokinetic parameters for all three compositions, as demonstrated in the cyno model under these conditions, with the construct containing a second XTEN linked to the C-terminus of the hGH showing a greater than about two-fold enhancement of the terminal half-life compared to the GHXTEN with a single XTEN at the N-terminus.
Example 33 Assessment of Pharmacodynamic Effects of AE912-hGH-AE144 GHXTEN by Measurement of IGF-1 Response in Cynomolgus Monkeys AE912-hGH-AE144 was administered to male and female cynos SC at 0.3, 1.5, and 7.5 mg/kg and dose volumes ranging from 0.80 to 1.13 ml. Blood samples (1.0 mL) were collected into prechilled heparinized tubes at predose, 2, 4, 8, 24, 48, 72, 96, 120, 168, 216, 264, 336, 388, 432, 504 hour timepoints (16), and processed into plasma. PK was measured by ELISA assay using the anti-XTEN capture antibody and the biotinylated anti-hGH detection antibody. IGF-1 samples were sent to and analyzed by Millipore. PK parameters were calculated by analysis using the WinNonLin software package and are shown in the table below. Plasma concentration profiles of the three doses of GHXTEN and IGF-1 levels are shown in FIG. 29 and FIG. 30, respectively (open circles=0.3 mg/kg; squares=1.5 mg/kg; triangles=7.5 mg/kg). The results show that administration of AE912-hGH-AE144 results in a sustained increase in IGF-1 levels, consistent with both the biological mode of action of growth hormone and the long plasma half-life of AE912-hGH-AE144.
TABLE 22
PK parameters in cynomolgus monkeys
0.3 mg/kg 1.5 mg/kg 7.5 mg/kg
Route SC SC SC
T ½ (hrs) 84.4 97.5 101.1
Cmax (nM) 41 910 340
AUC (nM*hr) 5,170 162,000 64,100
Example 34 Comparative Bioavailability of AE912-hGH-AE144 via Subcutaneous and Intramuscular Administration to Cynomolgus Monkeys AE912-hGH-AE144 was administered to male and female cynos SC at 1.5 mg/kg via intravenous, subcutaneous, and intramuscular routes. Blood samples (1.0 mL) were collected into prechilled heparinized tubes at predose, 2, 4, 8, 24, 48, 72, 96, 120, 168, 216, 264, 336, 388, 432, 504 hour timepoints (16), and processed into plasma. Plasma levels at each time point were measured by ELISA assay using the anti-XTEN capture antibody and the biotinylated anti-hGH detection antibody. PK and bioavailability parameters were calculated by analysis using the WinNonLin software package and are shown in the table below. Plasma concentration profiles are shown in FIG. 31 (open circles=subcutaneous; triangle=IV; squares=intramuscular). For bioavailability calculations, the AUC for intravenous administration was defined to be 100%. The results show that AE912-hGH-AE144 shows a high bioavailability and distributes rapidly from the injection site to the blood compartment following injection.
TABLE 23
PK parameters in cynomolgus monkeys
1.5 mg/kg 1.5 mg/kg 1.5 mg/kg
Route SC IV IM
T ½ (hrs) 97.5 107.7 102.2
Cmax (nM) 910 462 245
AUC (nM*hr) 162,000 60,300 43,200
Bioavailability ~100% 100% 72%
Example 35 Determination of the Therapeutic Window for AE912-hGH-AE144 The specific activity of the GHXTEN AE912-hGH-AE144 was assessed using the measured parameter of body weight gain in a hypophysectomized (hypox) rat in response to administered compound. FIG. 32 shows the effects of administration of vehicle (open circles), recombinant hGH dosed at 5 nmol/kg/day (closed circles), the GHXTEN AE912-hGH-AE144 at varying doses and dose frequency (closed triangles=0.5 nmol/kg/day; open triangles=1.5 nmol/day; squares=3 nmol/kg/Q2D) on body weight in hypox rats. The results show that a dose of the GHXTEN AE912-hGH-AE144 as low as 1.5 nmol/kg/day yields comparable growth to hGH alone. However, a lower dose of 0.5 nmol/kg/day does not promote growth in these animals. Based on the pharmacokinetic profiles determined in the rats, a model for plasma levels following repeat dosing was constructed as shown in FIG. 33 (same groups as per FIG. 32). The model clearly differentiates the efficacious doses from the non-efficacious lower dose. The results show that plasma concentration of AE912-hGH-AE144 generally should remain above about 1 nmol/L concentration in order to maintain optimal growth in the hypophysectomized rat model.
Example 36 Human Clinical Trial Designs for Evaluating GHXTEN Clinical trials can be designed such that the efficacy and advantages of the GHXTEN compositions, relative to the corresponding growth hormone biologics, can be verified in humans. For example, the GHXTEN fusion constructs comprising growth, as described in the Examples above, can be used in clinical trials for characterizing the efficacy of the compositions. The trials can be conducted in one or more growth hormone-related diseases, disorders, or conditions that are improved, ameliorated, or inhibited by the administration of growth hormone. Such studies in adult patients comprise three phases. First, a Phase I safety and pharmacokinetics study in adult patients is conducted to determine the maximum tolerated dose and pharmacokinetics and pharmacodynamics in humans (either normal subjects or patients with a growth disease or condition), as well as to define potential toxicities and adverse events to be tracked in future studies. The study is conducted in which single rising doses of compositions of fusion proteins of GHXTEN is administered and biochemical, PK, and clinical parameters is measured. This permits the determination of the maximum tolerated dose and establishes the threshold and maximum concentrations in dosage and circulating drug that constitute the therapeutic window for the respective components. Thereafter, clinical trials are conducted in patients with the disease, disorder or condition.
Phase II and III Clinical Trials
A phase II dosing study is conducted in patients where blood growth hormone pharmacodynamics and other physiologic, PK, safety and clinical parameters (such as listed below) appropriate for trials, such as for reversal of short stature due to GH deficiency in pediatric patients, treatment of Turner syndrome, chronic renal failure, Prader-Willi syndrome, intrauterine growth retardation, or improvements in body mass composition (increase in lean body mass, decrease in fat mass) in adult patients (such as HIV+ or acquired pituitary tumor patients). Parameters and clinical endpoints are measured as a function of the dosing of the fusion proteins compositions, yielding dose-ranging information on doses that would be appropriate for a subsequent Phase III trial, in addition to collecting safety data related to adverse events. The PK parameters are correlated to the physiologic, clinical and safety parameter data to establish the therapeutic window and the therapeutic dose regimen for the GHXTEN composition, permitting the clinician to establish the approrpirate dose ranges for a GHXTEN composition. Finally, a phase III efficacy study is conducted wherein patients would be administered the GHXTEN composition at the dose regimen, and a positive control (such as a commercially-available, approved growth hormone), or a placebo is administered daily or using other dosing schedule deemed appropriate given the pharmacokinetic and pharmacodynamic properties of the control composition, with all agents administered for an appropriately extended period of time to achieve the study endpoints. Parameters that are monitored include GH, IGF-1 and IGFBP3 concentrations, changes in height velocity, lean body mass, total body fat, trunk fat, parameters associated with insulin resistance syndrome, measurement of division and multiplication rates of chondrocytes, and/or changes in bone density and/or bone growth; parameters that would be tracked relative to the placebo or positive control groups. Efficacy outcomes would be determined using standard statistical methods. Toxicity and adverse event markers are also be followed in this study to verify that the compound is safe when used in the manner described.
Example 37 Analytical Size Exclusion Chromatography of XTEN Fusion Proteins with Diverse Payloads Size exclusion chromatography analyses were performed on fusion proteins containing various therapeutic proteins and unstructured recombinant proteins of increasing length. An exemplary assay used a TSKGel-G4000 SWXL (7.8 mm×30 cm) column in which 40 μg of purified glucagon fusion protein at a concentration of 1 mg/ml was separated at a flow rate of 0.6 ml/min in 20 mM phosphate pH 6.8, 114 mM NaCl. Chromatogram profiles were monitored using OD214 nm and OD280 nm. Column calibration for all assays were performed using a size exclusion calibration standard from BioRad; the markers include thyroglobulin (670 kDa), bovine gamma-globulin (158 kDa), chicken ovalbumin (44 kDa), equine myoglobuin (17 kDa) and vitamin B12 (1.35 kDa). Representative chromatographic profiles of Glucagon-Y288, Glucagon-Y144, Glucagon-Y72, Glucagon-Y36 are shown as an overlay in FIG. 34. The data show that the apparent molecular weight of each compound is proportional to the length of the attached XTEN sequence. However, the data also show that the apparent molecular weight of each construct is significantly larger than that expected for a globular protein (as shown by comparison to the standard proteins run in the same assay). Based on the SEC analyses for all constructs evaluated, including a GHXTEN composition, the Apparent Molecular Weights, the Apparent Molecular Weight Factor (expressed as the ratio of Apparent Molecular Weight to the calculated molecular weight) and the hydrodynamic radius (RH in nm) are shown in Table 24. The results indicate that incorporation of different XTENs of 576 amino acids or greater confers an apparent molecular weight for the fusion protein of approximately 339 kDa to 760, and that XTEN of 864 amino acids or greater confers an apparent molecular weight greater than approximately 800 kDA. The results of proportional increases in apparent molecular weight to actual molecular weight were consistent for fusion proteins created with XTEN from several different motif families; i.e., AD, AE, AF, AG, and AM, with increases of at least four-fold and ratios as high as about 17-fold. Additionally, the incorporation of XTEN fusion partners with 576 amino acids or more into fusion proteins with the various payloads (and 288 residues in the case of glucagon fused to Y288) resulted with a hydrodynamic radius of 7 nm or greater; well beyond the glomerular pore size of approximately 3-5 nm. Accordingly, it is expected that fusion proteins comprising growth and XTEN have reduced renal clearance, contributing to increased terminal half-life and improving the therapeutic or biologic effect relative to a corresponding un-fused biologic payload protein.
TABLE 24
SEC analysis of various polypeptides
Apparent
XTEN or Actual Apparent Molecular
Construct fusion Therapeutic MW MW Weight RH
Name partner Protein (kDa) (kDa) Factor (nm)
AC14 Y288 Glucagon 28.7 370 12.9 7.0
AC28 Y144 Glucagon 16.1 117 7.3 5.0
AC34 Y72 Glucagon 9.9 58.6 5.9 3.8
AC33 Y36 Glucagon 6.8 29.4 4.3 2.6
AC89 AF120 Glucagon 14.1 76.4 5.4 4.3
AC88 AF108 Glucagon 13.1 61.2 4.7 3.9
AC73 AF144 Glucagon 16.3 95.2 5.8 4.7
AC53 AG576 GFP 74.9 339 4.5 7.0
AC39 AD576 GFP 76.4 546 7.1 7.7
AC41 AE576 GFP 80.4 760 9.5 8.3
AC52 AF576 GFP 78.3 526 6.7 7.6
AC85 AE864 Exendin-4 83.6 938 11.2 8.9
AC114 AM875 Exendin-4 82.4 1344 16.3 9.4
AC143 AM875 hGH 100.6 846 8.4 8.7
AC227 AM875 IL-1ra 95.4 1103 11.6 9.2
AC228 AM1318 IL-1ra 134.8 2286 17.0 10.5
Example 38 Pharmacokinetics of Extended Polypeptides Fused to GFP in Cynomolgus Monkeys The pharmacokinetics of GFP-L288, GFP-L576, GFP-XTEN_AF576, GFP-XTEN_Y576 and XTEN_AD836-GFP were tested in cynomolgus monkeys to determine the effect of composition and length of the unstructured polypeptides on PK parameters. Blood samples were analyzed at various times after injection and the concentration of GFP in plasma was measured by ELISA using a polyclonal antibody against GFP for capture and a biotinylated preparation of the same polyclonal antibody for detection. Results are summarized in FIG. 35. They show a surprising increase of half-life with increasing length of the XTEN sequence. For example, a half-life of 10 h was determined for GFP-XTEN_L288 (with 288 amino acid residues in the XTEN). Doubling the length of the unstructured polypeptide fusion partner to 576 amino acids increased the half-life to 20-22 h for multiple fusion protein constructs; i.e., GFP-XTEN_L576, GFP-XTEN_AF576, GFP-XTEN_Y576. A further increase of the unstructured polypeptide fusion partner length to 836 residues resulted in a half-life of 72-75 h for XTEN_AD836-GFP. Thus, increasing the polymer length by 288 residues from 288 to 576 residues increased in vivo half-life by about 10 h. However, increasing the polypeptide length by 260 residues from 576 residues to 836 residues increased half-life by more than 50 h. These results show that there is a surprising threshold of unstructured polypeptide length that results in a greater than proportional gain in in vivo half-life. Thus, fusion proteins comprising extended, unstructured polypeptides are expected to have the property of enhanced pharmacokinetics compared to polypeptides of shorter lengths.
Example 39 Serum Stability of XTEN A fusion protein containing XTEN_AE864 fused to the N-terminus of GFP was incubated in monkey plasma and rat kidney lysate for up to 7 days at 37° C. Samples were withdrawn at time 0, Day 1 and Day 7 and analyzed by SDS PAGE followed by detection using Western analysis and detection with antibodies against GFP as shown in FIG. 14. The sequence of XTEN_AE864 showed negligible signs of degradation over 7 days in plasma. However, XTEN_AE864 was rapidly degraded in rat kidney lysate over 3 days. The in vivo stability of the fusion protein was tested in plasma samples wherein the GFP_AE864 was immunoprecipitated and analyzed by SDS PAGE as described above. Samples that were withdrawn up to 7 days after injection showed very few signs of degradation. The results demonstrate the resistance of GHXTEN to degradation due to serum proteases; a factor in the enhancement of pharmacokinetic properties of the GHXTEN fusion proteins.
Example 40 PK Analysis of Ex4-XTEN Fusion Protein in Multiple Species and Predicted Human Half-Life To determine the predicted pharmacokinetic profile in humans of a therapeutic protein fused to XTEN, studies were performed using exendin-4 fused to the AE864 XTEN as a single fusion polypeptide. The Ex4-XTEN construct was administered to four different animal species at 0.5-1.0 mg/kg, subcutaneously and intravenously. Serum samples were collected at intervals following administration, with serum concentrations determined using standard methods. The half-life for each species was determined, and is tabulated in Table 25. The results were used to predict the human half-life using allometric scaling of terminal half-life, volume of distribution, and clearance rates based on average body mass. FIG. 36A shows a plot of measured terminal half-life versus body mass in the animal species, with a predicted T1/2 in a 75 kg human of 140 h, compared to the reported half-life of exenatide of 2.4 h (Bond, A. Proc (Bayl Univ Med Cent) 19(3): 281-284. (2006)). FIG. 36B shows measured drug clearance versus body mass, with a predicted clearance rate value of 30 ml/h in a 75 kg human FIG. 36C shows measured volume of distribution versus body mass, with a predicted value of 5970 ml in a 75 kg human.
Conclusions: It can be concluded from the results that addition of an XTEN to a glucose-regulating peptide, such as exendin-4, can greatly increase the terminal half-life compared to the peptide not linked to XTEN.
TABLE 25
Half-life of Ex4-XTEN
Species Half-Life (hr)
Mouse 13.5
Rat 31.7
Monkey 60.7
Dog 72.8
Human 140*
*Predicted value based on allometric scaling
Example 41 Increasing Solubility and Stability of a Peptide Payload by Linking to XTEN In order to evaluate the ability of XTEN to enhance the physical/chemical properties of solubility and stability, fusion proteins of glucagon plus shorter-length XTEN were prepared and evaluated. The test articles were prepared in Tris-buffered saline at neutral pH and characterization of the Gcg-XTEN solution was by reverse-phase HPLC and size exclusion chromatography to affirm that the protein was homogeneous and non-aggregated in solution. The data are presented in Table 26. For comparative purposes, the solubility limit of unmodified glucagon in the same buffer was measured at 60 μM (0.2 mg/mL), and the result demonstrate that for all lengths of XTEN added, a substantial increase in solubility was attained. Importantly, in most cases the glucagon-XTEN fusion proteins were prepared to achieve target concentrations and were not evaluated to determine the maximum solubility limits for the given construct. However, in the case of glucagon linked to the AF-144 XTEN, the limit of solubility was determined, with the result that a 60-fold increase in solubility was achieved, compared to glucagon not linked to XTEN. In addition, the glucagon-AF144 GHXTEN was evaluated for stability, and was found to be stable in liquid formulation for at least 6 months under refrigerated conditions and for approximately one month at 37° C. (data not shown).
Conclusions: The data support the conclusion that the linking of short-length XTEN polypeptides to a biologically active protein such as glucagon can markedly enhance the solubility properties of the protein by the resulting fusion protein, as well as confer stability at the higher protein concentrations.
TABLE 26
Solubility of Glucagon-XTEN constructs
Test Article Solubility
Glucagon 60 μM
Glucagon-Y36 >370 μM
Glucagon-Y72 >293 μM
Glucagon-AF108 >145 μM
Glucagon-AF120 >160 μM
Glucagon-Y144 >497 μM
Glucagon-AE144 >467 μM
Glucagon-AF144 >3600 μM
Glucagon-Y288 >163 μM
Example 42 Characterization of XTEN Fusion Protein Secondary Structure The fusion protein Ex4-AE864 was evaluated for degree of secondary structure by circular dichroism spectroscopy. CD spectroscopy was performed on a Jasco J-715 (Jasco Corporation, Tokyo, Japan) spectropolarimeter equipped with Jasco Peltier temperature controller (TPC-348WI). The concentration of protein was adjusted to 0.2 mg/mL in 20 mM sodium phosphate pH 7.0, 50 mM NaCl. The experiments were carried out using HELLMA quartz cells with an optical path-length of 0.1 cm. The CD spectra were acquired at 5°, 25°, 45°, and 65° C. and processed using the J-700 version 1.08.01 (Build 1) Jasco software for Windows. The samples were equilibrated at each temperature for 5 min before performing CD measurements. All spectra were recorded in duplicate from 300 nm to 185 nm using a bandwidth of 1 nm and a time constant of 2 sec, at a scan speed of 100 nm/min. The CD spectrum shown in FIG. 37 shows no evidence of stable secondary structure and is consistent with an unstructured polypeptide.
Example 43 Analysis of Sequences for Secondary Structure by Prediction Algorithms Amino acid sequences can be assessed for secondary structure via certain computer programs or algorithms, such as the well-known Chou-Fasman algorithm (Chou, P. Y., et al. (1974) Biochemistry, 13: 222-45) and the Garnier-Osguthorpe-Robson, or “GOR” method (Gamier J, Gibrat J F, Robson B. (1996). GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540-553). For a given sequence, the algorithms can predict whether there exists some or no secondary structure at all, expressed as total and/or percentage of residues of the sequence that form, for example, alpha-helices or beta-sheets or the percentage of residues of the sequence predicted to result in random coil formation.
Several representative sequences from XTEN “families” have been assessed using two algorithm tools for the Chou-Fasman and GOR methods to assess the degree of secondary structure in these sequences. The Chou-Fasman tool was provided by William R Pearson and the University of Virginia, at the “Biosupport” internet site, URL located on the World Wide Web at fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi?rm=misc1 as it existed on Jun. 19, 2009. The GOR tool was provided by Pole Informatique Lyonnais at the Network Protein Sequence Analysis internet site, URL located on the World Wide Web at .npsa-pbil.ibcp.fr/cgi-bin/secpred_gor4.pl as it existed on Jun. 19, 2008.
As a first step in the analyses, a single XTEN sequence was analyzed by the two algorithms. The AE864 composition is a XTEN with 864 amino acid residues created from multiple copies of four 12 amino acid sequence motifs consisting of the amino acids G, S, T, E, P, and A. The sequence motifs are characterized by the fact that there is limited repetitiveness within the motifs and within the overall sequence in that the sequence of any two consecutive amino acids is not repeated more than twice in any one 12 amino acid motif, and that no three contiguous amino acids of full-length the XTEN are identical. Successively longer portions of the AF 864 sequence from the N-terminus were analyzed by the Chou-Fasman and GOR algorithms (the latter requires a minimum length of 17 amino acids). The sequences were analyzed by entering the FASTA format sequences into the prediction tools and running the analysis. The results from the analyses are presented in Table 27.
The results indicate that, by the Chou-Fasman calculations, the four motifs of the AE family (Table 1) have no alpha-helices or beta sheets. The sequence up to 288 residues was similarly found to have no alpha-helices or beta sheets. The 432 residue sequence is predicted to have a small amount of secondary structure, with only 2 amino acids contributing to an alpha-helix for an overall percentage of 0.5%. The full-length AF864 polypeptide has the same two amino acids contributing to an alpha-helix, for an overall percentage of 0.2%. Calculations for random coil formation revealed that with increasing length, the percentage of random coil formation increased. The first 24 amino acids of the sequence had 91% random coil formation, which increased with increasing length up to the 99.77% value for the full-length sequence.
Numerous XTEN sequences of 500 amino acids or longer from the other motif families were also analyzed and revealed that the majority had greater than 95% random coil formation. The exceptions were those sequences with one or more instances of three contiguous serine residues, which resulted in predicted beta-sheet formation. However, even these sequences still had approximately 99% random coil formation.
In contrast, a polypeptide sequence of 84 residues limited to A, S, and P amino acids was assessed by the Chou-Fasman algorithm, which predicted a high degree of predicted alpha-helices. The sequence, which had multiple repeat “AA” and “AAA” sequences, had an overall predicted percentage of alpha-helix structure of 69%. The GOR algorithm predicted 78.57% random coil formation; far less than any sequence consisting of 12 amino acid sequence motifs consisting of the amino acids G, S, T, E, P, analyzed in the present Example.
Conclusions: The analysis supports the conclusion that: 1) XTEN created from multiple sequence motifs of G, S, T, E, P, and A that have limited repetitiveness as to contiguous amino acids are predicted to have very low amounts of alpha-helices and beta-sheets; 2) that increasing the length of the XTEN does not appreciably increase the probability of alpha-helix or beta-sheet formation; and 3) that progressively increasing the length of the XTEN sequence by addition of non-repetitive 12-mers consisting of the amino acids G, S, T, E, P, and A results in increased percentage of random coil formation. In contrast, polypeptides created from amino acids limited to A, S and P that have a higher degree of internal repetitiveness are predicted to have a high percentage of alpha-helices, as determined by the Chou-Fasman algorithm, as well as random coil formation. Based on the numerous sequences evaluated by these methods, it is concluded that XTEN created from sequence motifs of G, S, T, E, P, and A that have limited repetitiveness (defined as no more than two identical contiguous amino acids in any one motif) greater than about 400 amino acid residues in length are expected to have very limited secondary structure. With the exception of motifs containing three contiguous serines, it is believed that any order or combination of sequence motifs from Table 1 can be used to create an XTEN polypeptide of a length greater than about 400 residues that will result in an XTEN sequence that is substantially devoid of secondary structure. Such sequences are expected to have the characteristics described in the GHXTEN embodiments of the invention disclosed herein.
TABLE 27
CHOU-FASMAN and GOR prediction calculations of polypeptide sequences
SEQ SEQ ID No. Chou-Fasman GOR
NAME Sequence NO: Residues Calculation Calculation
GSTSESPSGTAP 624 12 Residue totals*: H: 0 E: 0 Not
percent: H: 0.0 E: 0.0 Determined
GTSTPESGSASP 625 12 Residue totals: H: 0 E: 0 Not
percent: H: 0.0 E: 0.0 Determined
GTSPSGESSTAP 626 12 Residue totals: H: 0 E: 0 Not
percent: H: 0.0 E: 0.0 Determined
GSTSSTAESPGP 627 12 Residue totals: H: 0 E: 0 Not
percent: H: 0.0 E: 0.0 Determined
GSPAGSPTSTEEGTSESATPESGP 628 24 Residue totals: H: 0 E: 0 91.67%
percent: H: 0.0 E: 0.0
GSPAGSPTSTEEGTSESATPESGPG 629 36 Residue totals: H: 0 E: 0 94.44%
TSTEPSEGSAP percent: H: 0.0 E: 0.0
GSPAGSPTSTEEGTSESATPESGPG 630 48 Residue totals: H: 0 E: 0 93.75%
TSTEPSEGSAPGSPAGSPTSTEE percent: H: 0.0 E: 0.0
GSPAGSPTSTEEGTSESATPESGPG 631 60 Residue totals: H: 0 E: 0 96.67%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.0 E: 0.0
TEPSEGSAP
GSPAGSPTSTEEGTSESATPESGPG 632 108 Residue totals: H: 0 E: 0 97.22%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.0 E: 0.0
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSE
TPGSEPATSGSETP
GSPAGSPTSTEEGTSESATPESGPG 633 216 Residue totals: H: 0 E: 0 99.07%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.0 E: 0.0
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSETPGSEPAT
SGSETPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAP
GSPAGSPTSTEEGTSESATPESGPG 634 432 Residue totals: H: 2 E: 3 99.54%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.5 E: 0.7
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSETPGSEPAT
SGSETPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTS
TEPSEGSAPGTSESATPESGPGTSES
ATPESGPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAP
GSPAGSPTSTEEGTSTEPSEGSAP
AE864 GSPAGSPTSTEEGTSESATPESGPG 635 864 Residue totals: H: 2 E: 3 99.77%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.2 E: 0.3
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSETPGSEPAT
SGSETPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTS
TEPSEGSAPGTSESATPESGPGTSES
ATPESGPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAP
GSPAGSPTSTEEGTSTEPSEGSAPG
TSESATPESGPGSEPATSGSETPGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGTSTEPSEGSAPGTSESA
TPESGPGSPAGSPTSTEEGSPAGSPT
STEEGSPAGSPTSTEEGTSESATPES
GPGTSTEPSEGSAPGTSESATPESG
PGSEPATSGSETPGTSESATPESGP
GSEPATSGSETPGTSESATPESGPG
TSTEPSEGSAPGSPAGSPTSTEEGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGSPAGSPTSTEEGSPAGS
PTSTEEGTSTEPSEGSAPGTSESATP
ESGPGTSESATPESGPGTSESATPES
GPGSEPATSGSETPGSEPATSGSET
PGSPAGSPTSTEEGTSTEPSEGSAP
GTSTEPSEGSAPGSEPATSGSETPG
TSESATPESGPGTSTEPSEGSAP
AD 576 GSSESGSSEGGPGSGGEPSESGSSG 636 576 Residue totals: H: 7 E: 0 99.65%
SSESGSSEGGPGSSESGSSEGGPGSS percent: H: 1.2 E: 0.0
ESGSSEGGPGSSESGSSEGGPGSSE
SGSSEGGPGESPGGSSGSESGSEGS
SGPGESSGSSESGSSEGGPGSSESGS
SEGGPGSSESGSSEGGPGSGGEPSE
SGSSGESPGGSSGSESGESPGGSSG
SESGSGGEPSESGSSGSSESGSSEG
GPGSGGEPSESGSSGSGGEPSESGS
SGSEGSSGPGESSGESPGGSSGSES
GSGGEPSESGSSGSGGEPSESGSSG
SGGEPSESGSSGSSESGSSEGGPGE
SPGGSSGSESGESPGGSSGSESGESP
GGSSGSESGESPGGSSGSESGESPG
GSSGSESGSSESGSSEGGPGSGGEP
SESGSSGSEGSSGPGESSGSSESGSS
EGGPGSGGEPSESGSSGSSESGSSE
GGPGSGGEPSESGSSGESPGGSSGS
ESGESPGGSSGSESGSSESGSSEGG
PGSGGEPSESGSSGSSESGSSEGGP
GSGGEPSESGSSGSGGEPSESGSSG
ESPGGSSGSESGSEGSSGPGESSGSS
ESGSSEGGPGSEGSSGPGESS
AE576 GSPAGSPTSTEEGTSESATPESGPG 637 576 Residue totals: H: 2 E: 0 99.65%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.4 E: 0.0
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSETPGSEPAT
SGSETPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTS
TEPSEGSAPGTSESATPESGPGTSES
ATPESGPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAP
GSPAGSPTSTEEGTSTEPSEGSAPG
TSESATPESGPGSEPATSGSETPGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGTSTEPSEGSAPGTSESA
TPESGPGSPAGSPTSTEEGSPAGSPT
STEEGSPAGSPTSTE7EGTSESATPE
SGPGTSTEPSEGSAP
AF540 GSTSSTAESPGPGSTSSTAESPGPGS 638 540 Residue totals: H: 2 E: 0 99.65
TSESPSGTAPGSTSSTAESPGPGSTS percent: H: 0.4 E: 0.0
STAESPGPGTSTPESGSASPGSTSES
PSGTAPGTSPSGESSTAPGSTSESPS
GTAPGSTSESPSGTAPGTSPSGESST
APGSTSESPSGTAPGSTSESPSGTAP
GTSPSGESSTAPGSTSESPSGTAPGS
TSESPSGTAPGSTSESPSGTAPGTST
PESGSASPGSTSESPSGTAPGTSTPE
SGSASPGSTSSTAESPGPGSTSSTAE
SPGPGTSTPESGSASPGTSTPESGSA
SPGSTSESPSGTAPGTSTPESGSASP
GTSTPESGSASPGSTSESPSGTAPGS
TSESPSGTAPGSTSESPSGTAPGSTS
STAESPGPGTSTPESGSASPGTSTPE
SGSASPGSTSESPSGTAPGSTSESPS
GTAPGTSTPESGSASPGSTSESPSGT
APGSTSESPSGTAPGTSTPESGSASP
GTSPSGESSTAPGSTSSTAESPGPGT
SPSGESSTAPGSTSSTAESPGPGTST
PESGSASPGSTSESPSGTAP
AF504 GASPGTSSTGSPGSSPSASTGTGPG 639 504 Residue totals: H: 0 E: 0 94.44%
SSPSASTGTGPGTPGSGTASSSPGSS percent: H: 0.0 E: 0.0
TPSGATGSPGSNPSASTGTGPGASP
GTSSTGSPGTPGSGTASSSPGSSTPS
GATGSPGTPGSGTASSSPGASPGTS
STGSPGASPGTSSTGSPGTPGSGTA
SSSPGSSTPSGATGSPGASPGTSSTG
SPGTPGSGTASSSPGSSTPSGATGSP
GSNPSASTGTGPGSSPSASTGTGPG
SSTPSGATGSPGSSTPSGATGSPGA
SPGTSSTGSPGASPGTSSTGSPGASP
GTSSTGSPGTPGSGTASSSPGASPG
TSSTGSPGASPGTSSTGSPGASPGT
SSTGSPGSSPSASTGTGPGTPGSGT
ASSSPGASPGTSSTGSPGASPGTSST
GSPGASPGTSSTGSPGSSTPSGATG
SPGSSTPSGATGSPGASPGTSSTGSP
GTPGSGTASSSPGSSTPSGATGSPG
SSTPSGATGSPGSSTPSGATGSPGSS
PSASTGTGPGASPGTSSTGSP
AE864 GSPAGSPTSTEEGTSESATPESGPG 640 864 Residue totals: H: 2 E: 3 99.77%
TSTEPSEGSAPGSPAGSPTSTEEGTS percent: H: 0.2 E: 0.4
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGSEPATSGSETPGSEPAT
SGSETPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTS
TEPSEGSAPGTSESATPESGPGTSES
ATPESGPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSA
GSPAGSPTSTEEGTSTEPSEGSAPG
TSESATPESGPGSEPATSGSETPGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGTSTEPSEGSAPGTSESA
TPESGPGSPAGSPTSTEEGSPAGSPT
STEEGSPAGSPTSTEEGTSESATPES
GPGTSTEPSEGSAPGTSESATPESG
PGSEPATSGSETPGTSESATPESGP
GSEPATSGSETPGTSESATPESGPG
TSTEPSEGSAPGSPAGSPTSTEEGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGSPAGSPTSTEEGSPAGS
PTSTEEGTSTEPSEGSAPGTSESATP
ESGPGTSESATPESGPGTSESATPES
GPGSEPATSGSETPGSEPATSGSET
PGSPAGSPTSTEEGTSTEPSEGSAP
GTSTEPSEGSAPGSEPATSGSETPG
TSESATPESGPGTSTEPSSGSAP
AF864 GSTSESPSGTAPGTSPSGESSTAPGS 641 875 Residue totals: H: 2 E: 0 95.20%
TSESPSGTAPGSTSESPSGTAPGTST percent: H: 0.2 E: 0.0
PESGSASPGTSTPESGSASPGSTSES
PSGTAPGSTSESPSGTAPGTSPSGES
STAPGSTSESPSGTAPGTSPSGESST
APGTSPSGESSTAPGSTSSTAESPGP
GTSPSGESSTAPGTSPSGESSTAPGS
TSSTAESPGPGTSTPESGSASPGTST
PESGSASPGSTSESPSGTAPGSTSES
PSGTAPGTSTPESGSASPGSTSSTAE
SPGPGTSTPESGSASPGSTSESPSGT
APGTSPSGESSTAPGSTSSTAESPGP
GTSPSGESSTAPGTSTPESGSASPGS
TSSTAESPGPGSTSSTAESPGPGSTS
STAESPGPGSTSSTAESPGPGTSPSG
ESSTAPGSTSESPSGTAPGSTSESPS
GTAPGTSTPESGPXXXGASASGAP
STXXXXSESPSGTAPGSTSESPSGT
APGSTSESPSGTAPGSTSESPSGTAP
GSTSESPSGTAPGSTSESPSGTAPGT
STPESGSASPGTSPSGESSTAPGTSP
SGESSTAPGSTSSTAESPGPGTSPSG
ESSTAPGTSTPESGSASPGSTSESPS
GTAPGSTSESPSGTAPGTSPSGESST
APGSTSESPSGTAPGTSTPESGSASP
GTSTPESGSASPGSTSESPSGTAPGT
STPESGSASPGSTSSTAESPGPGSTS
ESPSGTAPGSTSESPSGTAPGTSPSG
ESSTAPGSTSSTAESPGPGTSPSGES
STAPGTSTPESGSASPGTSPSGESST
APGTSPSGESSTAPGTSPSGESSTAP
GSTSSTAESPGPGSTSSTAESPGPGT
SPSGESSTAPGSSPSASTGTGPGSST
PSGATGSPGSSTPSGATGSP
AG864 GGSPGASPGTSSTGSPGSSPSASTG 642 868 Residue totals: H: 0 E: 0 94.70%
TGPGSSPSASTGTGPGTPGSGTASS percent: H: 0.0 E: 00
SPGSSTPSGATGSPGSNPSASTGTG
PGASPGTSSTGSPGTPGSGTASSSP
GSSTPSGATGSPGTPGSGTASSSPG
ASPGTSSTGSPGASPGTSSTGSPGT
PGSGTASSSPGSSTPSGATGSPGAS
PGTSSTGSPGTPGSGTASSSPGSSTP
SGATGSPGSNPSASTGTGPGSSPSA
STGT7GPGSSTPSGATGSPGSSTPSG
ATGSPGASPGTSSTGSPGASPGTSS
TGSPGASPGTSSTGSPGTPGSGTAS
SSPGASPGTSSTGSPGASPGTSSTGS
PGASPGTSSTGSPGSSPSASTGTGP
GTPGSGTASSSPGASPGTSSTGSPG
ASPGTSSTGSPGASPGTSSTGSPGSS
TPSGATGSPGSSTPSGATGSPGASP
GTSSTGSPGTPGSGTASSSPGSSTPS
GATGSPGSSTPSGATGSPGSSTPSG
ATGSPGSSPSASTGTGPGASPGTSS
TGSPGASPGTSSTGSPGTPGSGTAS
SSPGASPGTSSTGSPGASPGTSSTGS
PGASPGTSSTGSPGASPGTSSTGSP
GTPGSGTASSSPGSSTPSGATGSPG
TPGSGTASSSPGSSTPSGATGSPGT
PGSGTASSSPGSSTPSGATGSPGSST
PSGATGSPGSSPSASTGTGPGSSPS
ASTGTGPGASPGTSSTGSPGTPGSG
TASSSPGSSTPSGATGSPGSSPSAST
GTGPGSSPSASTGTGPGASPGTSST
GSPGASPGTSSTGSPGSSTPSGATG
SPGSSPSASTGTGPGASPGTSSTGSP
GSSPSASTGTGPGTPGSGTASSSPG
SSTPSGATGSPGSSTPSGATGSPGA
SPGTSSTGSP
AM875 GTSTEPSEGSAPGSEPATSGSETPG 643 875 Residue totals: H: 7 E: 3 98.63%
SPAGSPTSTEEGSTSSTAESPGPGTS percent: H: 0.8 E: 0.3
TPESGSASPGSTSESPSGTAPGSTSE
SPSGTAPGTSTPESGSASPGTSTPES
GSASPGSEPATSGSETPGTSESATP
ESGPGSPAGSPTSTEEGTSTEPSEGS
APGTSESATPESGPGTSTEPSEGSA
PGTSTEPSEGSAPGSPAGSPTSTEE
GTSTEPSEGSAPGTSTEPSEGSAPG
TSESATPESGPGTSESATPESGPGTS
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGTSTEPSEGSAPGSEPAT
SGSETPGSPAGSPTSTEEGSSTPSGA
TGSPGTPGSGTASSSPGSSTPSGAT
GSPGTSTEPSEGSAPGTSTEPSEGS
APGSEPATSGSETPGSPAGSPTSTE
EGSPAGSPTSTEEGTSTEPSEGSAP
GASASGAPSTGGTSESATPESGPGS
PAGSPTSTEEGSPAGSPTSTEEGSTS
STAESPGPGSTSESPSGTAPGTSPSG
ESSTAPGTPGSGTASSSPGSSTPSG
ATGSPGSSPSASTGTGPGSEPATSG
SETPGTSESATPESGPGSEPATSGSE
TPGSTSSTAESPGPGSTSSTAESPGP
GTSPSGESSTAPGSEPATSGSETPGS
EPATSGSETPGTSTEPSEGSAPGSTS
STAESPGPGTSTPESGSASPGSTSES
PSGTAPGTSTEPSEGSAPGTSTEPSE
GSAPGTSTEPSEGSAPGSSTPSGAT
GSPGSSPSASTGTGPGASPGTSSTG
SPGSEPATSGSETPGTSESATPESGP
GSPAGSPTSTEEGSSTPSGATGSPG
SSPSASTGTGPGASPGTSSTGSPGT
SESATPESGPGTSTEPSEGSAPGTST
EPSEGSA
AM1318 GTSTEPSEGSAPGSEPATSGSETPG 644 1318 Residue totals: H: 7 E: 0 99.17%
SPAGSPTSTEEGSTSSTAESPGPGTS percent: H: 0.7: E: 0.0
TPESGSASPGSTSESPSGTAPGSTSE
SPSGTAPGTSTPESGSASPGTSTPES
GSASPGSEPATSGSETPGTSESATP
ESGPGSPAGSPTSTEEGTSTEPSEGS
APGTSESATPESGPGTSTEPSEGSA
PGTSTEPSEGSAPGSPAGSPTSTEE
GTSTEPSEGSAPGTSTEPSEGSAPG
TSESATPESGPGTSESATPESGPGTS
TEPSEGSAPGTSTEPSEGSAPGTSES
ATPESGPGTSTEPSEGSAPGSEPAT
SGSETPGSPAGSPTSTEEGSSTPSGA
TGSPGTPGSGTASSSPGSSTPSGAT
GSPGTSTEPSEGSAPGTSTEPSEGS
APGSEPATSGSETPGSPAGSPTSTE
EGSPAGSPTSTEEGTSTEPSEGSAP
GPEPTGPAPSGGSEPATSGSETPGT
SESATPESGPGSPAGSPTSTEEGTSE
SATPESGPGSPAGSPTSTEEGSPAG
SPTSTEEGTSESATPESGPGSPAGSP
TSTEEGSPAGSPTSTEEGSTSSTAES
PGPGSTSESPSGTAPGTSPSGESSTA
PGSTSESPSGTAPGSTSESPSGTAPG
TSPSGESSTAPGTSTEPSEGSAPGTS
ESATPESGPGTSESATPESGPGSEP
ATSGSETPGTSESATPESGPGTSES
ATPESGPGTSTEPSEGSAPGTSESA
TPESGPGTSTEPSEGSAPGTSPSGES
STAPGTSPSGESSTAPGTSPSGESST
APGTSTEPSEGSAPGSPAGSPTSTE
EGTSTEPSEGSAPGSSPSASTGTGP
GSSTPSGATGSPGSSTPSGATGSPG
SSTPSGATGSPGSSTPSGATGSPGA
SPGTSSTGSPGASASGAPSTGGTSP
SGESSTAPGSTSSTAESPGPGTSPSG
ESSTAPGTSESATPESGPGTSTEPSE
GSAPGTSTEPSEGSAPGSSPSASTG
TGPGSSTPSGATGSPGASPGTSSTG
SPGTSTPESGSASPGTSPSGESSTAP
GTSPSGESSTAPGTSESATPESGPGS
EPATSGSETPGTSTEPSEGSAPGSTS
ESPSGTAPGSTSESPSGTAPGTSTPE
SGSASPGSPAGSPTSTEEGTSESATP
ESGPGTSTEPSEGSAPGSPAGSPTST
EEGTSESATPESGPGSEPATSGSETP
GSSTPSGATGSPGASPGTSSTGSPG
SSTPSGATGSPGSTSESPSGTAPGTS
PSGESSTAPGSTSSTAESPGPGSSTP
SGATGSPGASPGTSSTGSPGTPGSG
TASSSPGSPAGSPTSTEEGSPAGSPT
STEEGTSTEPSEGSAP
AM923 MAEPAGSPTSTEEGASPGTSSTGSP 645 924 Residue totals: H: 4 E: 3 98.70%
GSSTPSGATGSPGSSTPSGATGSPG percent: H: 0.4 E: 0.3
TSTEPSEGSAPGSEPATSGSETPGSP
AGSPTSTEEGSTSSTAESPGPGTSTP
ESGSASPGSTSESPSGTAPGSTSESP
SGTAPGTSTPESGSASPGTSTPESGS
ASPGSEPATSGSETPGTSESATPES
GPGSPAGSPTSTEEGTSTEPSEGSA
PGTSESATPESGPGTSTEPSEGSAP
GTSTEPSEGSAPGSPAGSPTSTEEG
TSTEPSEGSAPGTSTEPSEGSAPGTS
ESATPESGPGTSESATPESGPGTSTE
PSEGSAPGTSTEPSEGSAPGTSESA
TPESGPGTSTEPSEGSAPGSEPATS
GSETPGSPAGSPTSTEEGSSTPSGA
TGSPGTPGSGTASSSPGSSTPSGAT
GSPGTSTEPSEGSAPGTSTEPSEGS
APGSEPATSGSETPGSPAGSPTSTE
EGSPAGSPTSTEEGTSTEPSEGSAP
GASASGAPSTGGTSESATPESGPGS
PAGSPTSTEEGSPAGSPTSTEEGSTS
STAESPGPGSTSESPSGTAPGTSPSG
ESSTAPGTPGSGTASSSPGSSTPSG
ATGSPGSSPSASTGTGPGSEPATSG
SETPGTSESATPESGPGSEPATSGSE
TPGSTSSTAESPGPGSTSSTAESPGP
GTSPSGESSTAPGSEPATSGSETPGS
EPATSGSETPGTSTEPSEGSAPGSTS
STAESPGPGTSTPESGSASPGSTSES
PSGTAPGTSTEPSEGSAPGTSTEPSE
GSAPGTSTEPSEGSAPGSSTPSGAT
GSPGSSPSASTGTGPGASPGTSSTG
SPGSEPATSGSETPGTSESATPESGP
GSPAGSPTSTEEGSSTPSGATGSPG
SSPSASTGTGPGASPGTSSTGSPGT
SESATPESGPGTSTEPSEGSAPGTST
EPSEGSAP
AE912 MAEPAGSPTSTEEGTPGSGTASSSP 646 913 Residue totals: H: 8 E: 3 99.45%
GSSTPSGATGSPGASPGTSSTGSPG percent: H: 0.9 E: 0.3
SPAGSPTSTEEGTSESATPESGPGTS
TEPSEGSAPGSPAGSPTSTEEGTSTE
PSEGSAPGTSTEPSEGSAPGTSESA
TPESGPGSEPATSGSETPGSEPATS
GSETPGSPAGSPTSTEEGTSESATPE
SGPGTSTEPSEGSAPGTSTEPSEGS
APGSPAGSPTSTEEGTSTEPSEGSA
PGTSTEPSEGSAPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTS
TEPSEGSAPGTSESATPESGPGTSES
ATPESGPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGTSESATP
ESGPGTSTEPSEGSAPGTSTEPSEGS
APGTSTEPSEGSAPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAP
GSPAGSPTSTEEGTSTEPSEGSAPG
TSESATPESGPGSEPATSGSETPGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGTSTEPSEGSAPGTSESA
TPESGPGSPAGSPTSTEEGSPAGSPT
STEEGSPAGSPTSTEEGTSESATPES
GPGTSTEPSEGSAPGTSESATPESG
PGSEPATSGSETPGTSESATPESGP
GSEPATSGSETPGTSESATPESGPG
TSTEPSEGSAPGSPAGSPTSTEEGTS
ESATPESGPGSEPATSGSETPGTSES
ATPESGPGSPAGSPTSTEEGSPAGS
PTSTEEGTSTEPSEGSAPGTSESATP
ESGPGTSESATPESGPGTSESATPES
GPGSEPATSGSETPGSEPATSGSET
PGSPAGSPTSTEEGTSTEPSEGSAP
GTSTEPSEGSAPGSEPATSGSETPG
TSESATPESGPGTSTEPSEGSAP
BC 864 GTSTEPSEPGSAGTSTEPSEPGSAG 647 Residue totals: H: 0 E: 0 99.77%
SEPATSGTEPSGSGASEPTSTEPGSE percent: H: 0 E: 0
PATSGTEPSGSEPATSGTEPSGSEP
ATSGTEPSGSGASEPTSTEPGTSTEP
SEPGSAGSEPATSGTEPSGTSTEPSE
PGSAGSEPATSGTEPSGSEPATSGT
EPSGTSTEPSEPGSAGTSTEPSEPGS
AGSEPATSGTEPSGSEPATSGTEPS
GTSEPSTSEPGAGSGASEPTSTEPG
TSEPSTSEPGAGSEPATSGTEPSGSE
PATSGTEPSGTSTEPSEPGSAGTSTE
PSEPGSAGSGASEPTSTEPGSEPATS
GTEPSGSEPATSGTEPSGSEPATSG
TEPSGSEPATSGTEPSGTSTEPSEPG
SAGSEPATSGTEPSGSGASEPTSTE
PGTSTEPSEPGSAGSEPATSGTEPS
GSGASEPTSTEPGTSTEPSEPGSAG
SGASEPTSTEPGSEPATSGTEPSGS
GASEPTSTEPGSEPATSGTEPSGSG
ASEPTSTEPGTSTEPSEPGSAGSEPA
TSGTEPSGSGASEPTSTEPGTSTEPS
EPGSAGSEPATSGTEPSGTSTEPSEP
GSAGSEPATSGTEPSGTSTEPSEPG
SAGTSTEPSEPGSAGTSTEPSEPGS
AGTSTEPSEPGSAGTSTEPSEPGSA
GTSTEPSEPGSAGTSEPSTSEPGAG
SGASEPTSTEPGTSTEPSEPGSAGTS
TEPSEPGSAGTSTEPSEPGSAGSEP
ATSGTEPSGSGASEPTSTEPGSEPA
TSGTEPSGSEPATSGTEPSGSEPATS
GTEPSGSEPATSGTEPSGTSEPSTSE
PGAGSEPATSGTEPSGSGASEPTST
EPGTSTEPSEPGSAGSEPATSGTEPS
GSGASEPTSTEPGTSTEPSEPGSA
ASPAAPAPASPAAPAPSAPAAAPA 648 84 Residue totals: H: 58 E: 0 78.57%
SPAPAAPSAPAPAAPSAASPAAPSA percent: H: 69.0 E: 0.0
PPAAASPAAPSAPPAASAAAPAAA
SAAASAPSAAA
*H: alpha-helix E: beta-sheet
Example 44 Analysis of Polypeptide Sequences for Repetitiveness Polypeptide amino acid sequences can be assessed for repetitiveness by quantifying the number of times a shorter subsequence appears within the overall polypeptide. For example, a polypeptide of 200 amino acid residues has 192 overlapping 9-amino acid subsequences (or 9-mer “frames”), but the number of unique 9-mer subsequences will depend on the amount of repetitiveness within the sequence. In the present analysis, different sequences were assessed for repetitiveness by summing the occurrence of all unique 3-mer subsequences for each 3-amino acid frame across the first 200 amino acids of the polymer portion divided by the absolute number of unique 3-mer subsequences within the 200 amino acid sequence. The resulting subsequence score is a reflection of the degree of repetitiveness within the polypeptide.
The results, shown in Table 28, indicate that the unstructured polypeptides consisting of 2 or 3 amino acid types have high subsequence scores, while those of consisting of 12 amino acids motifs of the six amino acids G, S, T, E, P, and A with a low degree of internal repetitiveness, have subsequence scores of less than 10, and in some cases, less than 5. For example, the L288 sequence has two amino acid types and has short, highly repetitive sequences, resulting in a subsequence score of 50.0. The polypeptide J288 has three amino acid types but also has short, repetitive sequences, resulting in a subsequence score of 33.3. Y576 also has three amino acid types, but is not made of internal repeats, reflected in the subsequence score of 15.7 over the first 200 amino acids. W576 consists of four types of amino acids, but has a higher degree of internal repetitiveness, e.g., “GGSG” (SEQ ID NO: 649), resulting in a subsequence score of 23.4. The AD576 consists of four types of 12 amino acid motifs, each consisting of four types of amino acids. Because of the low degree of internal repetitiveness of the individual motifs, the overall subsequence score over the first 200 amino acids is 13.6. In contrast, XTEN's consisting of four motifs contains six types of amino acids, each with a low degree of internal repetitiveness have lower subsequence scores; i.e., AE864 (6.1), AF864 (7.5), and AM875 (4.5).
Conclusions: The results indicate that the combination of 12 amino acid subsequence motifs, each consisting of four to six amino acid types that are essentially non-repetitive, into a longer XTEN polypeptide results in an overall sequence that is non-repetitive. This is despite the fact that each subsequence motif may be used multiple times across the sequence. In contrast, polymers created from smaller numbers of amino acid types resulted in higher subsequence scores, although the actual sequence can be tailored to reduce the degree of repetitiveness to result in lower subsequence scores.
TABLE 28
Subsequence score calculations of polypeptide sequences
SEQ
Seq ID
Name Amino Acid Sequence NO: Score
J288 GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGE 650 33.3
GGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSG
GEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGS
GGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEG
GSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGEGGSGGE
GGSGGEGGSGGEGGSGGEGGSGGEG
K288 GEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGG 651 46.9
EGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEG
GGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEG
EGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGG
EGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGEGGEGEGGGE
GGEGEGGGEGGEGEGGGEGGEGEGGGEG
L288 SSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSS 652 50.0
ESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSES
SESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSE
SSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESSSSESSSESSESS
SSESSSESSESSSSESSSESSESSSSESSSESSESSSSES
Y288 GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGGSEGSEGEGGSEGSEG 653 26.8
EGSGEGSEGEGGSEGSEGEGSGEGSEGEGSEGGSEGEGGSEGSEGEGSGEGSEGE
GGEGGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGSGEGSEGEGSEGSGEGE
GSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGE
GSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGEGEGSEGGSEGEGSEGGSEGE
GSEGSGEGEGSEGSGE
Q576 GGKPGEGGKPEGGGGKPGGKPEGEGEGKPGGKPEGGGKPGGGEGGKPEGGKPE 654 18.5
GEGKPGGGEGKPGGKPEGGGGKPEGEGKPGGGGGKPGGKPEGEGKPGGGEGG
KPEGKPGEGGEGKPGGKPEGGGEGKPGGGKPGEGGKPGEGKPGGGEGGKPEGG
KPEGEGKPGGGEGKPGGKPGEGGKPEGGGEGKPGGKPGEGGEGKPGGGKPEGE
GKPGGGKPGGGEGGKPEGEGKPGGKPEGGGEGKPGGKPEGGGKPEGGGEGKP
GGGKPGEGGKPGEGEGKPGGKPEGEGKPGGEGGGKPEGKPGGGEGGKPEGGKP
GEGGKPEGGKPGEGGEGKPGGGKPGEGGKPEGGGKPEGEGKPGGGGKPGEGG
KPEGGKPEGGGEGKPGGGKPEGEGKPGGGEGKPGGKPEGGGGKPGEGGKPEGG
KPGGEGGGKPEGEGKPGGKPGEGGGGKPGGKPEGEGKPGEGGEGKPGGKPEGG
GEGKPGGKPEGGGEGKPGGGKPGEGGKPEGGGKPGEGGKPGEGGKPEGEGKPG
GGEGKPGGKPGEGGKPEGGGEGKPGGKPGGEGGGKPEGGKPGEGGKPEG
U576 GEGKPGGKPGSGGGKPGEGGKPGSGEGKPGGKPGSGGSGKPGGKPGEGGKPEG 655 18.1
GSGGKPGGGGKPGGKPGGEGSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGG
KPGGKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPEGGSGGKPGGK
PEGGSGGKPGGSGKPGGKPGEGGKPEGGSGGKPGGSGKPGGKPEGGGSGKPGG
KPGEGGKPGSGEGGKPGGGKPGGEGKPGSGKPGGEGSGKPGGKPGSGGEGKPG
GKPEGGSGGKPGGGKPGGEGKPGSGGKPGEGGKPGSGGGKPGGKPGGEGEGKP
GGKPGEGGKPGGEGSGKPGGGGKPGGKPGGEGGKPEGSGKPGGGSGKPGGKPE
GGGGKPEGSGKPGGGGKPEGSGKPGGGKPEGGSGGKPGGSGKPGGKPGEGGG
KPEGSGKPGGGSGKPGGKPEGGGKPEGGSGGKPGGKPEGGSGGKPGGKPGGEG
SGKPGGKPGSGEGGKPGGKPGEGSGGKPGGKPEGGSGGKPGGSGKPGGKPEGG
GSGKPGGKPGEGGKPGGEGSGKPGGSGKPG
W576 GGSGKPGKPGGSGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGSGKPGGGSGKP 656 23.4
GSGKPGGGGKPGSGSGKPGGGKPGGSGGKPGGGSGKPGKPGSGGSGKPGSGKP
GGGSGGKPGKPGSGGSGGKPGKPGSGGGSGKPGKPGSGGSGGKPGKPGSGGSG
GKPGKPGSGGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGKPGSG
KPGSGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGGKPGSGSGKPGG
GKPGSGSGKPGGGKPGGSGGKPGGSGGKPGKPGSGGGSGKPGKPGSGGGSGKP
GKPGGSGSGKPGSGKPGGGSGKPGSGKPGSGGSGKPGKPGSGGSGGKPGKPGS
GGGKPGSGSGKPGGGKPGSGSGKPGGGKPGSGSGKPGGGKPGSGSGKPGGSGK
PGSGKPGGGSGGKPGKPGSGGSGKPGSGKPGSGGSGKPGKPGGSGSGKPGSGKP
GGGSGKPGSGKPGGGSGKPGSGKPGGGSGKPGSGKPGGGGKPGSGSGKPGGSG
GKPGKPGSGGSGGKPGKPGSGGSGKPGSGKPGGGSGGKPGKPGSGG
Y576 GEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGE 657 15.7
GEGSGEGSEGEGGGEGSEGEGSGEGGEGEGSEGGSEGEGGSEGGEGEGSEGSGE
GEGSEGGSEGEGSEGGSEGEGSEGSGEGEGSEGSGEGEGSEGSGEGEGSEGSGEG
EGSEGGSEGEGGSEGSEGEGSGEGSEGEGGSEGSEGEGGGEGSEGEGSGEGSEGE
GGSEGSEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGE
GSEGSGEGEGGSEGSEGEGSGEGSEGEGSEGSGEGEGSEGSGEGEGGSEGSEGEG
GSEGSEGEGGSEGSEGEGGEGSGEGEGSEGSGEGEGSGEGSEGEGSEGSGEGEGS
EGSGEGEGGSEGSEGEGSEGSGEGEGGEGSGEGEGSGEGSEGEGGGEGSEGEGS
EGSGEGEGSEGSGEGEGSEGGSEGEGGSEGSEGEGSEGGSEGEGSEGGSEGEGSE
GSGEGEGSEGSGEGEGSGEGSEGEGGSEGGEGEGSEGGSEGEGSEGGSEGEGGE
GSGEGEGGGEGSEGEGSEGSGEGEGSGEGSE
AD576 GSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSSESGSSEGGPGSSESGSSE 658 13.6
GGPGSSESGSSEGGPGSSESGSSEGGPGESPGGSSGSESGSEGSSGPGESSGSSESG
SSEGGPGSSESGSSEGGPGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESGES
PGGSSGSESGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGSGGEPSESGSS
GSEGSSGPGESSGESPGGSSGSESGSGGEPSESGSSGSGGEPSESGSSGSGGEPSES
GSSGSSESGSSEGGPGESPGGSSGSESGESPGGSSGSESGESPGGSSGSESGESPGG
SSGSESGESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSEGSSGPGESSGSSE
SGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESGSSGESPGGSSGSESG
ESPGGSSGSESGSSESGSSEGGPGSGGEPSESGSSGSSESGSSEGGPGSGGEPSESG
SSGSGGEPSESGSSGESPGGSSGSESGSEGSSGPGESSGSSESGSSEGGPGSEGSSG
PGESS
AE576 AGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSE 659 6.1
GSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAG
SPTSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTS
TEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPG
SEPATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESG
PGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEG
SAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPS
EGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSES
ATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSP
AGSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAP
AF540 GSTSSTAESPGPGSTSSTAESPGPGSTSESPSGTAPGSTSSTAESPGPGSTSSTAESP 660 8.8
GPGTSTPESGSASPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPS
GTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSES
PSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGTST
PESGSASPGSTSSTAESPGPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGS
TSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAP
GSTSESPSGTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGT
APGSTSESPSGTAPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG
SASPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGSTSSTAESPGPGTSTPE
SGSASPGSTSESPSGTAP
AF504 GASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGAT 661 7.0
GSPGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSG
TASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGAS
PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSASTGTGP
GSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSST
GSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSSPSA
STGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSS
TPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSP
GSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSP
AE864 GSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGS 662 6.1
APGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSP
TSTEEGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE
PSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSE
PATSGSETPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPG
SPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSA
PGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEG
SAPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESAT
PESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSPA
GSPTSTEEGSPAGSPTSTEEGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGT
SESATPESGPGSEPATSGSETPGTSESATPESGPGSEPATSGSETPGTSESATPESGP
GTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPES
GPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATP
ESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEP
SEGSAP
AF864 GSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSA 663 7.5
SPGTSTPESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPS
GTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSPSG
ESSTAPGSTSSTAESPGPGTSTPESGSASPGTSTPESGSASPGSTSESPSGTAPGSTS
ESPSGTAPGTSTPESGSASPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAPGT
SPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTSTPESGSASPGSTSSTAESPGP
GSTSSTAESPGPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSTSESPSGT
APGSTSESPSGTAPGTSTPESGPXXXGASASGAPSTXXXXSESPSGTAPGSTSESPS
GTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGSTSESPSGTAPGTSTPE
SGSASPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTST
PESGSASPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSESPSGTAPGT
STPESGSASPGTSTPESGSASPGSTSESPSGTAPGTSTPESGSASPGSTSSTAESPGP
GSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGTSPSGESST
APGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSPSGESSTAPGSTSSTAE
SPGPGSTSSTAESPGPGTSPSGESSTAPGSSPSASTGTGPGSSTPSGATGSPGSSTPS
GATGSP
AG868 GGSPGASPGTSSTGSPGSSPSASTGTGPGSSPSASTGTGPGTPGSGTASSSPGSSTP 664 7.5
SGATGSPGSNPSASTGTGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGT
PGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGS
PGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSNPSASTGTGPGSSPSAST
GTGPGSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGASPGTSSTGSPGASPG
TSSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGSS
PSASTGTGPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSP
GSSTPSGATGSPGSSTPSGATGSPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGAT
GSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGASPGTSSTGSPGASPGT
SSTGSPGTPGSGTASSSPGASPGTSSTGSPGASPGTSSTGSPGASPGTSSTGSPGAS
PGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGTPGSGTASSSPGSSTPSGATGSP
GTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSPGSSPSASTGTGPGSSPSASTG
TGPGASPGTSSTGSPGTPGSGTASSSPGSSTPSGATGSPGSSPSASTGTGPGSSPSA
STGTGPGASPGTSSTGSPGASPGTSSTGSPGSSTPSGATGSPGSSPSASTGTGPGAS
PGTSSTGSPGSSPSASTGTGPGTPGSGTASSSPGSSTPSGATGSPGSSTPSGATGSP
GASPGTSSTGSP
AM875 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSA 665 4.5
SPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSG
SETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEP
SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE
SATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT
STEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSP
GSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST
EEGSPAGSPTSTEEGTSTEPSEGSAPGASASGAPSTGGTSESATPESGPGSPAGSPT
STEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSPSGESSTAPGTPGSG
TASSSPGSSTPSGATGSPGSSPSASTGTGPGSEPATSGSETPGTSESATPESGPGSEP
ATSGSETPGSTSSTAESPGPGSTSSTAESPGPGTSPSGESSTAPGSEPATSGSETPGS
EPATSGSETPGTSTEPSEGSAPGSTSSTAESPGPGTSTPESGSASPGSTSESPSGTAP
GTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSSTPSGATGSPGSSPSASTGT
GPGASPGTSSTGSPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSSTPSG
ATGSPGSSPSASTGTGPGASPGTSSTGSPGTSESATPESGPGTSTEPSEGSAPGTST
EPSEGSAP
AM1318 GTSTEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSTSSTAESPGPGTSTPESGSA 666 4.5
SPGSTSESPSGTAPGSTSESPSGTAPGTSTPESGSASPGTSTPESGSASPGSEPATSG
SETPGTSESATPESGPGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSTEP
SEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGTSE
SATPESGPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSESATPESGPGT
STEPSEGSAPGSEPATSGSETPGSPAGSPTSTEEGSSTPSGATGSPGTPGSGTASSSP
GSSTPSGATGSPGTSTEPSEGSAPGTSTEPSEGSAPGSEPATSGSETPGSPAGSPTST
EEGSPAGSPTSTEEGTSTEPSEGSAPGPEPTGPAPSGGSEPATSGSETPGTSESATP
ESGPGSPAGSPTSTEEGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSESA
TPESGPGSPAGSPTSTEEGSPAGSPTSTEEGSTSSTAESPGPGSTSESPSGTAPGTSP
SGESSTAPGSTSESPSGTAPGSTSESPSGTAPGTSPSGESSTAPGTSTEPSEGSAPGT
SESATPESGPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSESATPESGP
GTSTEPSEGSAPGTSESATPESGPGTSTEPSEGSAPGTSPSGESSTAPGTSPSGESST
APGTSPSGESSTAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGSSPSAST
GTGPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGSSTPSGATGSPGASPG
TSSTGSPGASASGAPSTGGTSPSGESSTAPGSTSSTAESPGPGTSPSGESSTAPGTS
ESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGSSPSASTGTGPGSSTPSGATGSP
GASPGTSSTGSPGTSTPESGSASPGTSPSGESSTAPGTSPSGESSTAPGTSESATPES
GPGSEPATSGSETPGTSTEPSEGSAPGSTSESPSGTAPGSTSESPSGTAPGTSTPESG
SASPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESA
TPESGPGSEPATSGSETPGSSTPSGATGSPGASPGTSSTGSPGSSTPSGATGSPGSTS
ESPSGTAPGTSPSGESSTAPGSTSSTAESPGPGSSTPSGATGSPGASPGTSSTGSPGT
PGSGTASSSPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAP
Example 45 Calculation of TEPITOPE Scores TEPITOPE scores of 9mer peptide sequence can be calculated by adding pocket potentials as described by Sturniolo [Sturniolo, T., et al. (1999) Nat Biotechnol, 17: 555]. In the present Example, separate Tepitope scores were calculated for individual HLA alleles. Table 29 shows as an example the pocket potentials for HLA*0101B, which occurs in high frequency in the Caucasian population. To calculate the TEPITOPE score of a peptide with sequence P1-P2-P3-P4-P5-P6-P7-P8-P9, the corresponding individual pocket potentials in Table 29 were added. The HLA*0101B score of a 9mer peptide with the sequence FDKLPRTSG (SEQ ID NO: 667) would be the sum of 0, −1.3, 0, 0.9, 0, −1.8, 0.09, 0, 0.
To evaluate the TEPITOPE scores for long peptides one can repeat the process for all 9mer subsequences of the sequences. This process can be repeated for the proteins encoded by other HLA alleles. Tables 30-33 give pocket potentials for the protein products of HLA alleles that occur with high frequency in the Caucasian population.
TEPITOPE scores calculated by this method range from approximately −10 to +10. However, 9mer peptides that lack a hydrophobic amino acid (FKLMVWY (SEQ ID NO: 668)) in P1 position have calculated TEPITOPE scores in the range of −1009 to −989. This value is biologically meaningless and reflects the fact that a hydrophobic amino acid serves as an anchor residue for HLA binding and peptides lacking a hydrophobic residue in P1 are considered non binders to HLA. Because most XTEN sequences lack hydrophobic residues, all combinations of 9mer subsequences will have TEPITOPEs in the range in the range of −1009 to −989. This method confirms that XTEN polypeptides may have few or no predicted T-cell epitopes.
TABLE 29
Pocket potential for HLA*0101B allele.
Amino
Acid P1 P2 P3 P4 P5 P6 P7 P8 P9
A −999 0 0 0 — 0 0 — 0
C −999 0 0 0 — 0 0 — 0
D −999 −1.3 −1.3 −2.4 — −2.7 −2 — −1.9
E −999 0.1 −1.2 −0.4 — −2.4 −0.6 — −1.9
F 0 0.8 0.8 0.08 — −2.1 0.3 — −0.4
G −999 0.5 0.2 −0.7 — −0.3 −1.1 — −0.8
H −999 0.8 0.2 −0.7 — −2.2 0.1 — −1.1
I −1 1.1 1.5 0.5 — −1.9 0.6 — 0.7
K −999 1.1 0 −2.1 — −2 −0.2 — −1.7
L −1 1 1 0.9 — −2 0.3 — 0.5
M −1 1.1 1.4 0.8 — −1.8 0.09 — 0.08
N −999 0.8 0.5 0.04 — −1.1 0.1 — −1.2
P −999 −0.5 0.3 −1.9 — −0.2 0.07 — −1.1
Q −999 1.2 0 0.1 — −1.8 0.2 — −1.6
R −999 2.2 0.7 −2.1 — −1.8 0.09 — −1
S −999 −0.3 0.2 −0.7 — −0.6 −0.2 — −0.3
T −999 0 0 −1 — −1.2 0.09 — −0.2
V −1 2.1 0.5 −0.1 — −1.1 0.7 — 0.3
W 0 −0.1 0 −1.8 — −2.4 −0.1 — −1.4
Y 0 0.9 0.8 −1.1 — −2 0.5 — −0.9
TABLE 30
Pocket potential for HLA*0301B allele.
Amino
acid P1 P2 P3 P4 P5 P6 P7 P8 P9
A −999 0 0 0 — 0 0 — 0
C −999 0 0 0 — 0 0 — 0
D −999 −1.3 −1.3 2.3 — −2.4 −0.6 — −0.6
E −999 0.1 −1.2 −1 — −1.4 −0.2 — −0.3
F −1 0.8 0.8 −1 — −1.4 0.5 — 0.9
G −999 0.5 0.2 0.5 — −0.7 0.1 — 0.4
H −999 0.8 0.2 0 — −0.1 −0.8 — −0.5
I 0 1.1 1.5 0.5 — 0.7 0.4 — 0.6
K −999 1.1 0 −1 — 1.3 −0.9 — −0.2
L 0 1 1 0 — 0.2 0.2 — −0
M 0 1.1 1.4 0 — −0.9 1.1 — 1.1
N −999 0.8 0.5 0.2 — −0.6 −0.1 — −0.6
P −999 −0.5 0.3 −1 — 0.5 0.7 — −0.3
Q −999 1.2 0 0 — −0.3 −0.1 — −0.2
R −999 2.2 0.7 −1 — 1 −0.9 — 0.5
S −999 −0.3 0.2 0.7 — −0.1 0.07 — 1.1
T −999 0 0 −1 — 0.8 −0.1 — −0.5
V 0 2.1 0.5 0 — 1.2 0.2 — 0.3
W −1 −0.1 0 −1 — −1.4 −0.6 — −1
Y −1 0.9 0.8 −1 — −1.4 −0.1 — 0.3
TABLE 31
Pocket potential for HLA*0401B allele.
Amino
acid P1 P2 P3 P4 P5 P6 P7 P8 P9
A −999 0 0 0 — 0 0 — 0
C −999 0 0 0 — 0 0 — 0
D −999 −1.3 −1.3 1.4 — −1.1 −0.3 — −1.7
E −999 0.1 −1.2 1.5 — −2.4 0.2 — −1.7
F 0 0.8 0.8 −0.9 — −1.1 −1 — −1
G −999 0.5 0.2 −1.6 — −1.5 −1.3 — −1
H −999 0.8 0.2 1.1 — −1.4 0 — 0.08
I −1 1.1 1.5 0.8 — −0.1 0.08 — −0.3
K −999 1.1 0 −1.7 — −2.4 −0.3 — −0.3
L −1 1 1 0.8 — −1.1 0.7 — −1
M −1 1.1 1.4 0.9 — −1.1 0.8 — −0.4
N −999 0.8 0.5 0.9 — 1.3 0.6 — −1.4
P −999 −0.5 0.3 −1.6 — 0 −0.7 — −1.3
Q −999 1.2 0 0.8 — −1.5 0 — 0.5
R −999 2.2 0.7 −1.9 — −2.4 −1.2 — −1
S −999 −0.3 0.2 0.8 — 1 −0.2 — 0.7
T −999 0 0 0.7 — 1.9 −0.1 — −1.2
V −1 2.1 0.5 −0.9 — 0.9 0.08 — −0.7
W 0 −0.1 0 −1.2 — −1 −1.4 — −1
Y 0 0.9 0.8 −1.6 — −1.5 −1.2 — −1
TABLE 32
Pocket potential for HLA*0701B allele.
Amino
acid P1 P2 P3 P4 P5 P6 P7 P8 P9
A −999 0 0 0 — 0 0 — 0
C −999 0 0 0 — 0 0 — 0
D −999 −1.3 −1.3 −1.6 — −2.5 −1.3 — −1.2
E −999 0.1 −1.2 −1.4 — −2.5 0.9 — −0.3
F 0 0.8 0.8 0.2 — −0.8 2.1 — 2.1
G −999 0.5 0.2 −1.1 — −0.6 0 — −0.6
H −999 0.8 0.2 0.1 — −0.8 0.9 — −0.2
I −1 1.1 1.5 1.1 — −0.5 2.4 — 3.4
K −999 1.1 0 −1.3 — −1.1 0.5 — −1.1
L −1 1 1 −0.8 — −0.9 2.2 — 3.4
M −1 1.1 1.4 −0.4 — −0.8 1.8 — 2
N −999 0.8 0.5 −1.1 — −0.6 1.4 — −0.5
P −999 −0.5 0.3 −1.2 — −0.5 −0.2 — −0.6
Q −999 1.2 0 −1.5 — −1.1 1.1 — −0.9
R −999 2.2 0.7 −1.1 — −1.1 0.7 — −0.8
S −999 −0.3 0.2 1.5 — 0.6 0.4 — −0.3
T −999 0 0 1.4 — −0.1 0.9 — 0.4
V −1 2.1 0.5 0.9 — 0.1 1.6 — 2
W 0 −0.1 0 −1.1 — −0.9 1.4 — 0.8
Y 0 0.9 0.8 −0.9 — −1 1.7 — 1.1
TABLE 33
Pocket potential for HLA*1501B allele.
Amino
acid P1 P2 P3 P4 P5 P6 P7 P8 P9
A −999 0 0 0 — 0 0 — 0
C −999 0 0 0 — 0 0 — 0
D −999 −1.3 −1.3 −0.4 — −0.4 −0.7 — −1.9
E −999 0.1 −1.2 −0.6 — −1 −0.7 — −1.9
F −1 0.8 0.8 2.4 — −0.3 1.4 — −0.4
G −999 0.5 0.2 0 — 0.5 0 — −0.8
H −999 0.8 0.2 1.1 — −0.5 0.6 — −1.1
I 0 1.1 1.5 0.6 — 0.05 1.5 — 0.7
K −999 1.1 0 −0.7 — −0.3 −0.3 — −1.7
L 0 1 1 0.5 — 0.2 1.9 — 0.5
M 0 1.1 1.4 1 — 0.1 1.7 — 0.08
N −999 0.8 0.5 −0.2 — 0.7 0.7 — −1.2
P −999 −0.5 0.3 −0.3 — −0.2 0.3 — −1.1
Q −999 1.2 0 −0.8 — −0.8 −0.3 — −1.6
R −999 2.2 0.7 0.2 — 1 −0.5 — −1
S −999 −0.3 0.2 −0.3 — 0.6 0.3 — −0.3
T −999 0 0 −0.3 — −0 0.2 — −0.2
V 0 2.1 0.5 0.2 — −0.3 0.3 — 0.3
W −1 −0.1 0 0.4 — −0.4 0.6 — −1.4
Y −1 0.9 0.8 2.5 — 0.4 0.7 — −0.9
TABLE 34
Exemplary Biological Activity, Exemplary Assays and Preferred Indications
Biologically Active Exemplary Activity
Protein Biological Activity Assay Preferred Indication:
Insulin-like IGF-1 is a pleiotropic IGF-1 activity may be Diabetes mellitus; Growth
growth polypeptide with a assayed in vitro using disorders; Frailty;
factor-1 wide range of actions an serum withdrawal Amyotrophic lateral
(Mecasermin; in both apoptosis-protection sclerosis; Osteoarthritis;
Somazon; IGF-1; central and assay. (J Endocrinol Kidney disease &
IGF-1 peripheral 2000 October; 167(1): neuropathy; Dwarfism; HIV-
complex; CEP nervous sytems. It is 165-74). Proliferation 1 infections; Myocardial
151; involved in growth assay using breast ischaemia; Osteoporosis;
CGP 35126; FK and carcinoma cell Multiple sclerosis; Nerve
780; development and line MCF-7 (Karey disorders; Burns; diabetes;
Mecar, RHIGF-1; protects neurons 1988 peripheral
Somatomedin-1; against cell death via Cancer Res. 48:
Somatomedin-C; the activation of 4083)
SOMATOKINE; intracellular
MYOTROPHIN; pathways
IGEF; implicating
DepoIGF-1) phosphatidylinositide
3/Akt kinase.
Human growth Binds to two GHR 1) Ba/F3-hGHR Acromegaly; Growth failure;
hormone molecules and proliferation assay, a Growth hormone
(Pegvisamont; Induces signal novel specific replacement; Growth
Somatrem; transduction through bioassay for serum hormone deficiency;
Somatropin; receptor dimerization human growth Pediatric Growth Hormone
TROVERT; hormone. J Clin Deficiency; Adult Growth
PROTROPIN; Endocrinol Metab Hormone Deficiency;
BIO-TROPIN; 2000 November; 85(11): Idiopathic Growth Hormone
HUMATROPE; 4274-9 Plasma Deficiency; Growth
NUTROPIN; growth hormone (GH) retardation; Prader-
NUTROPINAQ; immunoassay and Willi Syndrome; Prader-Willi
NUTROPHIN; tibial bioassay, Appl Syndrome in children 2
NORDITROPIN; Physiol (2000) 89(6): years or older; Growth
GENOTROPIN; 2174-8. deficiencies; Growth failure
SAIZEN; Growth hormone associated with chronic
SEROSTIM) (hGH) receptor renal insufficiency;
mediated cell Osteoporosis;
mediated Postmenopausal
proliferation, Growth osteoporosis; Osteopenia,
Horm IGF Res 2000 Osteoclastogenesis; burns;
October; 10(5): 248-55 Cachexia; Cancer
International standard Cachexia; Dwarfism;
for growth hormone, Metabolic Disorders;
Horm Res 1999; 51 Obesity; Renal failure;
Suppl 1: 7-12 Turner's Syndrome;
2) Detection of human Fibromyalgia, Fracture
growth hormone treatment; Frailty, AIDS
detected by direct wasting; Muscle Wasting;
radioimmunoassay Short Stature; Diagnostic
performed on serial Agents; Female Infertility;
dilutions of lysed cell lipodystrophy.
supernatants using
the Phadebas HGH
PRIST kit (Farmacia).
U.S. Pat. No.
4,898,830
TABLE 35
Exemplary GHXTEN comprising growth hormones and single XTEN
SEQ SEQ
GHXTEN ID ID
Name* Amino Acid Sequence NO: DNA Nucleotide Sequence NO:
AE48- MAEPAGSPTSTEEGTPGSG 669 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAG 670
hGH TASSSPGSSTPSGATGSPG GAAGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTC
ASPGTSSTGSPGFPTIPLSR CAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCC
LFDNAMLRAHRLHQLAFD AGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCA
TYQEFEEAYIPKEQKYSFL GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
QNPQTSLCFSESIPTPSNRE ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
ETQQKSNLELLRISLLLIQS CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
WLEPVQFLRSVFANSLVY TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
GASDSNVYDLLKDLEEGI ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
QTLMGRLEDGSPRTGQIFK CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
QTYSKFDTNSHNDDALLK CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
NYGLLYCFRKDMDKVETF GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
LRIVQCRSVEGSCGF CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AM48- MAEPAGSPTSTEEGASPGT 671 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAG 672
hGH SSTGSPGSSTPSGATGSPGS GAAGGTGCATCCCCGGGCACCAGCTCTACCGGTTCT
STPSGATGSPGFPTIPLSRL CCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTC
FDNAMLRAHRLHQLAFDT CAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCC
YQEFEEAYIPKEQKYSFLQ AGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT
NPQTSLCFSESIPTPSNREE AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTG
TQQKSNLELLRISLLLIQS GCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA
WLEPVQFLRSVFANSLVY TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACC
GASDSNVYDLLKDLEEGI CACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGAC
QTLMGRLEDGSPRTGQIFK GCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAA
QTYSKFDTNSHNDDALLK TCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG
NYGLLYCFRKDMDKVETF AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCT
LRIVQCRSVEGSCGF TCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCA
ACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AE144- GSEPATSGSETPGTSESATP 673 GGTAGCGAACCGGCAACTTCCGGCTCTGAAACCCCA 674
hGH ESGPGSEPATSGSETPGSPA GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGCCCA
GSPTSTEEGTSTEPSEGSAP GGTAGCGAACCTGCTACCTCTGGCTCTGAAACCCCA
GSEPATSGSETPGSEPATS GGTAGCCCGGCAGGCTCTCCGACTTCCACCGAGGAA
GSETPGSEPATSGSETPGTS GGTACCTCTACTGAACCTTCTGAGGGTAGCGCTCCA
TEPSEGSAPGTSESATPESG GGTAGCGAACCGGCAACCTCTGGCTCTGAAACCCCA
PGSEPATSGSETPGTSTEPS GGTAGCGAACCTGCTACCTCCGGCTCTGAAACTCCA
EGSAPGFPTIPLSRLFDNA GGTAGCGAACCGGCTACTTCCGGTTCTGAAACTCCA
MLRAHRLHQLAFDTYQEF GGTACCTCTACCGAACCTTCCGAAGGCAGCGCACCA
EEAYIPKEQKYSFLQNPQT GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
SLCFSESIPTPSNREETQQK GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA
SNLELLRISLLLIQSWLEPV GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
QFLRSVFANSLVYGASDS GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
NVYDLLKDLEEGIQTLMG ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
RLEDGSPRTGQIFKQTYSK CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
FDTNSHNDDALLKNYGLL TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
YCFRKDMDKVETFLRIVQ ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CRSVEGSCGF CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AE288- GTSESATPESGPGSEPATS 675 GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA 676
hGH GSETPGTSESATPESGPGSE GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
PATSGSETPGTSESATPESG GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
PGTSTEPSEGSAPGSPAGSP GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
TSTEEGTSESATPESGPGSE GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
PATSGSETPGTSESATPESG GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
PGSPAGSPTSTEEGSPAGSP GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
TSTEEGTSTEPSEGSAPGTS GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
ESATPESGPGTSESATPESG GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
PGTSESATPESGPGSEPATS GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
GSETPGSEPATSGSETPGSP GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
AGSPTSTEEGTSTEPSEGSA GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
PGTSTEPSEGSAPGSEPATS GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCA
GSETPGTSESATPESGPGTS GGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCA
TEPSEGSAPGFPTIPLSRLF GGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA
DNAMLRAHRLHQLAFDT GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
YQEFEEAYIPKEQKYSFLQ GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
NPQTSLCFSESIPTPSNREE GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
TQQKSNLELLRISLLLIQS GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
WLEPVQFLRSVFANSLVY GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
GASDSNVYDLLKDLEEGI GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
QTLMGRLEDGSPRTGQIFK GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
QTYSKFDTNSHNDDALLK GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
NYGLLYCFRKDMDKVETF GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
LRIVQCRSVEGSCGF GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AF144- GTSTPESGSASPGTSPSGES 677 GGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCCA 678
hGH STAPGTSPSGESSTAPGSTS GGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCAG
STAESPGPGSTSESPSGTAP GTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAGG
GSTSSTAESPGPGTSPSGES TTCTACCAGCTCTACCGCTGAATCTCCTGGCCCAGGT
STAPGTSTPESGSASPGSTS TCTACCAGCGAATCCCCGTCTGGCACCGCACCAGGT
STAESPGPGTSPSGESSTAP TCTACTAGCTCTACCGCAGAATCTCCGGGTCCAGGT
GTSPSGESSTAPGTSPSGES ACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTA
STAPGFPTIPLSRLFDNAM CCTCTACTCCGGAAAGCGGCTCCGCATCTCCAGGTTC
LRAHRLHQLAFDTYQEFE TACTAGCTCTACTGCTGAATCTCCTGGTCCAGGTACC
EAYIPKEQKYSFLQNPQTS TCCCCTAGCGGCGAATCTTCTACTGCTCCAGGTACCT
LCFSESIPTPSNREETQQKS CTCCTAGCGGCGAATCTTCTACCGCTCCAGGTACCTC
NLELLRISLLLIQSWLEPVQ CCCTAGCGGTGAATCTTCTACCGCACCAGGTTTTCCG
FLRSVFANSLVYGASDSN ACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATGC
VYDLLKDLEEGIQTLMGR TGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGATAC
LEDGSPRTGQIFKQTYSKF TTACCAGGAATTTGAAGAAGCcTACATTCCTAAAGA
DTNSHNDDALLKNYGLLY GCAGAAGTACTCTTTCCTGCAAAACCCACAGACTTC
CFRKDMDKVETFLRIVQC TCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAAT
RSVEGSCGF CGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACTA
CTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTAG
AACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATAG
CCTAGTTTATGGCGCATCCGACAGCAACGTATACGA
TCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTGG
TCAGATCTTCAAGCAGACTTACTCTAAATTTGATACT
AACAGCCACAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATATGGACAAA
GTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCG
TTGAGGGCAGCTGTGGTTTCTAA
AD576- GSSESGSSEGGPGSGGEPS 679 GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCA 680
hGH ESGSSGSSESGSSEGGPGSS GGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCA
ESGSSEGGPGSSESGSSEG GGTGAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCA
GPGSSESGSSEGGPGSSES GGTTCTGGTGGCGAACCTTCCGAGTCTGGTAGCTCA
GSSEGGPGESPGGSSGSES GGTGAATCTCCGGGTGGTTCTAGCGGTTCCGAGTCA
GSEGSSGPGESSGSSESGSS GGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCA
EGGPGSSESGSSEGGPGSS GGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCA
ESGSSEGGPGSGGEPSESG GGTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCA
SSGESPGGSSGSESGESPG GGTTCTTCTGAAAGCGGTTCTTCCGAGGGCGGTCCA
GSSGSESGSGGEPSESGSS GGTGAATCTCCTGGTGGTTCCAGCGGTTCCGAGTCA
GSSESGSSEGGPGSGGEPS GGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTCA
ESGSSGSGGEPSESGSSGSE GGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAG
GSSGPGESSGESPGGSSGS GTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAG
ESGSGGEPSESGSSGSGGE GTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG
PSESGSSGSGGEPSESGSSG GTTCTTCTGAAAGCGGTTCTTCCGAGGGCGGTCCAG
SSESGSSEGGPGESPGGSS GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
GSESGESPGGSSGSESGESP GTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG
GGSSGSESGESPGGSSGSE GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAG
SGESPGGSSGSESGSSESGS GTTCTGGTGGCGAACCGTCCGAGTCTGGTAGCTCAG
SEGGPGSGGEPSESGSSGS GTGAATCTCCGGGTGGCTCTAGCGGTTCCGAGTCAG
EGSSGPGESSGSSESGSSEG GTGAATCTCCTGGTGGTTCCAGCGGTTCCGAGTCAG
GPGSGGEPSESGSSGSSES GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAG
GSSEGGPGSGGEPSESGSS GTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAG
GESPGGSSGSESGESPGGS GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
SGSESGSSESGSSEGGPGS GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAG
GGEPSESGSSGSSESGSSEG GTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAG
GPGSGGEPSESGSSGSGGE GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
PSESGSSGESPGGSSGSESG GTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTCAG
SEGSSGPGESSGSSESGSSE GTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAG
GGPGSEGSSGPGESSGFPTI GTTCTGGTGGTGAACCTTCCGAGTCTGGTAGCTCAG
PLSRLFDNAMLRAHRLHQ GTTCTGGTGGCGAACCATCCGAGTCTGGTAGCTCAG
LAFDTYQEFEEAYIPKEQK GTTCTTCCGAAAGCGGTTCTTCCGAAGGCGGTCCAG
YSFLQNPQTSLCFSESIPTP GTTCTGGTGGTGAACCGTCCGAATCTGGTAGCTCAG
SNREETQQKSNLELLRISL GTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG
LLIQSWLEPVQFLRSVFAN GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAG
SLVYGASDSNVYDLLKDL GTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG
EEGIQTLMGRLEDGSPRTG GTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTTCAG
QIFKQTYSKFDTNSHNDD GTAGCGAAGGTTCTTCTGGTCCTGGTGAATCCTCAG
ALLKNYGLLYCFRKDMD GTTCCGGTGGCGAACCATCTGAATCTGGTAGCTCAG
KVETFLRIVQCRSVEGSCGF GTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAG
GTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAG
GTGAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCAG
GTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG
GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAG
GTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG
GTAGCGAAGGTTCTTCCGGTCCTGGTGAGTCTTCAG
GTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTCAG
GTAGCGAAGGTTCTTCTGGTCCTGGCGAGTCCTCAG
GTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAA
TGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGGC
CTTTGATACTTACCAGGAATTTGAAGAAGCcTACATT
CCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCCA
CAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACGC
CTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAATC
TGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGAG
CTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTC
GCCAATAGCCTAGTTTATGGCGCATCCGACAGCAAC
GTATACGATCTCCTGAAAGATCTCGAGGAAGGCATT
CAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTTACTCTAAAT
TTGATACTAACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCGTAAAGATAT
GGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGT
CGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AE576- GSPAGSPTSTEEGTSESATP 681 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAA 682
hGH ESGPGTSTEPSEGSAPGSPA GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA
GSPTSTEEGTSTEPSEGSAP GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
GTSTEPSEGSAPGTSESATP GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
ESGPGSEPATSGSETPGSEP GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
ATSGSETPGSPAGSPTSTEE GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GTSESATPESGPGTSTEPSE GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
GSAPGTSTEPSEGSAPGSP GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
AGSPTSTEEGTSTEPSEGSA GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
PGTSTEPSEGSAPGTSESAT GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
PESGPGTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
ESATPESGPGSEPATSGSET GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
PGTSTEPSEGSAPGTSTEPS GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
EGSAPGTSESATPESGPGT GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
SESATPESGPGSPAGSPTST GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
EEGTSESATPESGPGSEPAT GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
SGSETPGTSESATPESGPGT GGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA
STEPSEGSAPGTSTEPSEGS GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
APGTSTEPSEGSAPGTSTEP GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
SEGSAPGTSTEPSEGSAPG GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA
TSTEPSEGSAPGSPAGSPTS GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
TEEGTSTEPSEGSAPGTSES GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCA
ATPESGPGSEPATSGSETP GGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCA
GTSESATPESGPGSEPATS GGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GSETPGTSESATPESGPGTS GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
TEPSEGSAPGTSESATPESG GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
PGSPAGSPTSTEEGSPAGSP GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
TSTEEGSPAGSPTSTEEGTS GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCA
ESATPESGPGTSTEPSEGSA GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA
PGFPTIPLSRLFDNAMLRA GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
HRLHQLAFDTYQEFEEAYI GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCA
PKEQKYSFLQNPQTSLCFS GGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCA
ESIPTPSNREETQQKSNLEL GGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCA
LRISLLLIQSWLEPVQFLRS GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
VFANSLVYGASDSNVYDL GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
LKDLEEGIQTLMGRLEDGS GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
PRTGQIFKQTYSKFDTNSH GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
NDDALLKNYGLLYCFRKD GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
MDKVETFLRIVQCRSVEGS GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
CGF GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AF576- GSTSSTAESPGPGSTSSTAE 683 GGTTCTACTAGCTCTACCGCTGAATCTCCTGGCCCAG 684
hGH SPGPGSTSESPSGTAPGSTS GTTCCACTAGCTCTACCGCAGAATCTCCGGGCCCAG
STAESPGPGSTSSTAESPGP GTTCTACTAGCGAATCCCCTTCTGGTACCGCTCCAGG
GTSTPESGSASPGSTSESPS TTCTACTAGCTCTACCGCTGAATCTCCGGGTCCAGGT
GTAPGTSPSGESSTAPGSTS TCTACCAGCTCTACTGCAGAATCTCCTGGCCCAGGTA
ESPSGTAPGSTSESPSGTAP CTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTTC
GTSPSGESSTAPGSTSESPS TACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACC
GTAPGSTSESPSGTAPGTSP TCTCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTA
SGESSTAPGSTSESPSGTAP CTAGCGAATCTCCTTCTGGCACTGCACCAGGTTCTAC
GSTSESPSGTAPGSTSESPS CAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTCT
GTAPGTSTPESGSASPGSTS CCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTA
ESPSGTAPGTSTPESGSASP GCGAATCTCCTTCTGGCACTGCACCAGGTTCTACCAG
GSTSSTAESPGPGSTSSTAE CGAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCT
SPGPGTSTPESGSASPGTST AGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGC
PESGSASPGSTSESPSGTAP GAATCTCCTTCTGGCACTGCACCAGGTTCTACTAGCG
GTSTPESGSASPGTSTPESG AATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGA
SASPGSTSESPSGTAPGSTS ATCTCCGTCTGGCACTGCACCAGGTACCTCTACCCCT
ESPSGTAPGSTSESPSGTAP GAAAGCGGTTCCGCTTCTCCAGGTTCTACTAGCGAA
GSTSSTAESPGPGTSTPESG TCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCTG
SASPGTSTPESGSASPGSTS AAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTAC
ESPSGTAPGSTSESPSGTAP CGCTGAATCTCCGGGTCCAGGTTCTACTAGCTCTACT
GTSTPESGSASPGSTSESPS GCAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAA
GTAPGSTSESPSGTAPGTS AGCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAA
TPESGSASPGTSPSGESSTA GCGGTTCTGCATCTCCAGGTTCTACTAGCGAATCCCC
PGSTSSTAESPGPGTSPSGE GTCTGGTACCGCACCAGGTACTTCTACCCCGGAAAG
SSTAPGSTSSTAESPGPGTS CGGCTCTGCTTCTCCAGGTACTTCTACCCCGGAAAGC
TPESGSASPGSTSESPSGTA GGCTCCGCATCTCCAGGTTCTACTAGCGAATCTCCTT
PGSTSSTAESPGPGTSTPES CTGGTACCGCTCCAGGTTCTACCAGCGAATCCCCGTC
GSASPGTSTPESGSASPGFP TGGTACTGCTCCAGGTTCTACCAGCGAATCTCCTTCT
TIPLSRLFDNAMLRAHRLH GGTACTGCACCAGGTTCTACTAGCTCTACTGCAGAA
QLAFDTYQEFEEAYIPKEQ TCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGC
KYSFLQNPQTSLCFSESIPT TCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTT
PSNREETQQKSNLELLRISL CTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGG
LLIQSWLEPVQFLRSVFAN CACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGG
SLVYGASDSNVYDLLKDL CACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTC
EEGIQTLMGRLEDGSPRTG CGCTTCTCCAGGTTCTACTAGCGAATCTCCTTCTGGC
QIFKQTYSKFDTNSHNDD ACTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGC
ALLKNYGLLYCFRKDMD ACTGCACCAGGTACCTCTACCCCTGAAAGCGGTTCC
KVETFLRIVQCRSVEGSCGF GCTTCTCCAGGTACTTCTCCGAGCGGTGAATCTTCTA
CCGCACCAGGTTCTACTAGCTCTACCGCTGAATCTCC
GGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCTACT
GCTCCAGGTTCCACTAGCTCTACTGCTGAATCTCCTG
GCCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCTTC
TCCAGGTTCTACTAGCGAATCTCCGTCTGGCACCGCA
CCAGGTTCTACTAGCTCTACTGCAGAATCTCCTGGCC
CAGGTACCTCTACTCCGGAAAGCGGCTCTGCATCTC
CAGGTACTTCTACCCCTGAAAGCGGTTCTGCATCTCC
AGGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGAT
AATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTG
GCCTTTGATACTTACCAGGAATTTGAAGAAGCcTACA
TTCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACC
CACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGAC
GCCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAA
TCTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAG
AGCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCT
TCGCCAATAGCCTAGTTTATGGCGCATCCGACAGCA
ACGTATACGATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AE624- MAEPAGSPTSTEEGTPGSG 685 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAG 686
hGH TASSSPGSSTPSGATGSPG GAAGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTC
ASPGTSSTGSPGSPAGSPTS CAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCC
TEEGTSESATPESGPGTSTE AGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCA
PSEGSAPGSPAGSPTSTEEG GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAA
TSTEPSEGSAPGTSTEPSEG GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA
SAPGTSESATPESGPGSEPA GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
TSGSETPGSEPATSGSETPG GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
SPAGSPTSTEEGTSESATPE GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
SGPGTSTEPSEGSAPGTSTE GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
PSEGSAPGSPAGSPTSTEEG GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
TSTEPSEGSAPGTSTEPSEG GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
SAPGTSESATPESGPGTSTE GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
PSEGSAPGTSESATPESGPG GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
SEPATSGSETPGTSTEPSEG GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
SAPGTSTEPSEGSAPGTSES GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
ATPESGPGTSESATPESGP GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
GSPAGSPTSTEEGTSESATP GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
ESGPGSEPATSGSETPGTSE GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
SATPESGPGTSTEPSEGSAP GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTSTEPSE GGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA
GSAPGTSTEPSEGSAPGTS GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
TEPSEGSAPGTSTEPSEGSA GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
PGSPAGSPTSTEEGTSTEPS GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA
EGSAPGTSESATPESGPGS GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
EPATSGSETPGTSESATPES GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCA
GPGSEPATSGSETPGTSES GGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCA
ATPESGPGTSTEPSEGSAP GGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSPAGSPT GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
STEEGSPAGSPTSTEEGSPA GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
GSPTSTEEGTSESATPESGP GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
GTSTEPSEGSAPGFPTIPLS GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCA
RLFDNAMLRAHRLHQLAF GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA
DTYQEFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
LQNPQTSLCFSESIPTPSNR GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCA
EETQQKSNLELLRISLLLIQ GGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCA
SWLEPVQFLRSVFANSLV GGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCA
YGASDSNVYDLLKDLEEG GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
IQTLMGRLEDGSPRTGQIF GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
KQTYSKFDTNSHNDDALL GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
KNYGLLYCFRKDMDKVE GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
TFLRIVQCRSVEGSCGF GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AD836- GSSESGSSEGGPGSSESGSS 687 GGTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCA 688
hGH EGGPGESPGGSSGSESGSG GGTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCA
GEPSESGSSGESPGGSSGSE GGTGAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCA
SGESPGGSSGSESGSSESGS GGTTCTGGTGGCGAACCTTCCGAGTCTGGTAGCTCA
SEGGPGSSESGSSEGGPGS GGTGAATCTCCGGGTGGTTCTAGCGGTTCCGAGTCA
SESGSSEGGPGESPGGSSG GGTGAATCTCCGGGTGGTTCCAGCGGTTCTGAGTCA
SESGESPGGSSGSESGESPG GGTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCA
GSSGSESGSSESGSSEGGP GGTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCA
GSSESGSSEGGPGSSESGSS GGTTCTTCTGAAAGCGGTTCTTCCGAGGGCGGTCCA
EGGPGSSESGSSEGGPGSS GGTGAATCTCCTGGTGGTTCCAGCGGTTCCGAGTCA
ESGSSEGGPGSSESGSSEG GGTGAATCTCCAGGTGGCTCTAGCGGTTCCGAGTCA
GPGSGGEPSESGSSGESPG GGTGAATCTCCTGGTGGTTCTAGCGGTTCTGAATCAG
GSSGSESGESPGGSSGSES GTTCCTCCGAAAGCGGTTCTTCTGAGGGCGGTCCAG
GSGGEPSESGSSGSEGSSG GTTCCTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG
PGESSGSSESGSSEGGPGS GTTCTTCTGAAAGCGGTTCTTCCGAGGGCGGTCCAG
GGEPSESGSSGSEGSSGPG GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
ESSGSSESGSSEGGPGSGG GTTCTTCCGAAAGCGGTTCTTCCGAGGGCGGTCCAG
EPSESGSSGESPGGSSGSES GTTCTTCCGAAAGCGGTTCTTCTGAAGGCGGTCCAG
GSGGEPSESGSSGSGGEPS GTTCTGGTGGCGAACCGTCCGAGTCTGGTAGCTCAG
ESGSSGSSESGSSEGGPGS GTGAATCTCCGGGTGGCTCTAGCGGTTCCGAGTCAG
GGEPSESGSSGSGGEPSES GTGAATCTCCTGGTGGTTCCAGCGGTTCCGAGTCAG
GSSGSEGSSGPGESSGESP GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAG
GGSSGSESGSEGSSGPGES GTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAG
SGSEGSSGPGESSGSGGEP GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
SESGSSGSSESGSSEGGPGS GTTCCGGTGGCGAACCGTCCGAATCTGGTAGCTCAG
SESGSSEGGPGESPGGSSG GTAGCGAAGGTTCTTCTGGTCCAGGCGAATCTTCAG
SESGSGGEPSESGSSGSEGS GTTCCTCTGAAAGCGGTTCTTCTGAGGGCGGTCCAG
SGPGESSGESPGGSSGSES GTTCCGGTGGCGAACCTTCCGAATCTGGTAGCTCAG
GSEGSSGPGSSESGSSEGG GTGAATCTCCGGGTGGTTCTAGCGGTTCTGAGTCAG
PGSGGEPSESGSSGSEGSS GTTCTGGTGGTGAACCTTCCGAGTCTGGTAGCTCAG
GPGESSGSEGSSGPGESSG GTTCTGGTGGCGAACCATCCGAGTCTGGTAGCTCAG
SEGSSGPGESSGSGGEPSES GTTCTTCCGAAAGCGGTTCTTCCGAAGGCGGTCCAG
GSSGSGGEPSESGSSGESP GTTCTGGTGGTGAACCGTCCGAATCTGGTAGCTCAG
GGSSGSESGESPGGSSGSE GTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG
SGSGGEPSESGSSGSEGSS GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAG
GPGESSGESPGGSSGSESG GTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG
SSESGSSEGGPGSSESGSSE GTAGCGAAGGTTCTTCCGGTCCAGGTGAATCTTCAG
GGPGSSESGSSEGGPGSGG GTAGCGAAGGTTCTTCTGGTCCTGGTGAATCCTCAG
EPSESGSSGSSESGSSEGGP GTTCCGGTGGCGAACCATCTGAATCTGGTAGCTCAG
GESPGGSSGSESGSGGEPS GTTCCTCTGAAAGCGGTTCTTCCGAAGGTGGTCCAG
ESGSSGSSESGSSEGGPGES GTTCCTCTGAAAGCGGTTCTTCTGAGGGTGGTCCAG
PGGSSGSESGSGGEPSESG GTGAATCTCCGGGTGGCTCCAGCGGTTCCGAGTCAG
SSGESPGGSSGSESGSGGE GTTCTGGTGGCGAACCATCCGAATCTGGTAGCTCAG
PSESGSSGFPTIPLSRLFDN GTAGCGAAGGTTCTTCTGGTCCTGGCGAATCTTCAG
AMLRAHRLHQLAFDTYQE GTGAATCTCCAGGTGGCTCTAGCGGTTCCGAATCAG
FEEAYIPKEQKYSFLQNPQ GTAGCGAAGGTTCTTCCGGTCCaGGTTCCTCTGAAAG
TSLCFSESIPTPSNREETQQ CGGTTCTTCTGAGGGCGGTCCAGGTTCTGGTGGCGA
KSNLELLRISLLLIQSWLEP ACCATCTGAATCTGGTAGCTCAGGTAGCGAAGGTTC
VQFLRSVFANSLVYGASD TTCCGGTCCGGGTGAATCTTCAGGTAGCGAAGGTTC
SNVYDLLKDLEEGIQTLM TTCCGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTC
GRLEDGSPRTGQIFKQTYS TTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA
KFDTNSHNDDALLKNYGL CCATCTGAATCTGGTAGCTCAGGTTCTGGTGGCGAA
LYCFRKDMDKVETFLRIV CCATCCGAATCTGGTAGCTCAGGTGAATCTCCGGGT
QCRSVEGSCGF GGCTCCAGCGGTTCTGAATCAGGTGAATCTCCTGGT
GGCTCCAGCGGTTCTGAGTCAGGTTCTGGTGGCGAA
CCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCT
TCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTG
GCTCTAGCGGTTCCGAATCAGGTTCCTCTGAAAGCG
GTTCTTCTGAGGGCGGTCCAGGTTCTTCCGAAAGCG
GTTCTTCCGAGGGCGGTCCAGGTTCTTCCGAAAGCG
GTTCTTCTGAAGGCGGTCCAGGTTCTGGTGGCGAAC
CGTCCGAATCTGGTAGCTCAGGTTCCTCCGAAAGCG
GTTCTTCTGAAGGTGGTCCAGGTGAATCTCCAGGTG
GTTCTAGCGGTTCTGAATCAGGTTCTGGTGGCGAAC
CGTCCGAATCTGGTAGCTCAGGTTCCTCCGAAAGCG
GTTCTTCTGAAGGTGGTCCAGGTGAATCTCCAGGTG
GTTCTAGCGGTTCTGAATCAGGTTCTGGTGGCGAAC
CGTCCGAATCTGGTAGCTCAGGTGAATCTCCTGGTG
GTTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAAC
CTTCCGAATCTGGTAGCTCAGGTTTTCCGACTATTCC
GCTGTCTCGTCTGTTTGATAATGCTATGCTGCGTGCG
CACCGTCTGCACCAGCTGGCCTTTGATACTTACCAGG
AATTTGAAGAAGCcTACATTCCTAAAGAGCAGAAGT
ACTCTTTCCTGCAAAACCCACAGACTTCTCTCTGCTT
CAGCGAATCTATTCCGACGCCTTCCAATCGCGAGGA
AACTCAGCAAAAGTCCAATCTGGAACTACTCCGCAT
TTCTCTGCTTCTGATTCAGAGCTGGCTAGAACCAGTG
CAATTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACGATCTCCTGA
AAGATCTCGAGGAAGGCATTCAGACCCTGATGGGTC
GTCTCGAGGATGGCTCTCCGCGTACTGGTCAGATCTT
CAAGCAGACTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTATGGTCTGCT
GTATTGTTTTCGTAAAGATATGGACAAAGTTGAAAC
CTTCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGC
AGCTGTGGTTTCTAA
AE864- GSPAGSPTSTEEGTSESATP 689 GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAA 690
hGH ESGPGTSTEPSEGSAPGSPA GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA
GSPTSTEEGTSTEPSEGSAP GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
GTSTEPSEGSAPGTSESATP GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
ESGPGSEPATSGSETPGSEP GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
ATSGSETPGSPAGSPTSTEE GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GTSESATPESGPGTSTEPSE GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
GSAPGTSTEPSEGSAPGSP GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
AGSPTSTEEGTSTEPSEGSA GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
PGTSTEPSEGSAPGTSESAT GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
PESGPGTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
ESATPESGPGSEPATSGSET GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
PGTSTEPSEGSAPGTSTEPS GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
EGSAPGTSESATPESGPGT GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
SESATPESGPGSPAGSPTST GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
EEGTSESATPESGPGSEPAT GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
SGSETPGTSESATPESGPGT GGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA
STEPSEGSAPGTSTEPSEGS GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
APGTSTEPSEGSAPGTSTEP GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
SEGSAPGTSTEPSEGSAPG GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA
TSTEPSEGSAPGSPAGSPTS GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
TEEGTSTEPSEGSAPGTSES GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCA
ATPESGPGSEPATSGSETP GGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCA
GTSESATPESGPGSEPATS GGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GSETPGTSESATPESGPGTS GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
TEPSEGSAPGTSESATPESG GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
PGSPAGSPTSTEEGSPAGSP GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
TSTEEGSPAGSPTSTEEGTS GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCA
ESATPESGPGTSTEPSEGSA GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA
PGTSESATPESGPGSEPATS GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
GSETPGTSESATPESGPGSE GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCA
PATSGSETPGTSESATPESG GGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCA
PGTSTEPSEGSAPGSPAGSP GGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCA
TSTEEGTSESATPESGPGSE GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
PATSGSETPGTSESATPESG GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
PGSPAGSPTSTEEGSPAGSP GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
TSTEEGTSTEPSEGSAPGTS GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
ESATPESGPGTSESATPESG GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
PGTSESATPESGPGSEPATS GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
GSETPGSEPATSGSETPGSP GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
AGSPTSTEEGTSTEPSEGSA GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
PGTSTEPSEGSAPGSEPATS GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GSETPGTSESATPESGPGTS GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
TEPSEGSAPGFPTIPLSRLF GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
DNAMLRAHRLHQLAFDT GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
YQEFEEAYIPKEQKYSFLQ GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
NPQTSLCFSESIPTPSNREE GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
TQQKSNLELLRISLLLIQS GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
WLEPVQFLRSVFANSLVY GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
GASDSNVYDLLKDLEEGI GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
QTLMGRLEDGSPRTGQIFK GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
QTYSKFDTNSHNDDALLK GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
NYGLLYCFRKDMDKVETF GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
LRIVQCRSVEGSCGF GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCA
GGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCA
GGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AF864- GSTSESPSGTAPGTSPSGES 691 GGTTCTACCAGCGAATCTCCTTCTGGCACCGCTCCAG 692
hGH STAPGSTSESPSGTAPGSTS GTACCTCTCCTAGCGGCGAATCTTCTACCGCTCCAGG
ESPSGTAPGTSTPESGSASP TTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGGT
GTSTPESGSASPGSTSESPS TCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGTA
GTAPGSTSESPSGTAPGTSP CTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTAC
SGESSTAPGSTSESPSGTAP CTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTTCT
GTSPSGESSTAPGTSPSGES ACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTCTA
STAPGSTSSTAESPGPGTSP CTAGCGAATCCCCGTCTGGTACCGCACCAGGTACTT
SGESSTAPGTSPSGESSTAP CTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCTAC
GSTSSTAESPGPGTSTPESG TAGCGAATCTCCGTCTGGCACTGCTCCAGGTACTTCT
SASPGTSTPESGSASPGSTS CCTAGCGGTGAATCTTCTACCGCTCCAGGTACTTCCC
ESPSGTAPGSTSESPSGTAP CTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACTAG
GTSTPESGSASPGSTSSTAE CTCTACTGCAGAATCTCCGGGCCCAGGTACCTCTCCT
SPGPGTSTPESGSASPGSTS AGCGGTGAATCTTCTACCGCTCCAGGTACTTCTCCGA
ESPSGTAPGTSPSGESSTAP GCGGTGAATCTTCTACCGCTCCAGGTTCTACTAGCTC
GSTSSTAESPGPGTSPSGES TACTGCAGAATCTCCTGGCCCAGGTACCTCTACTCCG
STAPGTSTPESGSASPGSTS GAAAGCGGCTCTGCATCTCCAGGTACTTCTACCCCTG
STAESPGPGSTSSTAESPGP AAAGCGGTTCTGCATCTCCAGGTTCTACTAGCGAAT
GSTSSTAESPGPGSTSSTAE CTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATC
SPGPGTSPSGESSTAPGSTS TCCGTCTGGCACTGCACCAGGTACCTCTACCCCTGAA
ESPSGTAPGSTSESPSGTAP AGCGGTTCCGCTTCTCCAGGTTCTACCAGCTCTACCG
GTSTPESGPXXXGASASGA CAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAA
PSTXXXXSESPSGTAPGST GCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCC
SESPSGTAPGSTSESPSGTA TTCTGGCACTGCACCAGGTACTTCTCCGAGCGGTGA
PGSTSESPSGTAPGSTSESP ATCTTCTACCGCACCAGGTTCTACTAGCTCTACCGCT
SGTAPGSTSESPSGTAPGTS GAATCTCCGGGCCCAGGTACTTCTCCGAGCGGTGAA
TPESGSASPGTSPSGESSTA TCTTCTACTGCTCCAGGTACCTCTACTCCTGAAAGCG
PGTSPSGESSTAPGSTSSTA GTTCTGCATCTCCAGGTTCCACTAGCTCTACCGCAGA
ESPGPGTSPSGESSTAPGTS ATCTCCGGGCCCAGGTTCTACTAGCTCTACTGCTGAA
TPESGSASPGSTSESPSGTA TCTCCTGGCCCAGGTTCTACTAGCTCTACTGCTGAAT
PGSTSESPSGTAPGTSPSGE CTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAATC
SSTAPGSTSESPSGTAPGTS TCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTCT
TPESGSASPGTSTPESGSAS ACTGCACCAGGTTCTACTAGCGAATCTCCTTCTGGCA
PGSTSESPSGTAPGTSTPES CTGCACCAGGTTCTACCAGCGAATCTCCGTCTGGCA
GSASPGSTSSTAESPGPGST CTGCACCAGGTACCTCTACCCCTGAAAGCGGTCCXX
SESPSGTAPGSTSESPSGTA XXXXXXXXXXTGCAAGCGCAAGCGGCGCGCCAAGC
PGTSPSGESSTAPGSTSSTA ACGGGAXXXXXXXXTAGCGAATCTCCTTCTGGTACC
ESPGPGTSPSGESSTAPGTS GCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTACTG
TPESGSASPGTSPSGESSTA CTCCAGGTTCTACCAGCGAATCTCCTTCTGGTACTGC
PGTSPSGESSTAPGTSPSGE ACCAGGTTCTACTAGCGAATCTCCTTCTGGTACCGCT
SSTAPGSTSSTAESPGPGST CCAGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTC
SSTAESPGPGTSPSGESSTA CAGGTTCTACCAGCGAATCTCCTTCTGGTACTGCACC
PGSSPSASTGTGPGSSTPSG AGGTACTTCTACTCCGGAAAGCGGTTCCGCATCTCC
ATGSPGSSTPSGATGSPGF AGGTACTTCTCCTAGCGGTGAATCTTCTACTGCTCCA
PTIPLSRLFDNAMLRAHRL GGTACCTCTCCTAGCGGCGAATCTTCTACTGCTCCAG
HQLAFDTYQEFEEAYIPKE GTTCTACCAGCTCTACTGCTGAATCTCCGGGTCCAGG
QKYSFLQNPQTSLCFSESIP TACTTCCCCGAGCGGTGAATCTTCTACTGCACCAGGT
TPSNREETQQKSNLELLRIS ACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT
LLLIQSWLEPVQFLRSVFA CTACCAGCGAATCTCCTTCTGGCACCGCTCCAGGTTC
NSLVYGASDSNVYDLLKD TACTAGCGAATCCCCGTCTGGTACCGCACCAGGTAC
LEEGIQTLMGRLEDGSPRT TTCTCCTAGCGGCGAATCTTCTACCGCACCAGGTTCT
GQIFKQTYSKFDTNSHND ACTAGCGAATCCCCGTCTGGTACCGCACCAGGTACT
DALLKNYGLLYCFRKDM TCTACCCCGGAAAGCGGCTCTGCTTCTCCAGGTACTT
DKVETFLRIVQCRSVEGSC CTACCCCGGAAAGCGGCTCCGCATCTCCAGGTTCTA
GF CTAGCGAATCTCCTTCTGGTACCGCTCCAGGTACTTC
TACCCCTGAAAGCGGCTCCGCTTCTCCAGGTTCCACT
AGCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCA
GCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAG
CGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT
AGCGGCGAATCTTCTACCGCACCAGGTTCTACCAGC
TCTACTGCTGAATCTCCGGGTCCAGGTACTTCCCCGA
GCGGTGAATCTTCTACTGCACCAGGTACTTCTACTCC
GGAAAGCGGTTCCGCTTCTCCAGGTACCTCCCCTAG
CGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGC
GGCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCG
GTGAATCTTCTACCGCACCAGGTTCTACTAGCTCTAC
TGCTGAATCTCCGGGTCCAGGTTCTACCAGCTCTACT
GCTGAATCTCCTGGTCCAGGTACCTCCCCGAGCGGT
GAATCTTCTACTGCACCAGGTTCTAGCCCTTCTGCTT
CCACCGGTACCGGCCCAGGTAGCTCTACTCCGTCTG
GTGCAACTGGCTCTCCAGGTAGCTCTACTCCGTCTGG
TGCAACCGGCTCCCCAGGTTTTCCGACTATTCCGCTG
TCTCGTCTGTTTGATAATGCTATGCTGCGTGCGCACC
GTCTGCACCAGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAGAAGTACTC
TTTCCTGCAAAACCCACAGACTTCTCTCTGCTTCAGC
GAATCTATTCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCCGCATTTCT
CTGCTTCTGATTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTCTTCGCCAATAGCCTAGTTTATG
GCGCATCCGACAGCAACGTATACGATCTCCTGAAAG
ATCTCGAGGAAGGCATTCAGACCCTGATGGGTCGTC
TCGAGGATGGCTCTCCGCGTACTGGTCAGATCTTCA
AGCAGACTTACTCTAAATTTGATACTAACAGCCACA
ATGACGATGCGCTTCTAAAAAACTATGGTCTGCTGT
ATTGTTTTCGTAAAGATATGGACAAAGTTGAAACCT
TCCTGCGTATTGTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAA
AG864- GASPGTSSTGSPGSSPSAST 693 GGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCCAG 694
hGH GTGPGSSPSASTGTGPGTP GTTCTAGCCCGTCTGCTTCTACTGGTACTGGTCCAGG
GSGTASSSPGSSTPSGATG TTCTAGCCCTTCTGCTTCCACTGGTACTGGTCCAGGT
SPGSNPSASTGTGPGASPG ACCCCGGGTAGCGGTACCGCTTCTTCTTCTCCAGGTA
TSSTGSPGTPGSGTASSSPG GCTCTACTCCGTCTGGTGCTACCGGCTCTCCAGGTTC
SSTPSGATGSPGTPGSGTA TAACCCTTCTGCATCCACCGGTACCGGCCCAGGTGCT
SSSPGASPGTSSTGSPGASP TCTCCGGGCACCAGCTCTACTGGTTCTCCAGGTACCC
GTSSTGSPGTPGSGTASSSP CGGGCAGCGGTACCGCATCTTCTTCTCCAGGTAGCTC
GSSTPSGATGSPGASPGTS TACTCCTTCTGGTGCAACTGGTTCTCCAGGTACTCCT
STGSPGTPGSGTASSSPGSS GGCAGCGGTACCGCTTCTTCTTCTCCAGGTGCTTCTC
TPSGATGSPGSNPSASTGT CTGGTACTAGCTCTACTGGTTCTCCAGGTGCTTCTCC
GPGSSPSASTGTGPGSSTPS GGGCACTAGCTCTACTGGTTCTCCAGGTACCCCGGG
GATGSPGSSTPSGATGSPG TAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACC
ASPGTSSTGSPGASPGTSST CCTTCTGGTGCAACCGGCTCTCCAGGTGCTTCTCCGG
GSPGASPGTSSTGSPGTPG GCACCAGCTCTACCGGTTCTCCAGGTACCCCGGGTA
SGTASSSPGASPGTSSTGSP GCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTACTCC
GASPGTSSTGSPGASPGTS GTCTGGTGCTACCGGCTCTCCAGGTTCTAACCCTTCT
STGSPGSSPSASTGTGPGTP GCATCCACCGGTACCGGCCCAGGTTCTAGCCCTTCTG
GSGTASSSPGASPGTSSTG CTTCCACCGGTACTGGCCCAGGTAGCTCTACCCCTTC
SPGASPGTSSTGSPGASPG TGGTGCTACCGGCTCCCCAGGTAGCTCTACTCCTTCT
TSSTGSPGSSTPSGATGSPG GGTGCAACTGGCTCTCCAGGTGCATCTCCGGGCACT
SSTPSGATGSPGASPGTSST AGCTCTACTGGTTCTCCAGGTGCATCCCCTGGCACTA
GSPGTPGSGTASSSPGSSTP GCTCTACTGGTTCTCCAGGTGCTTCTCCTGGTACCAG
SGATGSPGSSTPSGATGSP CTCTACTGGTTCTCCAGGTACTCCTGGCAGCGGTACC
GSSTPSGATGSPGSSPSAST GCTTCTTCTTCTCCAGGTGCTTCTCCTGGTACTAGCT
GTGPGASPGTSSTGSPGAS CTACTGGTTCTCCAGGTGCTTCTCCGGGCACTAGCTC
PGTSSTGSPGTPGSGTASSS TACTGGTTCTCCAGGTGCTTCCCCGGGCACTAGCTCT
PGASPGTSSTGSPGASPGT ACCGGTTCTCCAGGTTCTAGCCCTTCTGCATCTACTG
SSTGSPGASPGTSSTGSPG GTACTGGCCCAGGTACTCCGGGCAGCGGTACTGCTT
ASPGTSSTGSPGTPGSGTA CTTCCTCTCCAGGTGCATCTCCGGGCACTAGCTCTAC
SSSPGSSTPSGATGSPGTPG TGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTACT
SGTASSSPGSSTPSGATGSP GGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACTG
GTPGSGTASSSPGSSTPSG GTTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGG
ATGSPGSSTPSGATGSPGS TTCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGC
SPSASTGTGPGSSPSASTGT TCCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTT
GPGASPGTSSTGSPGTPGS CTCCAGGTACCCCGGGCAGCGGTACCGCATCTTCCT
GTASSSPGSSTPSGATGSP CTCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGTTC
GSSPSASTGTGPGSSPSAST CCCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTC
GTGPGASPGTSSTGSPGAS CCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGCTCC
PGTSSTGSPGSSTPSGATGS CCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGGCC
PGSSPSASTGTGPGASPGT CAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCTCC
SSTGSPGSSPSASTGTGPGT AGGTGCATCCCCGGGTACCAGCTCTACCGGTTCTCC
PGSGTASSSPGSSTPSGAT AGGTACTCCTGGCAGCGGTACTGCATCTTCCTCTCCA
GSPGSSTPSGATGSPGASP GGTGCTTCTCCGGGCACCAGCTCTACTGGTTCTCCAG
GTSSTGSPGFPTIPLSRLFD GTGCATCTCCGGGCACTAGCTCTACTGGTTCTCCAGG
NAMLRAHRLHQLAFDTY TGCATCCCCTGGCACTAGCTCTACTGGTTCTCCAGGT
QEFEEAYIPKEQKYSFLQN GCTTCTCCTGGTACCAGCTCTACTGGTTCTCCAGGTA
PQTSLCFSESIPTPSNREET CCCCTGGTAGCGGTACTGCTTCTTCCTCTCCAGGTAG
QQKSNLELLRISLLLIQSW CTCTACTCCGTCTGGTGCTACCGGTTCTCCAGGTACC
LEPVQFLRSVFANSLVYGA CCGGGTAGCGGTACCGCATCTTCTTCTCCAGGTAGCT
SDSNVYDLLKDLEEGIQTL CTACCCCGTCTGGTGCTACTGGTTCTCCAGGTACTCC
MGRLEDGSPRTGQIFKQT GGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGCTCT
YSKFDTNSHNDDALLKNY ACCCCTTCTGGTGCTACTGGCTCTCCAGGTAGCTCTA
GLLYCFRKDMDKVETFLR CCCCGTCTGGTGCTACTGGCTCCCCAGGTTCTAGCCC
IVQCRSVEGSCGF TTCTGCATCCACCGGTACCGGTCCAGGTTCTAGCCCG
TCTGCATCTACTGGTACTGGTCCAGGTGCATCCCCGG
GCACTAGCTCTACCGGTTCTCCAGGTACTCCTGGTAG
CGGTACTGCTTCTTCTTCTCCAGGTAGCTCTACTCCT
TCTGGTGCTACTGGTTCTCCAGGTTCTAGCCCTTCTG
CATCCACCGGTACCGGCCCAGGTTCTAGCCCGTCTG
CTTCTACCGGTACTGGTCCAGGTGCTTCTCCGGGTAC
TAGCTCTACTGGTTCTCCAGGTGCATCTCCTGGTACT
AGCTCTACTGGTTCTCCAGGTAGCTCTACTCCGTCTG
GTGCAACCGGCTCTCCAGGTTCTAGCCCTTCTGCATC
TACCGGTACTGGTCCAGGTGCATCCCCTGGTACCAG
CTCTACCGGTTCTCCAGGTTCTAGCCCTTCTGCTTCT
ACCGGTACCGGTCCAGGTACCCCTGGCAGCGGTACC
GCATCTTCCTCTCCAGGTAGCTCTACTCCGTCTGGTG
CAACCGGTTCCCCAGGTAGCTCTACTCCTTCTGGTGC
TACTGGCTCCCCAGGTGCATCCCCTGGCACCAGCTCT
ACCGGTTCTCCAGGTTTTCCGACTATTCCGCTGTCTC
GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT
GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGA
AGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTC
CTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAAT
CTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC
AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT
TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCT
GCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA
TCCGACAGCAACGTATACGATCTCCTGAAAGATCTC
GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGCCACAATGAC
GATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT
TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGC
GTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG
TTTCTAA
AM875- GTSTEPSEGSAPGSEPATS 695 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCA 696
hGH GSETPGSPAGSPTSTEEGST GGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCA
SSTAESPGPGTSTPESGSAS GGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAA
PGSTSESPSGTAPGSTSESP GGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAG
SGTAPGTSTPESGSASPGTS GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAG
TPESGSASPGSEPATSGSET GTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG
PGTSESATPESGPGSPAGSP TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGT
TSTEEGTSTEPSEGSAPGTS ACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTA
ESATPESGPGTSTEPSEGSA CCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTA
PGTSTEPSEGSAPGSPAGSP GCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGTA
TSTEEGTSTEPSEGSAPGTS CCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTA
TEPSEGSAPGTSESATPESG GCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTA
PGTSESATPESGPGTSTEPS CCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA
EGSAPGTSTEPSEGSAPGT CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA
SESATPESGPGTSTEPSEGS CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTA
APGSEPATSGSETPGSPAG CTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA
SPTSTEEGSSTPSGATGSPG GCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTA
TPGSGTASSSPGSSTPSGAT CTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA
GSPGTSTEPSEGSAPGTSTE CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTA
PSEGSAPGSEPATSGSETPG CTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA
SPAGSPTSTEEGSPAGSPTS CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTA
TEEGTSTEPSEGSAPGASA CCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA
SGAPSTGGTSESATPESGP CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTA
GSPAGSPTSTEEGSPAGSPT CTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTA
STEEGSTSSTAESPGPGSTS CTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTA
ESPSGTAPGTSPSGESSTAP GCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTA
GTPGSGTASSSPGSSTPSG GCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTA
ATGSPGSSPSASTGTGPGS GCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTAC
EPATSGSETPGTSESATPES TCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGC
GPGSEPATSGSETPGSTSST TCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCT
AESPGPGSTSSTAESPGPGT CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT
SPSGESSTAPGSEPATSGSE CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCG
TPGSEPATSGSETPGTSTEP AACCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCC
SEGSAPGSTSSTAESPGPGT CTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCC
STPESGSASPGSTSESPSGT CGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTC
APGTSTEPSEGSAPGTSTEP TACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAAG
SEGSAPGTSTEPSEGSAPGS CGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTGA
STPSGATGSPGSSPSASTGT AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGC
GPGASPGTSSTGSPGSEPA TGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGC
TSGSETPGTSESATPESGPG TGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGC
SPAGSPTSTEEGSSTPSGAT TCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAGCG
GSPGSSPSASTGTGPGASP AATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG
GTSSTGSPGTSESATPESGP CGGTGAATCTTCTACTGCACCAGGTACCCCTGGCAG
GTSTEPSEGSAPGTSTEPSE CGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCCG
GSAPGFPTIPLSRLFDNAM TCTGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCTG
LRAHRLHQLAFDTYQEFE CATCTACCGGTACCGGCCCAGGTAGCGAACCGGCAA
EAYIPKEQKYSFLQNPQTS CCTCCGGCTCTGAAACTCCAGGTACTTCTGAAAGCG
LCFSESIPTPSNREETQQKS CTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCTA
NLELLRISLLLIQSWLEPVQ CTTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTAC
FLRSVFANSLVYGASDSN TGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTACT
VYDLLKDLEEGIQTLMGR GCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGGC
LEDGSPRTGQIFKQTYSKF GAATCTTCTACCGCTCCAGGTAGCGAACCGGCAACC
DTNSHNDDALLKNYGLLY TCTGGCTCTGAAACTCCAGGTAGCGAACCTGCAACC
CFRKDMDKVETFLRIVQC TCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCTT
RSVEGSCGF CTGAGGGCAGCGCACCAGGTTCTACCAGCTCTACCG
CAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAAA
GCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTCC
TTCTGGCACTGCACCAGGTACTTCTACCGAACCGTCC
GAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTCC
GAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTCT
GAAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGGT
GCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCT
CTACTGGTTCTCCAGGTAGCGAACCTGCTACCTCCGG
TTCTGAAACCCCAGGTACCTCTGAAAGCGCAACTCC
GGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTAC
CTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTGC
AACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCACT
GGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTCT
ACTGGTTCTCCAGGTACCTCTGAAAGCGCTACTCCG
GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAG
GGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA
GGTAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTC
GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT
GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGA
AGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTC
CTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAAT
CTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC
AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT
TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCT
GCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA
TCCGACAGCAACGTATACGATCTCCTGAAAGATCTC
GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGCCACAATGAC
GATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT
TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGC
GTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG
TTTCTAA
AE912- MAEPAGSPTSTEEGTPGSG 697 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAG 698
hGH TASSSPGSSTPSGATGSPG GAAGGTACCCCGGGTAGCGGTACTGCTTCTTCCTCTC
ASPGTSSTGSPGSPAGSPTS CAGGTAGCTCTACCCCTTCTGGTGCAACCGGCTCTCC
TEEGTSESATPESGPGTSTE AGGTGCTTCTCCGGGCACCAGCTCTACCGGTTCTCCA
PSEGSAPGSPAGSPTSTEEG GGTAGCCCGGCTGGCTCTCCTACCTCTACTGAGGAA
TSTEPSEGSAPGTSTEPSEG GGTACTTCTGAAAGCGCTACTCCTGAGTCTGGTCCA
SAPGTSESATPESGPGSEPA GGTACCTCTACTGAACCGTCCGAAGGTAGCGCTCCA
TSGSETPGSEPATSGSETPG GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
SPAGSPTSTEEGTSESATPE GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
SGPGTSTEPSEGSAPGTSTE GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
PSEGSAPGSPAGSPTSTEEG GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
TSTEPSEGSAPGTSTEPSEG GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
SAPGTSESATPESGPGTSTE GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
PSEGSAPGTSESATPESGPG GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
SEPATSGSETPGTSTEPSEG GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
SAPGTSTEPSEGSAPGTSES GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
ATPESGPGTSESATPESGP GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
GSPAGSPTSTEEGTSESATP GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
ESGPGSEPATSGSETPGTSE GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
SATPESGPGTSTEPSEGSAP GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTSTEPSE GGTACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCA
GSAPGTSTEPSEGSAPGTS GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
TEPSEGSAPGTSTEPSEGSA GGTACTTCTGAAAGCGCAACCCCTGAATCCGGTCCA
PGSPAGSPTSTEEGTSTEPS GGTAGCGAACCGGCTACTTCTGGCTCTGAGACTCCA
EGSAPGTSESATPESGPGS GGTACTTCTACCGAACCGTCCGAAGGTAGCGCACCA
EPATSGSETPGTSESATPES GGTACTTCTACTGAACCGTCTGAAGGTAGCGCACCA
GPGSEPATSGSETPGTSES GGTACTTCTGAAAGCGCAACCCCGGAATCCGGCCCA
ATPESGPGTSTEPSEGSAP GGTACCTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSPAGSPT GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
STEEGSPAGSPTSTEEGSPA GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
GSPTSTEEGTSESATPESGP GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
GTSTEPSEGSAPGTSESATP GGTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCA
ESGPGSEPATSGSETPGTSE GGTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCA
SATPESGPGSEPATSGSETP GGTACTTCTACTGAACCGTCCGAAGGTAGCGCACCA
GTSESATPESGPGTSTEPSE GGTACTTCTACCGAACCGTCCGAAGGCAGCGCTCCA
GSAPGSPAGSPTSTEEGTS GGTACCTCTACTGAACCTTCCGAGGGCAGCGCTCCA
ESATPESGPGSEPATSGSET GGTACCTCTACCGAACCTTCTGAAGGTAGCGCACCA
PGTSESATPESGPGSPAGSP GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
TSTEEGSPAGSPTSTEEGTS GGTAGCCCAGCAGGTTCTCCTACCTCCACCGAGGAA
TEPSEGSAPGTSESATPESG GGTACTTCTACCGAACCGTCCGAGGGTAGCGCACCA
PGTSESATPESGPGTSESAT GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
PESGPGSEPATSGSETPGSE GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
PATSGSETPGSPAGSPTSTE GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
EGTSTEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
EGSAPGSEPATSGSETPGT GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
SESATPESGPGTSTEPSEGS GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
APGFPTIPLSRLFDNAMLR GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
AHRLHQLAFDTYQEFEEA GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
YIPKEQKYSFLQNPQTSLC GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
FSESIPTPSNREETQQKSNL GGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGAA
ELLRISLLLIQSWLEPVQFL GGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCCA
RSVFANSLVYGASDSNVY GGTACCTCTACCGAACCGTCTGAGGGCAGCGCACCA
DLLKDLEEGIQTLMGRLE GGTACCTCTGAAAGCGCAACTCCTGAGTCTGGCCCA
DGSPRTGQIFKQTYSKFDT GGTAGCGAACCTGCTACCTCCGGCTCTGAGACTCCA
NSHNDDALLKNYGLLYCF GGTACCTCTGAAAGCGCAACCCCGGAATCTGGTCCA
RKDMDKVETFLRIVQCRS GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
VEGSCGF GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGAA
GGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCCA
GGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTACTGAAGAA
GGTACTTCTACCGAACCTTCCGAGGGCAGCGCACCA
GGTACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCA
GGTACTTCTGAAAGCGCTACTCCTGAATCCGGTCCA
GGTACTTCTGAAAGCGCTACCCCGGAATCTGGCCCA
GGTAGCGAACCGGCTACTTCTGGTTCTGAAACCCCA
GGTAGCGAACCGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTCCACTGAGGAA
GGTACTTCTACTGAACCTTCCGAAGGCAGCGCACCA
GGTACCTCTACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTGAAACCCCA
GGTACCTCTGAAAGCGCTACTCCTGAATCTGGCCCA
GGTACTTCTACTGAACCGTCCGAGGGCAGCGCACCA
GGTTTTCCGACTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAGAAGCcTACAT
TCCTAAAGAGCAGAAGTACTCTTTCCTGCAAAACCC
ACAGACTTCTCTCTGCTTCAGCGAATCTATTCCGACG
CCTTCCAATCGCGAGGAAACTCAGCAAAAGTCCAAT
CTGGAACTACTCCGCATTTCTCTGCTTCTGATTCAGA
GCTGGCTAGAACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCGAGGAAGGCAT
TCAGACCCTGATGGGTCGTCTCGAGGATGGCTCTCC
GCGTACTGGTCAGATCTTCAAGCAGACTTACTCTAA
ATTTGATACTAACAGCCACAATGACGATGCGCTTCT
AAAAAACTATGGTCTGCTGTATTGTTTTCGTAAAGAT
ATGGACAAAGTTGAAACCTTCCTGCGTATTGTTCAGT
GTCGTTCCGTTGAGGGCAGCTGTGGTTTCTAA
AM923- MAEPAGSPTSTEEGASPGT 699 ATGGCTGAACCTGCTGGCTCTCCAACCTCCACTGAG 700
hGH SSTGSPGSSTPSGATGSPGS GAAGGTGCATCCCCGGGCACCAGCTCTACCGGTTCT
STPSGATGSPGTSTEPSEGS CCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCTCTC
APGSEPATSGSETPGSPAG CAGGTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCC
SPTSTEEGSTSSTAESPGPG AGGTACTTCTACTGAACCGTCTGAAGGCAGCGCACC
TSTPESGSASPGSTSESPSG AGGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCC
TAPGSTSESPSGTAPGTSTP AGGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGA
ESGSASPGTSTPESGSASPG AGGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCA
SEPATSGSETPGTSESATPE GGTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCA
SGPGSPAGSPTSTEEGTSTE GGTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAG
PSEGSAPGTSESATPESGPG GTTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGG
TSTEPSEGSAPGTSTEPSEG TACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGT
SAPGSPAGSPTSTEEGTSTE ACCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGT
PSEGSAPGTSTEPSEGSAPG AGCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGT
TSESATPESGPGTSESATPE ACCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGT
SGPGTSTEPSEGSAPGTSTE AGCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGT
PSEGSAPGTSESATPESGPG ACCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGT
TSTEPSEGSAPGSEPATSGS ACTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGT
ETPGSPAGSPTSTEEGSSTP ACTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGT
SGATGSPGTPGSGTASSSP ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT
GSSTPSGATGSPGTSTEPSE AGCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGT
GSAPGTSTEPSEGSAPGSEP ACTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGT
ATSGSETPGSPAGSPTSTEE ACTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGT
GSPAGSPTSTEEGTSTEPSE ACTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGT
GSAPGASASGAPSTGGTSE ACTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGT
SATPESGPGSPAGSPTSTEE ACCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGT
GSPAGSPTSTEEGSTSSTAE ACCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGT
SPGPGSTSESPSGTAPGTSP ACTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGT
SGESSTAPGTPGSGTASSSP ACTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGT
GSSTPSGATGSPGSSPSAST AGCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGT
GTGPGSEPATSGSETPGTS AGCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGT
ESATPESGPGSEPATSGSET AGCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTA
PGSTSSTAESPGPGSTSSTA CTCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAG
ESPGPGTSPSGESSTAPGSE CTCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACC
PATSGSETPGSEPATSGSET TCTACCGAACCGTCCGAGGGTAGCGCACCAGGTACC
PGTSTEPSEGSAPGSTSSTA TCTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGC
ESPGPGTSTPESGSASPGST GAACCGGCAACCTCCGGTTCTGAAACTCCAGGTAGC
SESPSGTAPGTSTEPSEGSA CCTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGC
PGTSTEPSEGSAPGTSTEPS CCGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTT
EGSAPGSSTPSGATGSPGS CTACCGAACCTTCCGAAGGTAGCGCTCCAGGTGCAA
SPSASTGTGPGASPGTSST GCGCAAGCGGCGCGCCAAGCACGGGAGGTACTTCTG
GSPGSEPATSGSETPGTSES AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG
ATPESGPGSPAGSPTSTEE CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG
GSSTPSGATGSPGSSPSAST CTGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAG
GTGPGASPGTSSTGSPGTS CTCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAGC
ESATPESGPGTSTEPSEGSA GAATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTA
PGTSTEPSEGSAPGFPTIPL GCGGTGAATCTTCTACTGCACCAGGTACCCCTGGCA
SRLFDNAMLRAHRLHQLA GCGGTACCGCTTCTTCCTCTCCAGGTAGCTCTACCCC
FDTYQEFEEAYIPKEQKYS GTCTGGTGCTACTGGCTCTCCAGGTTCTAGCCCGTCT
FLQNPQTSLCFSESIPTPSN GCATCTACCGGTACCGGCCCAGGTAGCGAACCGGCA
REETQQKSNLELLRISLLLI ACCTCCGGCTCTGAAACTCCAGGTACTTCTGAAAGC
QSWLEPVQFLRSVFANSL GCTACTCCGGAATCCGGCCCAGGTAGCGAACCGGCT
VYGASDSNVYDLLKDLEE ACTTCCGGCTCTGAAACCCCAGGTTCCACCAGCTCTA
GIQTLMGRLEDGSPRTGQI CTGCAGAATCTCCGGGCCCAGGTTCTACTAGCTCTAC
FKQTYSKFDTNSHNDDAL TGCAGAATCTCCGGGTCCAGGTACTTCTCCTAGCGG
LKNYGLLYCFRKDMDKV CGAATCTTCTACCGCTCCAGGTAGCGAACCGGCAAC
ETFLRIVQCRSVEGSCGF CTCTGGCTCTGAAACTCCAGGTAGCGAACCTGCAAC
CTCCGGCTCTGAAACCCCAGGTACTTCTACTGAACCT
TCTGAGGGCAGCGCACCAGGTTCTACCAGCTCTACC
GCAGAATCTCCTGGTCCAGGTACCTCTACTCCGGAA
AGCGGCTCTGCATCTCCAGGTTCTACTAGCGAATCTC
CTTCTGGCACTGCACCAGGTACTTCTACCGAACCGTC
CGAAGGCAGCGCTCCAGGTACCTCTACTGAACCTTC
CGAGGGCAGCGCTCCAGGTACCTCTACCGAACCTTC
TGAAGGTAGCGCACCAGGTAGCTCTACTCCGTCTGG
TGCAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCC
ACTGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGC
TCTACTGGTTCTCCAGGTAGCGAACCTGCTACCTCCG
GTTCTGAAACCCCAGGTACCTCTGAAAGCGCAACTC
CGGAGTCTGGTCCAGGTAGCCCTGCAGGTTCTCCTA
CCTCCACTGAGGAAGGTAGCTCTACTCCGTCTGGTG
CAACCGGCTCCCCAGGTTCTAGCCCGTCTGCTTCCAC
TGGTACTGGCCCAGGTGCTTCCCCGGGCACCAGCTC
TACTGGTTCTCCAGGTACCTCTGAAAGCGCTACTCCG
GAGTCTGGCCCAGGTACCTCTACTGAACCGTCTGAG
GGTAGCGCTCCAGGTACTTCTACTGAACCGTCCGAA
GGTAGCGCACCAGGTTTTCCGACTATTCCGCTGTCTC
GTCTGTTTGATAATGCTATGCTGCGTGCGCACCGTCT
GCACCAGCTGGCCTTTGATACTTACCAGGAATTTGA
AGAAGCcTACATTCCTAAAGAGCAGAAGTACTCTTTC
CTGCAAAACCCACAGACTTCTCTCTGCTTCAGCGAAT
CTATTCCGACGCCTTCCAATCGCGAGGAAACTCAGC
AAAAGTCCAATCTGGAACTACTCCGCATTTCTCTGCT
TCTGATTCAGAGCTGGCTAGAACCAGTGCAATTTCT
GCGTTCCGTCTTCGCCAATAGCCTAGTTTATGGCGCA
TCCGACAGCAACGTATACGATCTCCTGAAAGATCTC
GAGGAAGGCATTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGCCACAATGAC
GATGCGCTTCTAAAAAACTATGGTCTGCTGTATTGTT
TTCGTAAAGATATGGACAAAGTTGAAACCTTCCTGC
GTATTGTTCAGTGTCGTTCCGTTGAGGGCAGCTGTGG
TTTCTAA
AM1318- GTSTEPSEGSAPGSEPATS 701 GGTACTTCTACTGAACCGTCTGAAGGCAGCGCACCA 702
hGH GSETPGSPAGSPTSTEEGST GGTAGCGAACCGGCTACTTCCGGTTCTGAAACCCCA
SSTAESPGPGTSTPESGSAS GGTAGCCCAGCAGGTTCTCCAACTTCTACTGAAGAA
PGSTSESPSGTAPGSTSESP GGTTCTACCAGCTCTACCGCAGAATCTCCTGGTCCAG
SGTAPGTSTPESGSASPGTS GTACCTCTACTCCGGAAAGCGGCTCTGCATCTCCAG
TPESGSASPGSEPATSGSET GTTCTACTAGCGAATCTCCTTCTGGCACTGCACCAGG
PGTSESATPESGPGSPAGSP TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGT
TSTEEGTSTEPSEGSAPGTS ACTTCTACTCCTGAAAGCGGTTCCGCTTCTCCAGGTA
ESATPESGPGTSTEPSEGSA CCTCTACTCCGGAAAGCGGTTCTGCATCTCCAGGTA
PGTSTEPSEGSAPGSPAGSP GCGAACCGGCAACCTCCGGCTCTGAAACCCCAGGTA
TSTEEGTSTEPSEGSAPGTS CCTCTGAAAGCGCTACTCCTGAATCCGGCCCAGGTA
TEPSEGSAPGTSESATPESG GCCCGGCAGGTTCTCCGACTTCCACTGAGGAAGGTA
PGTSESATPESGPGTSTEPS CCTCTACTGAACCTTCTGAGGGCAGCGCTCCAGGTA
EGSAPGTSTEPSEGSAPGT CTTCTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTA
SESATPESGPGTSTEPSEGS CTTCTACTGAACCGTCCGAAGGTAGCGCACCAGGTA
APGSEPATSGSETPGSPAG CTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA
SPTSTEEGSSTPSGATGSPG GCCCAGCAGGTTCTCCTACCTCCACCGAGGAAGGTA
TPGSGTASSSPGSSTPSGAT CTTCTACCGAACCGTCCGAGGGTAGCGCACCAGGTA
GSPGTSTEPSEGSAPGTSTE CTTCTACCGAACCTTCCGAGGGCAGCGCACCAGGTA
PSEGSAPGSEPATSGSETPG CTTCTGAAAGCGCTACCCCTGAGTCCGGCCCAGGTA
SPAGSPTSTEEGSPAGSPTS CTTCTGAAAGCGCTACTCCTGAATCCGGTCCAGGTA
TEEGTSTEPSEGSAPGPEPT CCTCTACTGAACCTTCCGAAGGCAGCGCTCCAGGTA
GPAPSGGSEPATSGSETPG CCTCTACCGAACCGTCCGAGGGCAGCGCACCAGGTA
TSESATPESGPGSPAGSPTS CTTCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTA
TEEGTSESATPESGPGSPA CTTCTACTGAACCTTCCGAAGGTAGCGCTCCAGGTA
GSPTSTEEGSPAGSPTSTEE GCGAACCTGCTACTTCTGGTTCTGAAACCCCAGGTA
GTSESATPESGPGSPAGSPT GCCCGGCTGGCTCTCCGACCTCCACCGAGGAAGGTA
STEEGSPAGSPTSTEEGSTS GCTCTACCCCGTCTGGTGCTACTGGTTCTCCAGGTAC
STAESPGPGSTSESPSGTAP TCCGGGCAGCGGTACTGCTTCTTCCTCTCCAGGTAGC
GTSPSGESSTAPGSTSESPS TCTACCCCTTCTGGTGCTACTGGCTCTCCAGGTACCT
GTAPGSTSESPSGTAPGTSP CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT
SGESSTAPGTSTEPSEGSAP CTACTGAACCGTCTGAGGGTAGCGCTCCAGGTAGCG
GTSESATPESGPGTSESATP AACCGGCAACCTCCGGTTCTGAAACTCCAGGTAGCC
ESGPGSEPATSGSETPGTSE CTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCC
SATPESGPGTSESATPESGP CGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTC
GTSTEPSEGSAPGTSESATP TACCGAACCTTCCGAAGGTAGCGCTCCAGGTCCAGA
ESGPGTSTEPSEGSAPGTSP ACCAACGGGGCCGGCCCCAAGCGGAGGTAGCGAAC
SGESSTAPGTSPSGESSTAP CGGCAACCTCCGGCTCTGAAACCCCAGGTACCTCTG
GTSPSGESSTAPGTSTEPSE AAAGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGG
GSAPGSPAGSPTSTEEGTS CAGGTTCTCCGACTTCCACTGAGGAAGGTACTTCTG
TEPSEGSAPGSSPSASTGTG AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG
PGSSTPSGATGSPGSSTPSG CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG
ATGSPGSSTPSGATGSPGS CTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTGA
STPSGATGSPGASPGTSST AAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGC
GSPGASASGAPSTGGTSPS TGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGC
GESSTAPGSTSSTAESPGPG TGGCTCTCCAACTTCTACTGAAGAAGGTTCTACCAGC
TSPSGESSTAPGTSESATPE TCTACCGCTGAATCTCCTGGCCCAGGTTCTACTAGCG
SGPGTSTEPSEGSAPGTSTE AATCTCCGTCTGGCACCGCACCAGGTACTTCCCCTAG
PSEGSAPGSSPSASTGTGP CGGTGAATCTTCTACTGCACCAGGTTCTACCAGCGA
GSSTPSGATGSPGASPGTS ATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAA
STGSPGTSTPESGSASPGTS TCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCG
PSGESSTAPGTSPSGESSTA GCGAATCTTCTACCGCACCAGGTACTTCTACCGAAC
PGTSESATPESGPGSEPATS CTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGCG
GSETPGTSTEPSEGSAPGST CTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAGCG
SESPSGTAPGSTSESPSGTA CTACTCCTGAATCCGGTCCAGGTAGCGAACCGGCAA
PGTSTPESGSASPGSPAGSP CCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAGCG
TSTEEGTSESATPESGPGTS CTACTCCGGAATCTGGTCCAGGTACTTCTGAAAGCG
TEPSEGSAPGSPAGSPTSTE CTACTCCGGAATCCGGTCCAGGTACCTCTACTGAAC
EGTSESATPESGPGSEPATS CTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAAGCG
GSETPGSSTPSGATGSPGA CTACCCCGGAGTCCGGTCCAGGTACTTCTACTGAAC
SPGTSSTGSPGSSTPSGATG CGTCCGAAGGTAGCGCACCAGGTACCTCCCCTAGCG
SPGSTSESPSGTAPGTSPSG GCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGCGG
ESSTAPGSTSSTAESPGPGS CGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCGGT
STPSGATGSPGASPGTSST GAATCTTCTACCGCACCAGGTACTTCTACCGAACCGT
GSPGTPGSGTASSSPGSPA CCGAGGGTAGCGCACCAGGTAGCCCAGCAGGTTCTC
GSPTSTEEGSPAGSPTSTEE CTACCTCCACCGAGGAAGGTACTTCTACCGAACCGT
GTSTEPSEGSAPGFPTIPLS CCGAGGGTAGCGCACCAGGTTCTAGCCCTTCTGCTTC
RLFDNAMLRAHRLHQLAF CACCGGTACCGGCCCAGGTAGCTCTACTCCGTCTGG
DTYQEFEEAYIPKEQKYSF TGCAACTGGCTCTCCAGGTAGCTCTACTCCGTCTGGT
LQNPQTSLCFSESIPTPSNR GCAACCGGCTCCCCAGGTAGCTCTACCCCGTCTGGT
EETQQKSNLELLRISLLLIQ GCTACCGGCTCTCCAGGTAGCTCTACCCCGTCTGGTG
SWLEPVQFLRSVFANSLV CAACCGGCTCCCCAGGTGCATCCCCGGGTACTAGCT
YGASDSNVYDLLKDLEEG CTACCGGTTCTCCAGGTGCAAGCGCAAGCGGCGCGC
IQTLMGRLEDGSPRTGQIF CAAGCACGGGAGGTACTTCTCCGAGCGGTGAATCTT
KQTYSKFDTNSHNDDALL CTACCGCACCAGGTTCTACTAGCTCTACCGCTGAATC
KNYGLLYCFRKDMDKVE TCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTCT
TFLRIVQCRSVEGSCGF ACTGCTCCAGGTACCTCTGAAAGCGCTACTCCGGAG
TCTGGCCCAGGTACCTCTACTGAACCGTCTGAGGGT
AGCGCTCCAGGTACTTCTACTGAACCGTCCGAAGGT
AGCGCACCAGGTTCTAGCCCTTCTGCATCTACTGGTA
CTGGCCCAGGTAGCTCTACTCCTTCTGGTGCTACCGG
CTCTCCAGGTGCTTCTCCGGGTACTAGCTCTACCGGT
TCTCCAGGTACTTCTACTCCGGAAAGCGGTTCCGCAT
CTCCAGGTACTTCTCCTAGCGGTGAATCTTCTACTGC
TCCAGGTACCTCTCCTAGCGGCGAATCTTCTACTGCT
CCAGGTACTTCTGAAAGCGCAACCCCTGAATCCGGT
CCAGGTAGCGAACCGGCTACTTCTGGCTCTGAGACT
CCAGGTACTTCTACCGAACCGTCCGAAGGTAGCGCA
CCAGGTTCTACCAGCGAATCCCCTTCTGGTACTGCTC
CAGGTTCTACCAGCGAATCCCCTTCTGGCACCGCAC
CAGGTACTTCTACCCCTGAAAGCGGCTCCGCTTCTCC
AGGTAGCCCGGCAGGCTCTCCGACCTCTACTGAGGA
AGGTACTTCTGAAAGCGCAACCCCGGAGTCCGGCCC
AGGTACCTCTACCGAACCGTCTGAGGGCAGCGCACC
AGGTAGCCCTGCTGGCTCTCCAACCTCCACCGAAGA
AGGTACCTCTGAAAGCGCAACCCCTGAATCCGGCCC
AGGTAGCGAACCGGCAACCTCCGGTTCTGAAACCCC
AGGTAGCTCTACCCCGTCTGGTGCTACCGGTTCCCCA
GGTGCTTCTCCTGGTACTAGCTCTACCGGTTCTCCAG
GTAGCTCTACCCCGTCTGGTGCTACTGGCTCTCCAGG
TTCTACTAGCGAATCCCCGTCTGGTACTGCTCCAGGT
ACTTCCCCTAGCGGTGAATCTTCTACTGCTCCAGGTT
CTACCAGCTCTACCGCAGAATCTCCGGGTCCAGGTA
GCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC
ATCCCCGGGTACCAGCTCTACCGGTTCTCCAGGTACT
CCGGGTAGCGGTACCGCTTCTTCCTCTCCAGGTAGCC
CTGCTGGCTCTCCGACTTCTACTGAGGAAGGTAGCC
CGGCTGGTTCTCCGACTTCTACTGAGGAAGGTACTTC
TACCGAACCTTCCGAAGGTAGCGCTCCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGATAATGCTATG
CTGCGTGCGCACCGTCTGCACCAGCTGGCCTTTGATA
CTTACCAGGAATTTGAAGAAGCcTACATTCCTAAAG
AGCAGAAGTACTCTTTCCTGCAAAACCCACAGACTT
CTCTCTGCTTCAGCGAATCTATTCCGACGCCTTCCAA
TCGCGAGGAAACTCAGCAAAAGTCCAATCTGGAACT
ACTCCGCATTTCTCTGCTTCTGATTCAGAGCTGGCTA
GAACCAGTGCAATTTCTGCGTTCCGTCTTCGCCAATA
GCCTAGTTTATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCATTCAGACCC
TGATGGGTCGTCTCGAGGATGGCTCTCCGCGTACTG
GTCAGATCTTCAAGCAGACTTACTCTAAATTTGATAC
TAACAGCCACAATGACGATGCGCTTCTAAAAAACTA
TGGTCTGCTGTATTGTTTTCGTAAAGATATGGACAAA
GTTGAAACCTTCCTGCGTATTGTTCAGTGTCGTTCCG
TTGAGGGCAGCTGTGGTTTCTAA
hGH- FPTIPLSRLFDNAMLRAHR 703 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 704
AE144 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSEPATSGSETPGTSE ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
SATPESGPGSEPATSGSETP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSPAGSPTSTEEGTSTEPSE ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
GSAPGSEPATSGSETPGSEP ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ATSGSETPGSEPATSGSETP CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
GTSTEPSEGSAPGTSESATP TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGC
ESGPGSEPATSGSETPGTST GAACCGGCAACTTCCGGCTCTGAAACCCCAGGTACT
EPSEGSAP TCTGAAAGCGCTACTCCTGAGTCTGGCCCAGGTAGC
GAACCTGCTACCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGAGGAAGGTACC
TCTACTGAACCTTCTGAGGGTAGCGCTCCAGGTAGC
GAACCGGCAACCTCTGGCTCTGAAACCCCAGGTAGC
GAACCTGCTACCTCCGGCTCTGAAACTCCAGGTAGC
GAACCGGCTACTTCCGGTTCTGAAACTCCAGGTACC
TCTACCGAACCTTCCGAAGGCAGCGCACCAGGTACT
TCTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGC
GAACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTT
CTACCGAACCGTCCGAAGGTAGCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 705 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 706
AE288 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGTSESATPESGPGSEP ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
ATSGSETPGTSESATPESGP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSEPATSGSETPGTSESATP ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
ESGPGTSTEPSEGSAPGSPA ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
GSPTSTEEGTSESATPESGP CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
GSEPATSGSETPGTSESATP TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACCT
ESGPGSPAGSPTSTEEGSPA CTGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCG
GSPTSTEEGTSTEPSEGSAP AACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTC
GTSESATPESGPGTSESATP TGAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGA
ESGPGTSESATPESGPGSEP ACCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCT
ATSGSETPGSEPATSGSETP GAAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCT
GSPAGSPTSTEEGTSTEPSE ACTGAACCGTCCGAGGGCAGCGCACCAGGTAGCCCT
GSAPGTSTEPSEGSAPGSEP GCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT
ATSGSETPGTSESATPESGP GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAA
GTSTEPSEGSAP CCGGCAACCTCCGGTTCTGAAACCCCAGGTACTTCT
GAAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCG
GCTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCG
GCTGGCTCTCCAACTTCTACTGAAGAAGGTACTTCTA
CCGAACCTTCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACCCCTGAGTCCGGCCCAGGTACTTCTG
AAAGCGCTACTCCTGAATCCGGTCCAGGTACTTCTG
AAAGCGCTACCCCGGAATCTGGCCCAGGTAGCGAAC
CGGCTACTTCTGGTTCTGAAACCCCAGGTAGCGAAC
CGGCTACCTCCGGTTCTGAAACTCCAGGTAGCCCAG
CAGGCTCTCCGACTTCCACTGAGGAAGGTACTTCTA
CTGAACCTTCCGAAGGCAGCGCACCAGGTACCTCTA
CTGAACCTTCTGAGGGCAGCGCTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG
AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 707 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 708
AF144 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGTSTPESGSASPGTSPS ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
GESSTAPGTSPSGESSTAPG ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
STSSTAESPGPGSTSESPSG ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
TAPGSTSSTAESPGPGTSPS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
GESSTAPGTSTPESGSASPG CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
STSSTAESPGPGTSPSGESS TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACTT
TAPGTSPSGESSTAPGTSPS CTACTCCGGAAAGCGGTTCCGCATCTCCAGGTACTTC
GESSTAP TCCTAGCGGTGAATCTTCTACTGCTCCAGGTACCTCT
CCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTACCA
GCTCTACCGCTGAATCTCCTGGCCCAGGTTCTACCAG
CGAATCCCCGTCTGGCACCGCACCAGGTTCTACTAG
CTCTACCGCAGAATCTCCGGGTCCAGGTACTTCCCCT
AGCGGTGAATCTTCTACTGCTCCAGGTACCTCTACTC
CGGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCT
CTACTGCTGAATCTCCTGGTCCAGGTACCTCCCCTAG
CGGCGAATCTTCTACTGCTCCAGGTACCTCTCCTAGC
GGCGAATCTTCTACCGCTCCAGGTACCTCCCCTAGCG
GTGAATCTTCTACCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 709 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 710
AD576 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSSESGSSEGGPGSGG ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
EPSESGSSGSSESGSSEGGP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSSESGSSEGGPGSSESGSS ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
EGGPGSSESGSSEGGPGSS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ESGSSEGGPGESPGGSSGS CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
ESGSEGSSGPGESSGSSESG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTTCCT
SSEGGPGSSESGSSEGGPG CTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCT
SSESGSSEGGPGSGGEPSES CTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAAT
GSSGESPGGSSGSESGESP CTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTG
GGSSGSESGSGGEPSESGS GTGGCGAACCTTCCGAGTCTGGTAGCTCAGGTGAAT
SGSSESGSSEGGPGSGGEP CTCCGGGTGGTTCTAGCGGTTCCGAGTCAGGTGAAT
SESGSSGSGGEPSESGSSGS CTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGTTCCTC
EGSSGPGESSGESPGGSSG CGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTC
SESGSGGEPSESGSSGSGG CGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTC
EPSESGSSGSGGEPSESGSS TGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTGAATC
GSSESGSSEGGPGESPGGS TCCTGGTGGTTCCAGCGGTTCCGAGTCAGGTGAATCT
SGSESGESPGGSSGSESGES CCAGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCT
PGGSSGSESGESPGGSSGS CCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCTCCG
ESGESPGGSSGSESGSSESG AAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCG
SSEGGPGSGGEPSESGSSG AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTG
SEGSSGPGESSGSSESGSSE AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCCTCTG
GGPGSGGEPSESGSSGSSE AAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCTTCCG
SGSSEGGPGSGGEPSESGS AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCCG
SGESPGGSSGSESGESPGG AAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGTG
SSGSESGSSESGSSEGGPGS GCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTC
GGEPSESGSSGSSESGSSEG CGGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCTC
GPGSGGEPSESGSSGSGGE CTGGTGGTTCCAGCGGTTCCGAGTCAGGTTCCGGTG
PSESGSSGESPGGSSGSESG GCGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAG
SEGSSGPGESSGSSESGSSE GTTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGA
GGPGSEGSSGPGESS AAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG
CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGG
TTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGAA
AGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGGC
GAACCTTCCGAATCTGGTAGCTCAGGTGAATCTCCG
GGTGGTTCTAGCGGTTCTGAGTCAGGTTCTGGTGGTG
AACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCG
AACCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAA
GCGGTTCTTCCGAAGGCGGTCCAGGTTCTGGTGGTG
AACCGTCCGAATCTGGTAGCTCAGGTTCTGGTGGCG
AACCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTT
CTTCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGG
TGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTC
TTCCGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTC
TTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA
CCATCTGAATCTGGTAGCTCAGGTTCCTCTGAAAGC
GGTTCTTCCGAAGGTGGTCCAGGTTCCTCTGAAAGC
GGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT
GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAA
CCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCT
TCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTG
GCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTT
CCGGTCCTGGTGAGTCTTCAGGTGAATCTCCAGGTG
GCTCTAGCGGTTCCGAGTCAGGTAGCGAAGGTTCTT
CTGGTCCTGGCGAGTCCTCA
hGH- FPTIPLSRLFDNAMLRAHR 711 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 712
AE576 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSPAGSPTSTEEGTSE ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
SATPESGPGTSTEPSEGSAP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSPAGSPTSTEEGTSTEPSE ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
GSAPGTSTEPSEGSAPGTS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ESATPESGPGSEPATSGSET CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
PGSEPATSGSETPGSPAGSP TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGC
TSTEEGTSESATPESGPGTS CCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTT
TEPSEGSAPGTSTEPSEGSA CTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCT
PGSPAGSPTSTEEGTSTEPS CTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC
EGSAPGTSTEPSEGSAPGT CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT
SESATPESGPGTSTEPSEGS CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCT
APGTSESATPESGPGSEPA CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
TSGSETPGTSTEPSEGSAPG CTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCG
TSTEPSEGSAPGTSESATPE AACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG
SGPGTSESATPESGPGSPA AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCC
GSPTSTEEGTSESATPESGP CGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTT
GSEPATSGSETPGTSESATP CTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCT
ESGPGTSTEPSEGSAPGTST CTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTT
EPSEGSAPGTSTEPSEGSAP CTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC
GTSTEPSEGSAPGTSTEPSE CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTT
GSAPGTSTEPSEGSAPGSP CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT
AGSPTSTEEGTSTEPSEGSA CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
PGTSESATPESGPGSEPATS CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTT
GSETPGTSESATPESGPGSE CTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTT
PATSGSETPGTSESATPESG CTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG
PGTSTEPSEGSAPGTSESAT AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC
PESGPGSPAGSPTSTEEGSP TACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
AGSPTSTEEGSPAGSPTSTE TACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTC
EGTSESATPESGPGTSTEPS TGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTC
EGSAP TGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCC
TGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC
TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTC
TACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTC
TACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
TACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTC
TACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTC
TACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTC
TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC
AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTC
TACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTC
TGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA
ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT
GAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA
CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG
AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG
CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGG
CAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTG
AAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTA
CCGAACCGTCTGAGGGCAGCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 713 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 714
AF576 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSTSSTAESPGPGSTSS ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
TAESPGPGSTSESPSGTAPG ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
STSSTAESPGPGSTSSTAES ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
PGPGTSTPESGSASPGSTSE ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
SPSGTAPGTSPSGESSTAPG CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
STSESPSGTAPGSTSESPSG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTTCTA
TAPGTSPSGESSTAPGSTSE CTAGCTCTACCGCTGAATCTCCTGGCCCAGGTTCCAC
SPSGTAPGSTSESPSGTAPG TAGCTCTACCGCAGAATCTCCGGGCCCAGGTTCTACT
TSPSGESSTAPGSTSESPSG AGCGAATCCCCTTCTGGTACCGCTCCAGGTTCTACTA
TAPGSTSESPSGTAPGSTSE GCTCTACCGCTGAATCTCCGGGTCCAGGTTCTACCAG
SPSGTAPGTSTPESGSASPG CTCTACTGCAGAATCTCCTGGCCCAGGTACTTCTACT
STSESPSGTAPGTSTPESGS CCGGAAAGCGGTTCCGCTTCTCCAGGTTCTACCAGC
ASPGSTSSTAESPGPGSTSS GAATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTA
TAESPGPGTSTPESGSASPG GCGGCGAATCTTCTACCGCTCCAGGTTCTACTAGCG
TSTPESGSASPGSTSESPSG AATCTCCTTCTGGCACTGCACCAGGTTCTACCAGCGA
TAPGTSTPESGSASPGTSTP ATCTCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGC
ESGSASPGSTSESPSGTAPG GGCGAATCTTCTACCGCTCCAGGTTCTACTAGCGAAT
STSESPSGTAPGSTSESPSG CTCCTTCTGGCACTGCACCAGGTTCTACCAGCGAATC
TAPGSTSSTAESPGPGTSTP TCCTTCTGGCACCGCTCCAGGTACCTCTCCTAGCGGC
ESGSASPGTSTPESGSASPG GAATCTTCTACCGCTCCAGGTTCTACTAGCGAATCTC
STSESPSGTAPGSTSESPSG CTTCTGGCACTGCACCAGGTTCTACTAGCGAATCTCC
TAPGTSTPESGSASPGSTSE TTCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCG
SPSGTAPGSTSESPSGTAPG TCTGGCACTGCACCAGGTACCTCTACCCCTGAAAGC
TSTPESGSASPGTSPSGESS GGTTCCGCTTCTCCAGGTTCTACTAGCGAATCTCCTT
TAPGSTSSTAESPGPGTSPS CTGGTACCGCTCCAGGTACTTCTACCCCTGAAAGCG
GESSTAPGSTSSTAESPGPG GCTCCGCTTCTCCAGGTTCCACTAGCTCTACCGCTGA
TSTPESGSASPGSTSESPSG ATCTCCGGGTCCAGGTTCTACTAGCTCTACTGCAGAA
TAPGSTSSTAESPGPGTSTP TCTCCTGGCCCAGGTACCTCTACTCCGGAAAGCGGC
ESGSASPGTSTPESGSASP TCTGCATCTCCAGGTACTTCTACCCCTGAAAGCGGTT
CTGCATCTCCAGGTTCTACTAGCGAATCCCCGTCTGG
TACCGCACCAGGTACTTCTACCCCGGAAAGCGGCTC
TGCTTCTCCAGGTACTTCTACCCCGGAAAGCGGCTCC
GCATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGTA
CCGCTCCAGGTTCTACCAGCGAATCCCCGTCTGGTAC
TGCTCCAGGTTCTACCAGCGAATCTCCTTCTGGTACT
GCACCAGGTTCTACTAGCTCTACTGCAGAATCTCCTG
GCCCAGGTACCTCTACTCCGGAAAGCGGCTCTGCAT
CTCCAGGTACTTCTACCCCTGAAAGCGGTTCTGCATC
TCCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCA
CCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCA
CCAGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTC
CAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCACC
AGGTTCTACCAGCGAATCTCCGTCTGGCACTGCACC
AGGTACCTCTACCCCTGAAAGCGGTTCCGCTTCTCCA
GGTACTTCTCCGAGCGGTGAATCTTCTACCGCACCA
GGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCAG
GTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAGG
TTCCACTAGCTCTACTGCTGAATCTCCTGGCCCAGGT
ACTTCTACTCCGGAAAGCGGTTCCGCTTCTCCAGGTT
CTACTAGCGAATCTCCGTCTGGCACCGCACCAGGTT
CTACTAGCTCTACTGCAGAATCTCCTGGCCCAGGTAC
CTCTACTCCGGAAAGCGGCTCTGCATCTCCAGGTACT
TCTACCCCTGAAAGCGGTTCTGCATCTCCA
hGH- FPTIPLSRLFDNAMLRAHR 715 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 716
AE624 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGMAEPAGSPTSTEEGTP ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
GSGTASSSPGSSTPSGATG ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
SPGASPGTSSTGSPGSPAGS ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
PTSTEEGTSESATPESGPGT ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
STEPSEGSAPGSPAGSPTST CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
EEGTSTEPSEGSAPGTSTEP TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTATGGCT
SEGSAPGTSESATPESGPGS GAACCTGCTGGCTCTCCAACCTCCACTGAGGAAGGT
EPATSGSETPGSEPATSGSE ACCCCGGGTAGCGGTACTGCTTCTTCCTCTCCAGGTA
TPGSPAGSPTSTEEGTSESA GCTCTACCCCTTCTGGTGCAACCGGCTCTCCAGGTGC
TPESGPGTSTEPSEGSAPGT TTCTCCGGGCACCAGCTCTACCGGTTCTCCAGGTAGC
STEPSEGSAPGSPAGSPTST CCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTT
EEGTSTEPSEGSAPGTSTEP CTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCT
SEGSAPGTSESATPESGPG CTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC
TSTEPSEGSAPGTSESATPE CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT
SGPGSEPATSGSETPGTSTE CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCT
PSEGSAPGTSTEPSEGSAPG CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
TSESATPESGPGTSESATPE CTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCG
SGPGSPAGSPTSTEEGTSES AACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG
ATPESGPGSEPATSGSETP AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCC
GTSESATPESGPGTSTEPSE CGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTT
GSAPGTSTEPSEGSAPGTS CTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCT
TEPSEGSAPGTSTEPSEGSA CTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTT
PGTSTEPSEGSAPGTSTEPS CTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC
EGSAPGSPAGSPTSTEEGT CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTT
STEPSEGSAPGTSESATPES CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT
GPGSEPATSGSETPGTSES CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
ATPESGPGSEPATSGSETP CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTT
GTSESATPESGPGTSTEPSE CTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTT
GSAPGTSESATPESGPGSP CTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG
AGSPTSTEEGSPAGSPTSTE AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC
EGSPAGSPTSTEEGTSESAT TACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
PESGPGTSTEPSEGSAP TACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTC
TGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTC
TGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCC
TGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC
TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTC
TACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTC
TACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
TACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTC
TACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTC
TACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTC
TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC
AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTC
TACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTC
TGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA
ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT
GAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA
CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG
AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG
CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGG
CAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTG
AAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTA
CCGAACCGTCTGAGGGCAGCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 717 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 718
AD836 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSSESGSSEGGPGSSE ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
SGSSEGGPGESPGGSSGSE ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
SGSGGEPSESGSSGESPGG ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
SSGSESGESPGGSSGSESGS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
SESGSSEGGPGSSESGSSEG CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
GPGSSESGSSEGGPGESPG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTTCCT
GSSGSESGESPGGSSGSES CTGAAAGCGGTTCTTCCGAAGGTGGTCCAGGTTCCT
GESPGGSSGSESGSSESGSS CTGAAAGCGGTTCTTCTGAGGGTGGTCCAGGTGAAT
EGGPGSSESGSSEGGPGSS CTCCGGGTGGCTCCAGCGGTTCCGAGTCAGGTTCTG
ESGSSEGGPGSSESGSSEG GTGGCGAACCTTCCGAGTCTGGTAGCTCAGGTGAAT
GPGSSESGSSEGGPGSSES CTCCGGGTGGTTCTAGCGGTTCCGAGTCAGGTGAAT
GSSEGGPGSGGEPSESGSS CTCCGGGTGGTTCCAGCGGTTCTGAGTCAGGTTCCTC
GESPGGSSGSESGESPGGS CGAAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTC
SGSESGSGGEPSESGSSGSE CGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTC
GSSGPGESSGSSESGSSEG TGAAAGCGGTTCTTCCGAGGGCGGTCCAGGTGAATC
GPGSGGEPSESGSSGSEGS TCCTGGTGGTTCCAGCGGTTCCGAGTCAGGTGAATCT
SGPGESSGSSESGSSEGGP CCAGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCT
GSGGEPSESGSSGESPGGS CCTGGTGGTTCTAGCGGTTCTGAATCAGGTTCCTCCG
SGSESGSGGEPSESGSSGS AAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCTCCG
GGEPSESGSSGSSESGSSEG AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCTG
GPGSGGEPSESGSSGSGGE AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCCTCTG
PSESGSSGSEGSSGPGESSG AAAGCGGTTCTTCTGAGGGCGGTCCAGGTTCTTCCG
ESPGGSSGSESGSEGSSGP AAAGCGGTTCTTCCGAGGGCGGTCCAGGTTCTTCCG
GESSGSEGSSGPGESSGSG AAAGCGGTTCTTCTGAAGGCGGTCCAGGTTCTGGTG
GEPSESGSSGSSESGSSEGG GCGAACCGTCCGAGTCTGGTAGCTCAGGTGAATCTC
PGSSESGSSEGGPGESPGG CGGGTGGCTCTAGCGGTTCCGAGTCAGGTGAATCTC
SSGSESGSGGEPSESGSSGS CTGGTGGTTCCAGCGGTTCCGAGTCAGGTTCCGGTG
EGSSGPGESSGESPGGSSG GCGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAG
SESGSEGSSGPGSSESGSSE GTTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGA
GGPGSGGEPSESGSSGSEG AAGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGG
SSGPGESSGSEGSSGPGESS CGAACCGTCCGAATCTGGTAGCTCAGGTAGCGAAGG
GSEGSSGPGESSGSGGEPS TTCTTCTGGTCCAGGCGAATCTTCAGGTTCCTCTGAA
ESGSSGSGGEPSESGSSGES AGCGGTTCTTCTGAGGGCGGTCCAGGTTCCGGTGGC
PGGSSGSESGESPGGSSGS GAACCTTCCGAATCTGGTAGCTCAGGTGAATCTCCG
ESGSGGEPSESGSSGSEGSS GGTGGTTCTAGCGGTTCTGAGTCAGGTTCTGGTGGTG
GPGESSGESPGGSSGSESG AACCTTCCGAGTCTGGTAGCTCAGGTTCTGGTGGCG
SSESGSSEGGPGSSESGSSE AACCATCCGAGTCTGGTAGCTCAGGTTCTTCCGAAA
GGPGSSESGSSEGGPGSGG GCGGTTCTTCCGAAGGCGGTCCAGGTTCTGGTGGTG
EPSESGSSGSSESGSSEGGP AACCGTCCGAATCTGGTAGCTCAGGTTCTGGTGGCG
GESPGGSSGSESGSGGEPS AACCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTT
ESGSSGSSESGSSEGGPGES CTTCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGG
PGGSSGSESGSGGEPSESG TGGCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTC
SSGESPGGSSGSESGSGGE TTCCGGTCCAGGTGAATCTTCAGGTAGCGAAGGTTC
PSESGSS TTCTGGTCCTGGTGAATCCTCAGGTTCCGGTGGCGAA
CCATCTGAATCTGGTAGCTCAGGTTCCTCTGAAAGC
GGTTCTTCCGAAGGTGGTCCAGGTTCCTCTGAAAGC
GGTTCTTCTGAGGGTGGTCCAGGTGAATCTCCGGGT
GGCTCCAGCGGTTCCGAGTCAGGTTCTGGTGGCGAA
CCATCCGAATCTGGTAGCTCAGGTAGCGAAGGTTCT
TCTGGTCCTGGCGAATCTTCAGGTGAATCTCCAGGTG
GCTCTAGCGGTTCCGAATCAGGTAGCGAAGGTTCTT
CCGGTCCaGGTTCCTCTGAAAGCGGTTCTTCTGAGGG
CGGTCCAGGTTCTGGTGGCGAACCATCTGAATCTGG
TAGCTCAGGTAGCGAAGGTTCTTCCGGTCCGGGTGA
ATCTTCAGGTAGCGAAGGTTCTTCCGGTCCAGGTGA
ATCTTCAGGTAGCGAAGGTTCTTCTGGTCCTGGTGAA
TCCTCAGGTTCCGGTGGCGAACCATCTGAATCTGGT
AGCTCAGGTTCTGGTGGCGAACCATCCGAATCTGGT
AGCTCAGGTGAATCTCCGGGTGGCTCCAGCGGTTCT
GAATCAGGTGAATCTCCTGGTGGCTCCAGCGGTTCT
GAGTCAGGTTCTGGTGGCGAACCATCCGAATCTGGT
AGCTCAGGTAGCGAAGGTTCTTCTGGTCCTGGCGAA
TCTTCAGGTGAATCTCCAGGTGGCTCTAGCGGTTCCG
AATCAGGTTCCTCTGAAAGCGGTTCTTCTGAGGGCG
GTCCAGGTTCTTCCGAAAGCGGTTCTTCCGAGGGCG
GTCCAGGTTCTTCCGAAAGCGGTTCTTCTGAAGGCG
GTCCAGGTTCTGGTGGCGAACCGTCCGAATCTGGTA
GCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGTG
GTCCAGGTGAATCTCCAGGTGGTTCTAGCGGTTCTG
AATCAGGTTCTGGTGGCGAACCGTCCGAATCTGGTA
GCTCAGGTTCCTCCGAAAGCGGTTCTTCTGAAGGTG
GTCCAGGTGAATCTCCAGGTGGTTCTAGCGGTTCTG
AATCAGGTTCTGGTGGCGAACCGTCCGAATCTGGTA
GCTCAGGTGAATCTCCTGGTGGTTCCAGCGGTTCCG
AGTCAGGTTCTGGTGGCGAACCTTCCGAATCTGGTA
GCTCA
hGH- FPTIPLSRLFDNAMLRAHR 719 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 720
AE864 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSPAGSPTSTEEGTSE ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
SATPESGPGTSTEPSEGSAP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSPAGSPTSTEEGTSTEPSE ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
GSAPGTSTEPSEGSAPGTS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ESATPESGPGSEPATSGSET CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
PGSEPATSGSETPGSPAGSP TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTAGC
TSTEEGTSESATPESGPGTS CCGGCTGGCTCTCCTACCTCTACTGAGGAAGGTACTT
TEPSEGSAPGTSTEPSEGSA CTGAAAGCGCTACTCCTGAGTCTGGTCCAGGTACCT
PGSPAGSPTSTEEGTSTEPS CTACTGAACCGTCCGAAGGTAGCGCTCCAGGTAGCC
EGSAPGTSTEPSEGSAPGT CAGCAGGCTCTCCGACTTCCACTGAGGAAGGTACTT
SESATPESGPGTSTEPSEGS CTACTGAACCTTCCGAAGGCAGCGCACCAGGTACCT
APGTSESATPESGPGSEPA CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
TSGSETPGTSTEPSEGSAPG CTGAAAGCGCTACCCCGGAATCTGGCCCAGGTAGCG
TSTEPSEGSAPGTSESATPE AACCGGCTACTTCTGGTTCTGAAACCCCAGGTAGCG
SGPGTSESATPESGPGSPA AACCGGCTACCTCCGGTTCTGAAACTCCAGGTAGCC
GSPTSTEEGTSESATPESGP CGGCAGGCTCTCCGACCTCTACTGAGGAAGGTACTT
GSEPATSGSETPGTSESATP CTGAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCT
ESGPGTSTEPSEGSAPGTST CTACCGAACCGTCTGAGGGCAGCGCACCAGGTACTT
EPSEGSAPGTSTEPSEGSAP CTACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCC
GTSTEPSEGSAPGTSTEPSE CAGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTT
GSAPGTSTEPSEGSAPGSP CTACCGAACCGTCCGAGGGTAGCGCACCAGGTACCT
AGSPTSTEEGTSTEPSEGSA CTACTGAACCTTCTGAGGGCAGCGCTCCAGGTACTT
PGTSESATPESGPGSEPATS CTGAAAGCGCTACCCCGGAGTCCGGTCCAGGTACTT
GSETPGTSESATPESGPGSE CTACTGAACCGTCCGAAGGTAGCGCACCAGGTACTT
PATSGSETPGTSESATPESG CTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG
PGTSTEPSEGSAPGTSESAT AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC
PESGPGSPAGSPTSTEEGSP TACCGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
AGSPTSTEEGSPAGSPTSTE TACTGAACCGTCTGAAGGTAGCGCACCAGGTACTTC
EGTSESATPESGPGTSTEPS TGAAAGCGCAACCCCGGAATCCGGCCCAGGTACCTC
EGSAPGTSESATPESGPGS TGAAAGCGCAACCCCGGAGTCCGGCCCAGGTAGCCC
EPATSGSETPGTSESATPES TGCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTC
GPGSEPATSGSETPGTSES TGAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGA
ATPESGPGTSTEPSEGSAP ACCGGCAACCTCCGGTTCTGAAACCCCAGGTACCTC
GSPAGSPTSTEEGTSESATP TGAAAGCGCTACTCCGGAGTCTGGCCCAGGTACCTC
ESGPGSEPATSGSETPGTSE TACTGAACCGTCTGAGGGTAGCGCTCCAGGTACTTC
SATPESGPGSPAGSPTSTEE TACTGAACCGTCCGAAGGTAGCGCACCAGGTACTTC
GSPAGSPTSTEEGTSTEPSE TACCGAACCGTCCGAAGGCAGCGCTCCAGGTACCTC
GSAPGTSESATPESGPGTS TACTGAACCTTCCGAGGGCAGCGCTCCAGGTACCTC
ESATPESGPGTSESATPESG TACCGAACCTTCTGAAGGTAGCGCACCAGGTACTTC
PGSEPATSGSETPGSEPATS TACCGAACCGTCCGAGGGTAGCGCACCAGGTAGCCC
GSETPGSPAGSPTSTEEGTS AGCAGGTTCTCCTACCTCCACCGAGGAAGGTACTTC
TEPSEGSAPGTSTEPSEGSA TACCGAACCGTCCGAGGGTAGCGCACCAGGTACCTC
PGSEPATSGSETPGTSESAT TGAAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGA
PESGPGTSTEPSEGSAP ACCTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCT
GAAAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAA
CCTGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTG
AAAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGG
CTGGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGGTAGCCCGG
CAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCTG
AAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCTA
CCGAACCGTCTGAGGGCAGCGCACCAGGTACCTCTG
AAAGCGCAACTCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAGGTACCTCTGA
AAGCGCAACCCCGGAATCTGGTCCAGGTAGCGAACC
TGCAACCTCTGGCTCTGAAACCCCAGGTACCTCTGA
AAGCGCTACTCCTGAATCTGGCCCAGGTACTTCTACT
GAACCGTCCGAGGGCAGCGCACCAGGTAGCCCTGCT
GGCTCTCCAACCTCCACCGAAGAAGGTACCTCTGAA
AGCGCAACCCCTGAATCCGGCCCAGGTAGCGAACCG
GCAACCTCCGGTTCTGAAACCCCAGGTACTTCTGAA
AGCGCTACTCCTGAGTCCGGCCCAGGTAGCCCGGCT
GGCTCTCCGACTTCCACCGAGGAAGGTAGCCCGGCT
GGCTCTCCAACTTCTACTGAAGAAGGTACTTCTACCG
AACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAA
GCGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAA
GCGCTACTCCTGAATCCGGTCCAGGTACTTCTGAAA
GCGCTACCCCGGAATCTGGCCCAGGTAGCGAACCGG
CTACTTCTGGTTCTGAAACCCCAGGTAGCGAACCGG
CTACCTCCGGTTCTGAAACTCCAGGTAGCCCAGCAG
GCTCTCCGACTTCCACTGAGGAAGGTACTTCTACTGA
ACCTTCCGAAGGCAGCGCACCAGGTACCTCTACTGA
ACCTTCTGAGGGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTACTTCTACTGAA
CCGTCCGAGGGCAGCGCACCA
hGH- FPTIPLSRLFDNAMLRAHR 721 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 722
AF864 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGSTSESPSGTAPGTSPS ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
GESSTAPGSTSESPSGTAPG ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
STSESPSGTAPGTSTPESGS ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
ASPGTSTPESGSASPGSTSE ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
SPSGTAPGSTSESPSGTAPG CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
TSPSGESSTAPGSTSESPSG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTTCTA
TAPGTSPSGESSTAPGTSPS CCAGCGAATCTCCTTCTGGCACCGCTCCAGGTACCTC
GESSTAPGSTSSTAESPGPG TCCTAGCGGCGAATCTTCTACCGCTCCAGGTTCTACT
TSPSGESSTAPGTSPSGESS AGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTA
TAPGSTSSTAESPGPGTSTP GCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTAC
ESGSASPGTSTPESGSASPG TCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACT
STSESPSGTAPGSTSESPSG CCGGAAAGCGGTTCTGCATCTCCAGGTTCTACCAGC
TAPGTSTPESGSASPGSTSS GAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAGCG
TAESPGPGTSTPESGSASPG AATCCCCGTCTGGTACCGCACCAGGTACTTCTCCTAG
STSESPSGTAPGTSPSGESS CGGCGAATCTTCTACCGCACCAGGTTCTACTAGCGA
TAPGSTSSTAESPGPGTSPS ATCTCCGTCTGGCACTGCTCCAGGTACTTCTCCTAGC
GESSTAPGTSTPESGSASPG GGTGAATCTTCTACCGCTCCAGGTACTTCCCCTAGCG
STSSTAESPGPGSTSSTAES GCGAATCTTCTACCGCTCCAGGTTCTACTAGCTCTAC
PGPGSTSSTAESPGPGSTSS TGCAGAATCTCCGGGCCCAGGTACCTCTCCTAGCGG
TAESPGPGTSPSGESSTAPG TGAATCTTCTACCGCTCCAGGTACTTCTCCGAGCGGT
STSESPSGTAPGSTSESPSG GAATCTTCTACCGCTCCAGGTTCTACTAGCTCTACTG
TAPGTSTPESGPXXXGASA CAGAATCTCCTGGCCCAGGTACCTCTACTCCGGAAA
SGAPSTXXXXSESPSGTAP GCGGCTCTGCATCTCCAGGTACTTCTACCCCTGAAAG
GSTSESPSGTAPGSTSESPS CGGTTCTGCATCTCCAGGTTCTACTAGCGAATCTCCT
GTAPGSTSESPSGTAPGSTS TCTGGCACTGCACCAGGTTCTACCAGCGAATCTCCGT
ESPSGTAPGSTSESPSGTAP CTGGCACTGCACCAGGTACCTCTACCCCTGAAAGCG
GTSTPESGSASPGTSPSGES GTTCCGCTTCTCCAGGTTCTACCAGCTCTACCGCAGA
STAPGTSPSGESSTAPGSTS ATCTCCTGGTCCAGGTACCTCTACTCCGGAAAGCGG
STAESPGPGTSPSGESSTAP CTCTGCATCTCCAGGTTCTACTAGCGAATCTCCTTCT
GTSTPESGSASPGSTSESPS GGCACTGCACCAGGTACTTCTCCGAGCGGTGAATCT
GTAPGSTSESPSGTAPGTSP TCTACCGCACCAGGTTCTACTAGCTCTACCGCTGAAT
SGESSTAPGSTSESPSGTAP CTCCGGGCCCAGGTACTTCTCCGAGCGGTGAATCTTC
GTSTPESGSASPGTSTPESG TACTGCTCCAGGTACCTCTACTCCTGAAAGCGGTTCT
SASPGSTSESPSGTAPGTST GCATCTCCAGGTTCCACTAGCTCTACCGCAGAATCTC
PESGSASPGSTSSTAESPGP CGGGCCCAGGTTCTACTAGCTCTACTGCTGAATCTCC
GSTSESPSGTAPGSTSESPS TGGCCCAGGTTCTACTAGCTCTACTGCTGAATCTCCG
GTAPGTSPSGESSTAPGSTS GGTCCAGGTTCTACCAGCTCTACTGCTGAATCTCCTG
STAESPGPGTSPSGESSTAP GTCCAGGTACCTCCCCGAGCGGTGAATCTTCTACTGC
GTSTPESGSASPGTSPSGES ACCAGGTTCTACTAGCGAATCTCCTTCTGGCACTGCA
STAPGTSPSGESSTAPGTSP CCAGGTTCTACCAGCGAATCTCCGTCTGGCACTGCA
SGESSTAPGSTSSTAESPGP CCAGGTACCTCTACCCCTGAAAGCGGTCCXXXXXXX
GSTSSTAESPGPGTSPSGES XXXXXTGCAAGCGCAAGCGGCGCGCCAAGCACGGG
STAPGSSPSASTGTGPGSST AXXXXXXXXTAGCGAATCTCCTTCTGGTACCGCTCC
PSGATGSPGSSTPSGATGSP AGGTTCTACCAGCGAATCCCCGTCTGGTACTGCTCCA
GGTTCTACCAGCGAATCTCCTTCTGGTACTGCACCAG
GTTCTACTAGCGAATCTCCTTCTGGTACCGCTCCAGG
TTCTACCAGCGAATCCCCGTCTGGTACTGCTCCAGGT
TCTACCAGCGAATCTCCTTCTGGTACTGCACCAGGTA
CTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTAC
TTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACC
TCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTTCTA
CCAGCTCTACTGCTGAATCTCCGGGTCCAGGTACTTC
CCCGAGCGGTGAATCTTCTACTGCACCAGGTACTTCT
ACTCCGGAAAGCGGTTCCGCTTCTCCAGGTTCTACCA
GCGAATCTCCTTCTGGCACCGCTCCAGGTTCTACTAG
CGAATCCCCGTCTGGTACCGCACCAGGTACTTCTCCT
AGCGGCGAATCTTCTACCGCACCAGGTTCTACTAGC
GAATCCCCGTCTGGTACCGCACCAGGTACTTCTACCC
CGGAAAGCGGCTCTGCTTCTCCAGGTACTTCTACCCC
GGAAAGCGGCTCCGCATCTCCAGGTTCTACTAGCGA
ATCTCCTTCTGGTACCGCTCCAGGTACTTCTACCCCT
GAAAGCGGCTCCGCTTCTCCAGGTTCCACTAGCTCTA
CCGCTGAATCTCCGGGTCCAGGTTCTACCAGCGAAT
CTCCTTCTGGCACCGCTCCAGGTTCTACTAGCGAATC
CCCGTCTGGTACCGCACCAGGTACTTCTCCTAGCGGC
GAATCTTCTACCGCACCAGGTTCTACCAGCTCTACTG
CTGAATCTCCGGGTCCAGGTACTTCCCCGAGCGGTG
AATCTTCTACTGCACCAGGTACTTCTACTCCGGAAAG
CGGTTCCGCTTCTCCAGGTACCTCCCCTAGCGGCGAA
TCTTCTACTGCTCCAGGTACCTCTCCTAGCGGCGAAT
CTTCTACCGCTCCAGGTACCTCCCCTAGCGGTGAATC
TTCTACCGCACCAGGTTCTACTAGCTCTACTGCTGAA
TCTCCGGGTCCAGGTTCTACCAGCTCTACTGCTGAAT
CTCCTGGTCCAGGTACCTCCCCGAGCGGTGAATCTTC
TACTGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGT
ACCGGCCCAGGTAGCTCTACTCCGTCTGGTGCAACT
GGCTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCG
GCTCCCCA
hGH- FPTIPLSRLFDNAMLRAHR 723 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 724
AG864 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGASPGTSSTGSPGSSPS ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
ASTGTGPGSSPSASTGTGP ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GTPGSGTASSSPGSSTPSG ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
ATGSPGSNPSASTGTGPGA ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
SPGTSSTGSPGTPGSGTASS CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
SPGSSTPSGATGSPGTPGS TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTGCTT
GTASSSPGASPGTSSTGSP CCCCGGGCACCAGCTCTACTGGTTCTCCAGGTTCTAG
GASPGTSSTGSPGTPGSGT CCCGTCTGCTTCTACTGGTACTGGTCCAGGTTCTAGC
ASSSPGSSTPSGATGSPGAS CCTTCTGCTTCCACTGGTACTGGTCCAGGTACCCCGG
PGTSSTGSPGTPGSGTASSS GTAGCGGTACCGCTTCTTCTTCTCCAGGTAGCTCTAC
PGSSTPSGATGSPGSNPSAS TCCGTCTGGTGCTACCGGCTCTCCAGGTTCTAACCCT
TGTGPGSSPSASTGTGPGS TCTGCATCCACCGGTACCGGCCCAGGTGCTTCTCCGG
STPSGATGSPGSSTPSGAT GCACCAGCTCTACTGGTTCTCCAGGTACCCCGGGCA
GSPGASPGTSSTGSPGASP GCGGTACCGCATCTTCTTCTCCAGGTAGCTCTACTCC
GTSSTGSPGASPGTSSTGSP TTCTGGTGCAACTGGTTCTCCAGGTACTCCTGGCAGC
GTPGSGTASSSPGASPGTS GGTACCGCTTCTTCTTCTCCAGGTGCTTCTCCTGGTA
STGSPGASPGTSSTGSPGA CTAGCTCTACTGGTTCTCCAGGTGCTTCTCCGGGCAC
SPGTSSTGSPGSSPSASTGT TAGCTCTACTGGTTCTCCAGGTACCCCGGGTAGCGGT
GPGTPGSGTASSSPGASPG ACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTCTG
TSSTGSPGASPGTSSTGSPG GTGCAACCGGCTCTCCAGGTGCTTCTCCGGGCACCA
ASPGTSSTGSPGSSTPSGAT GCTCTACCGGTTCTCCAGGTACCCCGGGTAGCGGTA
GSPGSSTPSGATGSPGASP CCGCTTCTTCTTCTCCAGGTAGCTCTACTCCGTCTGG
GTSSTGSPGTPGSGTASSSP TGCTACCGGCTCTCCAGGTTCTAACCCTTCTGCATCC
GSSTPSGATGSPGSSTPSG ACCGGTACCGGCCCAGGTTCTAGCCCTTCTGCTTCCA
ATGSPGSSTPSGATGSPGS CCGGTACTGGCCCAGGTAGCTCTACCCCTTCTGGTGC
SPSASTGTGPGASPGTSST TACCGGCTCCCCAGGTAGCTCTACTCCTTCTGGTGCA
GSPGASPGTSSTGSPGTPG ACTGGCTCTCCAGGTGCATCTCCGGGCACTAGCTCTA
SGTASSSPGASPGTSSTGSP CTGGTTCTCCAGGTGCATCCCCTGGCACTAGCTCTAC
GASPGTSSTGSPGASPGTS TGGTTCTCCAGGTGCTTCTCCTGGTACCAGCTCTACT
STGSPGASPGTSSTGSPGTP GGTTCTCCAGGTACTCCTGGCAGCGGTACCGCTTCTT
GSGTASSSPGSSTPSGATG CTTCTCCAGGTGCTTCTCCTGGTACTAGCTCTACTGG
SPGTPGSGTASSSPGSSTPS TTCTCCAGGTGCTTCTCCGGGCACTAGCTCTACTGGT
GATGSPGTPGSGTASSSPG TCTCCAGGTGCTTCCCCGGGCACTAGCTCTACCGGTT
SSTPSGATGSPGSSTPSGAT CTCCAGGTTCTAGCCCTTCTGCATCTACTGGTACTGG
GSPGSSPSASTGTGPGSSPS CCCAGGTACTCCGGGCAGCGGTACTGCTTCTTCCTCT
ASTGTGPGASPGTSSTGSP CCAGGTGCATCTCCGGGCACTAGCTCTACTGGTTCTC
GTPGSGTASSSPGSSTPSG CAGGTGCATCCCCTGGCACTAGCTCTACTGGTTCTCC
ATGSPGSSPSASTGTGPGS AGGTGCTTCTCCTGGTACCAGCTCTACTGGTTCTCCA
SPSASTGTGPGASPGTSST GGTAGCTCTACTCCGTCTGGTGCAACCGGTTCCCCAG
GSPGASPGTSSTGSPGSSTP GTAGCTCTACTCCTTCTGGTGCTACTGGCTCCCCAGG
SGATGSPGSSPSASTGTGP TGCATCCCCTGGCACCAGCTCTACCGGTTCTCCAGGT
GASPGTSSTGSPGSSPSAST ACCCCGGGCAGCGGTACCGCATCTTCCTCTCCAGGT
GTGPGTPGSGTASSSPGSS AGCTCTACCCCGTCTGGTGCTACCGGTTCCCCAGGTA
TPSGATGSPGSSTPSGATG GCTCTACCCCGTCTGGTGCAACCGGCTCCCCAGGTA
SPGASPGTSSTGSP GCTCTACTCCGTCTGGTGCAACCGGCTCCCCAGGTTC
TAGCCCGTCTGCTTCCACTGGTACTGGCCCAGGTGCT
TCCCCGGGCACCAGCTCTACTGGTTCTCCAGGTGCAT
CCCCGGGTACCAGCTCTACCGGTTCTCCAGGTACTCC
TGGCAGCGGTACTGCATCTTCCTCTCCAGGTGCTTCT
CCGGGCACCAGCTCTACTGGTTCTCCAGGTGCATCTC
CGGGCACTAGCTCTACTGGTTCTCCAGGTGCATCCCC
TGGCACTAGCTCTACTGGTTCTCCAGGTGCTTCTCCT
GGTACCAGCTCTACTGGTTCTCCAGGTACCCCTGGTA
GCGGTACTGCTTCTTCCTCTCCAGGTAGCTCTACTCC
GTCTGGTGCTACCGGTTCTCCAGGTACCCCGGGTAG
CGGTACCGCATCTTCTTCTCCAGGTAGCTCTACCCCG
TCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCG
GTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTC
TGGTGCTACTGGCTCTCCAGGTAGCTCTACCCCGTCT
GGTGCTACTGGCTCCCCAGGTTCTAGCCCTTCTGCAT
CCACCGGTACCGGTCCAGGTTCTAGCCCGTCTGCATC
TACTGGTACTGGTCCAGGTGCATCCCCGGGCACTAG
CTCTACCGGTTCTCCAGGTACTCCTGGTAGCGGTACT
GCTTCTTCTTCTCCAGGTAGCTCTACTCCTTCTGGTG
CTACTGGTTCTCCAGGTTCTAGCCCTTCTGCATCCAC
CGGTACCGGCCCAGGTTCTAGCCCGTCTGCTTCTACC
GGTACTGGTCCAGGTGCTTCTCCGGGTACTAGCTCTA
CTGGTTCTCCAGGTGCATCTCCTGGTACTAGCTCTAC
TGGTTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACC
GGCTCTCCAGGTTCTAGCCCTTCTGCATCTACCGGTA
CTGGTCCAGGTGCATCCCCTGGTACCAGCTCTACCG
GTTCTCCAGGTTCTAGCCCTTCTGCTTCTACCGGTAC
CGGTCCAGGTACCCCTGGCAGCGGTACCGCATCTTC
CTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGT
TCCCCAGGTAGCTCTACTCCTTCTGGTGCTACTGGCT
CCCCAGGTGCATCCCCTGGCACCAGCTCTACCGGTTC
TCCA
hGH- FPTIPLSRLFDNAMLRAHR 725 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 726
AM875 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGTSTEPSEGSAPGSEP ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
ATSGSETPGSPAGSPTSTEE ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSTSSTAESPGPGTSTPESG ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
SASPGSTSESPSGTAPGSTS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ESPSGTAPGTSTPESGSASP CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
GTSTPESGSASPGSEPATSG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACTT
SETPGTSESATPESGPGSPA CTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
GSPTSTEEGTSTEPSEGSAP AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCC
GTSESATPESGPGTSTEPSE CAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA
GSAPGTSTEPSEGSAPGSP CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTC
AGSPTSTEEGTSTEPSEGSA TACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACT
PGTSTEPSEGSAPGTSESAT AGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTA
PESGPGTSESATPESGPGTS GCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTAC
TEPSEGSAPGTSTEPSEGSA TCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACT
PGTSESATPESGPGTSTEPS CCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCG
EGSAPGSEPATSGSETPGSP GCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAA
AGSPTSTEEGSSTPSGATG AGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGGCA
SPGTPGSGTASSSPGSSTPS GGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTG
GATGSPGTSTEPSEGSAPG AACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA
TSTEPSEGSAPGSEPATSGS GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTG
ETPGSPAGSPTSTEEGSPA AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCG
GSPTSTEEGTSTEPSEGSAP AACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAG
GASASGAPSTGGTSESATP GTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGA
ESGPGSPAGSPTSTEEGSPA ACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGA
GSPTSTEEGSTSSTAESPGP ACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG
GSTSESPSGTAPGTSPSGES CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAG
STAPGTPGSGTASSSPGSST CGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAA
PSGATGSPGSSPSASTGTG CCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAA
PGSEPATSGSETPGTSESAT CCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGC
PESGPGSEPATSGSETPGST GCAACCCCTGAATCCGGTCCAGGTACTTCTACTGAA
SSTAESPGPGSTSSTAESPG CCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCT
PGTSPSGESSTAPGSEPATS ACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGC
GSETPGSEPATSGSETPGTS TCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCG
TEPSEGSAPGSTSSTAESPG TCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCG
PGTSTPESGSASPGSTSESP GTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTC
SGTAPGTSTEPSEGSAPGT TGGTGCTACTGGCTCTCCAGGTACCTCTACCGAACCG
STEPSEGSAPGTSTEPSEGS TCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCG
APGSSTPSGATGSPGSSPSA TCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACC
STGTGPGASPGTSSTGSPG TCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTC
SEPATSGSETPGTSESATPE CGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTC
SGPGSPAGSPTSTEEGSSTP CGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTC
SGATGSPGSSPSASTGTGP CGAAGGTAGCGCTCCAGGTGCAAGCGCAAGCGGCG
GASPGTSSTGSPGTSESATP CGCCAAGCACGGGAGGTACTTCTGAAAGCGCTACTC
ESGPGTSTEPSEGSAPGTST CTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGA
EPSEGSAP CTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAA
CTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGA
ATCTCCTGGCCCAGGTTCTACTAGCGAATCTCCGTCT
GGCACCGCACCAGGTACTTCCCCTAGCGGTGAATCT
TCTACTGCACCAGGTACCCCTGGCAGCGGTACCGCT
TCTTCCTCTCCAGGTAGCTCTACCCCGTCTGGTGCTA
CTGGCTCTCCAGGTTCTAGCCCGTCTGCATCTACCGG
TACCGGCCCAGGTAGCGAACCGGCAACCTCCGGCTC
TGAAACTCCAGGTACTTCTGAAAGCGCTACTCCGGA
ATCCGGCCCAGGTAGCGAACCGGCTACTTCCGGCTC
TGAAACCCCAGGTTCCACCAGCTCTACTGCAGAATC
TCCGGGCCCAGGTTCTACTAGCTCTACTGCAGAATCT
CCGGGTCCAGGTACTTCTCCTAGCGGCGAATCTTCTA
CCGCTCCAGGTAGCGAACCGGCAACCTCTGGCTCTG
AAACTCCAGGTAGCGAACCTGCAACCTCCGGCTCTG
AAACCCCAGGTACTTCTACTGAACCTTCTGAGGGCA
GCGCACCAGGTTCTACCAGCTCTACCGCAGAATCTC
CTGGTCCAGGTACCTCTACTCCGGAAAGCGGCTCTG
CATCTCCAGGTTCTACTAGCGAATCTCCTTCTGGCAC
TGCACCAGGTACTTCTACCGAACCGTCCGAAGGCAG
CGCTCCAGGTACCTCTACTGAACCTTCCGAGGGCAG
CGCTCCAGGTACCTCTACCGAACCTTCTGAAGGTAG
CGCACCAGGTAGCTCTACTCCGTCTGGTGCAACCGG
CTCCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACT
GGCCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGT
TCTCCAGGTAGCGAACCTGCTACCTCCGGTTCTGAA
ACCCCAGGTACCTCTGAAAGCGCAACTCCGGAGTCT
GGTCCAGGTAGCCCTGCAGGTTCTCCTACCTCCACTG
AGGAAGGTAGCTCTACTCCGTCTGGTGCAACCGGCT
CCCCAGGTTCTAGCCCGTCTGCTTCCACTGGTACTGG
CCCAGGTGCTTCCCCGGGCACCAGCTCTACTGGTTCT
CCAGGTACCTCTGAAAGCGCTACTCCGGAGTCTGGC
CCAGGTACCTCTACTGAACCGTCTGAGGGTAGCGCT
CCAGGTACTTCTACTGAACCGTCCGAAGGTAGCGCA
CCA
hGH- FPTIPLSRLFDNAMLRAHR 727 TTTCCGACTATTCCGCTGTCTCGTCTGTTTGATAATG 728
AM1318 LHQLAFDTYQEFEEAYIPK CTATGCTGCGTGCGCACCGTCTGCACCAGCTGGCCTT
EQKYSFLQNPQTSLCFSESI TGATACTTACCAGGAATTTGAAGAAGCcTACATTCCT
PTPSNREETQQKSNLELLRI AAAGAGCAGAAGTACTCTTTCCTGCAAAACCCACAG
SLLLIQSWLEPVQFLRSVF ACTTCTCTCTGCTTCAGCGAATCTATTCCGACGCCTT
ANSLVYGASDSNVYDLLK CCAATCGCGAGGAAACTCAGCAAAAGTCCAATCTGG
DLEEGIQTLMGRLEDGSPR AACTACTCCGCATTTCTCTGCTTCTGATTCAGAGCTG
TGQIFKQTYSKFDTNSHND GCTAGAACCAGTGCAATTTCTGCGTTCCGTCTTCGCC
DALLKNYGLLYCFRKDM AATAGCCTAGTTTATGGCGCATCCGACAGCAACGTA
DKVETFLRIVQCRSVEGSC TACGATCTCCTGAAAGATCTCGAGGAAGGCATTCAG
GFGGTSTEPSEGSAPGSEP ACCCTGATGGGTCGTCTCGAGGATGGCTCTCCGCGT
ATSGSETPGSPAGSPTSTEE ACTGGTCAGATCTTCAAGCAGACTTACTCTAAATTTG
GSTSSTAESPGPGTSTPESG ATACTAACAGCCACAATGACGATGCGCTTCTAAAAA
SASPGSTSESPSGTAPGSTS ACTATGGTCTGCTGTATTGTTTTCGTAAAGATATGGA
ESPSGTAPGTSTPESGSASP CAAAGTTGAAACCTTCCTGCGTATTGTTCAGTGTCGT
GTSTPESGSASPGSEPATSG TCCGTTGAGGGCAGCTGTGGTTTCTAAGGTGGTACTT
SETPGTSESATPESGPGSPA CTACTGAACCGTCTGAAGGCAGCGCACCAGGTAGCG
GSPTSTEEGTSTEPSEGSAP AACCGGCTACTTCCGGTTCTGAAACCCCAGGTAGCC
GTSESATPESGPGTSTEPSE CAGCAGGTTCTCCAACTTCTACTGAAGAAGGTTCTA
GSAPGTSTEPSEGSAPGSP CCAGCTCTACCGCAGAATCTCCTGGTCCAGGTACCTC
AGSPTSTEEGTSTEPSEGSA TACTCCGGAAAGCGGCTCTGCATCTCCAGGTTCTACT
PGTSTEPSEGSAPGTSESAT AGCGAATCTCCTTCTGGCACTGCACCAGGTTCTACTA
PESGPGTSESATPESGPGTS GCGAATCCCCGTCTGGTACTGCTCCAGGTACTTCTAC
TEPSEGSAPGTSTEPSEGSA TCCTGAAAGCGGTTCCGCTTCTCCAGGTACCTCTACT
PGTSESATPESGPGTSTEPS CCGGAAAGCGGTTCTGCATCTCCAGGTAGCGAACCG
EGSAPGSEPATSGSETPGSP GCAACCTCCGGCTCTGAAACCCCAGGTACCTCTGAA
AGSPTSTEEGSSTPSGATG AGCGCTACTCCTGAATCCGGCCCAGGTAGCCCGGCA
SPGTPGSGTASSSPGSSTPS GGTTCTCCGACTTCCACTGAGGAAGGTACCTCTACTG
GATGSPGTSTEPSEGSAPG AACCTTCTGAGGGCAGCGCTCCAGGTACTTCTGAAA
TSTEPSEGSAPGSEPATSGS GCGCTACCCCGGAGTCCGGTCCAGGTACTTCTACTG
ETPGSPAGSPTSTEEGSPA AACCGTCCGAAGGTAGCGCACCAGGTACTTCTACCG
GSPTSTEEGTSTEPSEGSAP AACCGTCCGAGGGTAGCGCACCAGGTAGCCCAGCAG
GPEPTGPAPSGGSEPATSG GTTCTCCTACCTCCACCGAGGAAGGTACTTCTACCGA
SETPGTSESATPESGPGSPA ACCGTCCGAGGGTAGCGCACCAGGTACTTCTACCGA
GSPTSTEEGTSESATPESGP ACCTTCCGAGGGCAGCGCACCAGGTACTTCTGAAAG
GSPAGSPTSTEEGSPAGSPT CGCTACCCCTGAGTCCGGCCCAGGTACTTCTGAAAG
STEEGTSESATPESGPGSPA CGCTACTCCTGAATCCGGTCCAGGTACCTCTACTGAA
GSPTSTEEGSPAGSPTSTEE CCTTCCGAAGGCAGCGCTCCAGGTACCTCTACCGAA
GSTSSTAESPGPGSTSESPS CCGTCCGAGGGCAGCGCACCAGGTACTTCTGAAAGC
GTAPGTSPSGESSTAPGSTS GCAACCCCTGAATCCGGTCCAGGTACTTCTACTGAA
ESPSGTAPGSTSESPSGTAP CCTTCCGAAGGTAGCGCTCCAGGTAGCGAACCTGCT
GTSPSGESSTAPGTSTEPSE ACTTCTGGTTCTGAAACCCCAGGTAGCCCGGCTGGC
GSAPGTSESATPESGPGTS TCTCCGACCTCCACCGAGGAAGGTAGCTCTACCCCG
ESATPESGPGSEPATSGSET TCTGGTGCTACTGGTTCTCCAGGTACTCCGGGCAGCG
PGTSESATPESGPGTSESAT GTACTGCTTCTTCCTCTCCAGGTAGCTCTACCCCTTC
PESGPGTSTEPSEGSAPGTS TGGTGCTACTGGCTCTCCAGGTACCTCTACCGAACCG
ESATPESGPGTSTEPSEGSA TCCGAGGGTAGCGCACCAGGTACCTCTACTGAACCG
PGTSPSGESSTAPGTSPSGE TCTGAGGGTAGCGCTCCAGGTAGCGAACCGGCAACC
SSTAPGTSPSGESSTAPGTS TCCGGTTCTGAAACTCCAGGTAGCCCTGCTGGCTCTC
TEPSEGSAPGSPAGSPTSTE CGACTTCTACTGAGGAAGGTAGCCCGGCTGGTTCTC
EGTSTEPSEGSAPGSSPSAS CGACTTCTACTGAGGAAGGTACTTCTACCGAACCTTC
TGTGPGSSTPSGATGSPGS CGAAGGTAGCGCTCCAGGTCCAGAACCAACGGGGCC
STPSGATGSPGSSTPSGAT GGCCCCAAGCGGAGGTAGCGAACCGGCAACCTCCG
GSPGSSTPSGATGSPGASP GCTCTGAAACCCCAGGTACCTCTGAAAGCGCTACTC
GTSSTGSPGASASGAPSTG CTGAATCCGGCCCAGGTAGCCCGGCAGGTTCTCCGA
GTSPSGESSTAPGSTSSTAE CTTCCACTGAGGAAGGTACTTCTGAAAGCGCTACTC
SPGPGTSPSGESSTAPGTSE CTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGA
SATPESGPGTSTEPSEGSAP CTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAA
GTSTEPSEGSAPGSSPSAST CTTCTACTGAAGAAGGTACTTCTGAAAGCGCTACTC
GTGPGSSTPSGATGSPGAS CTGAGTCCGGCCCAGGTAGCCCGGCTGGCTCTCCGA
PGTSSTGSPGTSTPESGSAS CTTCCACCGAGGAAGGTAGCCCGGCTGGCTCTCCAA
PGTSPSGESSTAPGTSPSGE CTTCTACTGAAGAAGGTTCTACCAGCTCTACCGCTGA
SSTAPGTSESATPESGPGSE ATCTCCTGGCCCAGGTTCTACTAGCGAATCTCCGTCT
PATSGSETPGTSTEPSEGSA GGCACCGCACCAGGTACTTCCCCTAGCGGTGAATCT
PGSTSESPSGTAPGSTSESP TCTACTGCACCAGGTTCTACCAGCGAATCTCCTTCTG
SGTAPGTSTPESGSASPGSP GCACCGCTCCAGGTTCTACTAGCGAATCCCCGTCTG
AGSPTSTEEGTSESATPESG GTACCGCACCAGGTACTTCTCCTAGCGGCGAATCTTC
PGTSTEPSEGSAPGSPAGSP TACCGCACCAGGTACTTCTACCGAACCTTCCGAGGG
TSTEEGTSESATPESGPGSE CAGCGCACCAGGTACTTCTGAAAGCGCTACCCCTGA
PATSGSETPGSSTPSGATGS GTCCGGCCCAGGTACTTCTGAAAGCGCTACTCCTGA
PGASPGTSSTGSPGSSTPSG ATCCGGTCCAGGTAGCGAACCGGCAACCTCTGGCTC
ATGSPGSTSESPSGTAPGTS TGAAACCCCAGGTACCTCTGAAAGCGCTACTCCGGA
PSGESSTAPGSTSSTAESPG ATCTGGTCCAGGTACTTCTGAAAGCGCTACTCCGGA
PGSSTPSGATGSPGASPGT ATCCGGTCCAGGTACCTCTACTGAACCTTCTGAGGG
SSTGSPGTPGSGTASSSPGS CAGCGCTCCAGGTACTTCTGAAAGCGCTACCCCGGA
PAGSPTSTEEGSPAGSPTST GTCCGGTCCAGGTACTTCTACTGAACCGTCCGAAGG
EEGTSTEPSEGSAP TAGCGCACCAGGTACCTCCCCTAGCGGCGAATCTTC
TACTGCTCCAGGTACCTCTCCTAGCGGCGAATCTTCT
ACCGCTCCAGGTACCTCCCCTAGCGGTGAATCTTCTA
CCGCACCAGGTACTTCTACCGAACCGTCCGAGGGTA
GCGCACCAGGTAGCCCAGCAGGTTCTCCTACCTCCA
CCGAGGAAGGTACTTCTACCGAACCGTCCGAGGGTA
GCGCACCAGGTTCTAGCCCTTCTGCTTCCACCGGTAC
CGGCCCAGGTAGCTCTACTCCGTCTGGTGCAACTGG
CTCTCCAGGTAGCTCTACTCCGTCTGGTGCAACCGGC
TCCCCAGGTAGCTCTACCCCGTCTGGTGCTACCGGCT
CTCCAGGTAGCTCTACCCCGTCTGGTGCAACCGGCTC
CCCAGGTGCATCCCCGGGTACTAGCTCTACCGGTTCT
CCAGGTGCAAGCGCAAGCGGCGCGCCAAGCACGGG
AGGTACTTCTCCGAGCGGTGAATCTTCTACCGCACC
AGGTTCTACTAGCTCTACCGCTGAATCTCCGGGCCCA
GGTACTTCTCCGAGCGGTGAATCTTCTACTGCTCCAG
GTACCTCTGAAAGCGCTACTCCGGAGTCTGGCCCAG
GTACCTCTACTGAACCGTCTGAGGGTAGCGCTCCAG
GTACTTCTACTGAACCGTCCGAAGGTAGCGCACCAG
GTTCTAGCCCTTCTGCATCTACTGGTACTGGCCCAGG
TAGCTCTACTCCTTCTGGTGCTACCGGCTCTCCAGGT
GCTTCTCCGGGTACTAGCTCTACCGGTTCTCCAGGTA
CTTCTACTCCGGAAAGCGGTTCCGCATCTCCAGGTAC
TTCTCCTAGCGGTGAATCTTCTACTGCTCCAGGTACC
TCTCCTAGCGGCGAATCTTCTACTGCTCCAGGTACTT
CTGAAAGCGCAACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTCCAGGTACTTC
TACCGAACCGTCCGAAGGTAGCGCACCAGGTTCTAC
CAGCGAATCCCCTTCTGGTACTGCTCCAGGTTCTACC
AGCGAATCCCCTTCTGGCACCGCACCAGGTACTTCT
ACCCCTGAAAGCGGCTCCGCTTCTCCAGGTAGCCCG
GCAGGCTCTCCGACCTCTACTGAGGAAGGTACTTCT
GAAAGCGCAACCCCGGAGTCCGGCCCAGGTACCTCT
ACCGAACCGTCTGAGGGCAGCGCACCAGGTAGCCCT
GCTGGCTCTCCAACCTCCACCGAAGAAGGTACCTCT
GAAAGCGCAACCCCTGAATCCGGCCCAGGTAGCGAA
CCGGCAACCTCCGGTTCTGAAACCCCAGGTAGCTCT
ACCCCGTCTGGTGCTACCGGTTCCCCAGGTGCTTCTC
CTGGTACTAGCTCTACCGGTTCTCCAGGTAGCTCTAC
CCCGTCTGGTGCTACTGGCTCTCCAGGTTCTACTAGC
GAATCCCCGTCTGGTACTGCTCCAGGTACTTCCCCTA
GCGGTGAATCTTCTACTGCTCCAGGTTCTACCAGCTC
TACCGCAGAATCTCCGGGTCCAGGTAGCTCTACCCC
TTCTGGTGCAACCGGCTCTCCAGGTGCATCCCCGGGT
ACCAGCTCTACCGGTTCTCCAGGTACTCCGGGTAGC
GGTACCGCTTCTTCCTCTCCAGGTAGCCCTGCTGGCT
CTCCGACTTCTACTGAGGAAGGTAGCCCGGCTGGTT
CTCCGACTTCTACTGAGGAAGGTACTTCTACCGAAC
CTTCCGAAGGTAGCGCTCCA
*Sequence name reflects N- to C-terminus configuration of the growth factor and XTEN components
TABLE 36
Exemplary GHXTEN comprising growth hormones and two XTEN sequences
GHXTEN
Name* Amino Acid Sequence SEQ ID NO: DNA Nucleotide Sequence SEQ ID NO:
AE48- MAEPAGSPTSTEEGT 729 ATGGCTGAACCTGCTGGCTCTCCAAC 730
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE144 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGFPTIPLSRLFDN GCTCTACCCCTTCTGGTGCAACCGGCT
AMLRAHRLHQLAFD CTCCAGGTGCTTCTCCGGGCACCAGCT
TYQEFEEAYIPKEQK CTACCGGTTCTCCAGGTTTTCCGACTA
YSFLQNPQTSLCFSE TTCCGCTGTCTCGTCTGTTTGATAATG
SIPTPSNREETQQKS CTATGCTGCGTGCGCACCGTCTGCACC
NLELLRISLLLIQSWL AGCTGGCCTTTGATACTTACCAGGAA
EPVQFLRSVFANSLV TTTGAAGAAGCcTACATTCCTAAAGAG
YGASDSNVYDLLKD CAGAAGTACTCTTTCCTGCAAAACCC
LEEGIQTLMGRLEDG ACAGACTTCTCTCTGCTTCAGCGAATC
SPRTGQIFKQTYSKF TATTCCGACGCCTTCCAATCGCGAGG
DTNSHNDDALLKNY AAACTCAGCAAAAGTCCAATCTGGAA
GLLYCFRKDMDKVE CTACTCCGCATTTCTCTGCTTCTGATT
TFLRIVQCRSVEGSC CAGAGCTGGCTAGAACCAGTGCAATT
GFGGSEPATSGSETP TCTGCGTTCCGTCTTCGCCAATAGCCT
GTSESATPESGPGSE AGTTTATGGCGCATCCGACAGCAACG
PATSGSETPGSPAGS TATACGATCTCCTGAAAGATCTCGAG
PTSTEEGTSTEPSEGS GAAGGCATTCAGACCCTGATGGGTCG
APGSEPATSGSETPG TCTCGAGGATGGCTCTCCGCGTACTG
SEPATSGSETPGSEP GTCAGATCTTCAAGCAGACTTACTCTA
ATSGSETPGTSTEPSE AATTTGATACTAACAGCCACAATGAC
GSAPGTSESATPESG GATGCGCTTCTAAAAAACTATGGTCT
PGSEPATSGSETPGT GCTGTATTGTTTTCGTAAAGATATGGA
STEPSEGSAP CAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCT
GTGGTTTCTAAGGTGGTAGCGAACCG
GCAACTTCCGGCTCTGAAACCCCAGG
TACTTCTGAAAGCGCTACTCCTGAGTC
TGGCCCAGGTAGCGAACCTGCTACCT
CTGGCTCTGAAACCCCAGGTAGCCCG
GCAGGCTCTCCGACTTCCACCGAGGA
AGGTACCTCTACTGAACCTTCTGAGG
GTAGCGCTCCAGGTAGCGAACCGGCA
ACCTCTGGCTCTGAAACCCCAGGTAG
CGAACCTGCTACCTCCGGCTCTGAAA
CTCCAGGTAGCGAACCGGCTACTTCC
GGTTCTGAAACTCCAGGTACCTCTACC
GAACCTTCCGAAGGCAGCGCACCAGG
TACTTCTGAAAGCGCAACCCCTGAAT
CCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCT
ACCGAACCGTCCGAAGGTAGCGCACCA
AM48- MAEPAGSPTSTEEGA 731 ATGGCTGAACCTGCTGGCTCTCCAAC 732
hGH- SPGTSSTGSPGSSTPS CTCCACTGAGGAAGGTGCATCCCCGG
AE144 GATGSPGSSTPSGAT GCACCAGCTCTACCGGTTCTCCAGGT
GSPGFPTIPLSRLFDN AGCTCTACCCCGTCTGGTGCTACCGGC
AMLRAHRLHQLAFD TCTCCAGGTAGCTCTACCCCGTCTGGT
TYQEFEEAYIPKEQK GCTACTGGCTCTCCAGGTTTTCCGACT
YSFLQNPQTSLCFSE ATTCCGCTGTCTCGTCTGTTTGATAAT
SIPTPSNREETQQKS GCTATGCTGCGTGCGCACCGTCTGCA
NLELLRISLLLIQSWL CCAGCTGGCCTTTGATACTTACCAGG
EPVQFLRSVFANSLV AATTTGAAGAAGCcTACATTCCTAAAG
YGASDSNVYDLLKD AGCAGAAGTACTCTTTCCTGCAAAAC
LEEGIQTLMGRLEDG CCACAGACTTCTCTCTGCTTCAGCGAA
SPRTGQIFKQTYSKF TCTATTCCGACGCCTTCCAATCGCGAG
DTNSHNDDALLKNY GAAACTCAGCAAAAGTCCAATCTGGA
GLLYCFRKDMDKVE ACTACTCCGCATTTCTCTGCTTCTGAT
TFLRIVQCRSVEGSC TCAGAGCTGGCTAGAACCAGTGCAAT
GFGGSEPATSGSETP TTCTGCGTTCCGTCTTCGCCAATAGCC
GTSESATPESGPGSE TAGTTTATGGCGCATCCGACAGCAAC
PATSGSETPGSPAGS GTATACGATCTCCTGAAAGATCTCGA
PTSTEEGTSTEPSEGS GGAAGGCATTCAGACCCTGATGGGTC
APGSEPATSGSETPG GTCTCGAGGATGGCTCTCCGCGTACT
SEPATSGSETPGSEP GGTCAGATCTTCAAGCAGACTTACTCT
ATSGSETPGTSTEPSE AAATTTGATACTAACAGCCACAATGA
GSAPGTSESATPESG CGATGCGCTTCTAAAAAACTATGGTC
PGSEPATSGSETPGT TGCTGTATTGTTTTCGTAAAGATATGG
STEPSEGSAP ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AE144- GSEPATSGSETPGTS 733 GGTAGCGAACCGGCAACTTCCGGCTC 734
hGH- ESATPESGPGSEPAT TGAAACCCCAGGTACTTCTGAAAGCG
AE144 SGSETPGSPAGSPTST CTACTCCTGAGTCTGGCCCAGGTAGC
EEGTSTEPSEGSAPG GAACCTGCTACCTCTGGCTCTGAAAC
SEPATSGSETPGSEP CCCAGGTAGCCCGGCAGGCTCTCCGA
ATSGSETPGSEPATS CTTCCACCGAGGAAGGTACCTCTACT
GSETPGTSTEPSEGS GAACCTTCTGAGGGTAGCGCTCCAGG
APGTSESATPESGPG TAGCGAACCGGCAACCTCTGGCTCTG
SEPATSGSETPGTSTE AAACCCCAGGTAGCGAACCTGCTACC
PSEGSAPGFPTIPLSR TCCGGCTCTGAAACTCCAGGTAGCGA
LFDNAMLRAHRLHQ ACCGGCTACTTCCGGTTCTGAAACTCC
LAFDTYQEFEEAYIP AGGTACCTCTACCGAACCTTCCGAAG
KEQKYSFLQNPQTSL GCAGCGCACCAGGTACTTCTGAAAGC
CFSESIPTPSNREETQ GCAACCCCTGAATCCGGTCCAGGTAG
QKSNLELLRISLLLIQ CGAACCGGCTACTTCTGGCTCTGAGA
SWLEPVQFLRSVFA CTCCAGGTACTTCTACCGAACCGTCCG
NSLVYGASDSNVYD AAGGTAGCGCACCAGGTTTTCCGACT
LLKDLEEGIQTLMGR ATTCCGCTGTCTCGTCTGTTTGATAAT
LEDGSPRTGQIFKQT GCTATGCTGCGTGCGCACCGTCTGCA
YSKFDTNSHNDDAL CCAGCTGGCCTTTGATACTTACCAGG
LKNYGLLYCFRKDM AATTTGAAGAAGCcTACATTCCTAAAG
DKVETFLRIVQCRSV AGCAGAAGTACTCTTTCCTGCAAAAC
EGSCGFGGSEPATSG CCACAGACTTCTCTCTGCTTCAGCGAA
SETPGTSESATPESGP TCTATTCCGACGCCTTCCAATCGCGAG
GSEPATSGSETPGSP GAAACTCAGCAAAAGTCCAATCTGGA
AGSPTSTEEGTSTEPS ACTACTCCGCATTTCTCTGCTTCTGAT
EGSAPGSEPATSGSE TCAGAGCTGGCTAGAACCAGTGCAAT
TPGSEPATSGSETPG TTCTGCGTTCCGTCTTCGCCAATAGCC
SEPATSGSETPGTSTE TAGTTTATGGCGCATCCGACAGCAAC
PSEGSAPGTSESATP GTATACGATCTCCTGAAAGATCTCGA
ESGPGSEPATSGSET GGAAGGCATTCAGACCCTGATGGGTC
PGTSTEPSEGSAP GTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AE288- GTSESATPESGPGSE 735 GGTACCTCTGAAAGCGCAACTCCTGA 736
hGH- PATSGSETPGTSESA GTCTGGCCCAGGTAGCGAACCTGCTA
AE144 TPESGPGSEPATSGS CCTCCGGCTCTGAGACTCCAGGTACCT
ETPGTSESATPESGP CTGAAAGCGCAACCCCGGAATCTGGT
GTSTEPSEGSAPGSP CCAGGTAGCGAACCTGCAACCTCTGG
AGSPTSTEEGTSESA CTCTGAAACCCCAGGTACCTCTGAAA
TPESGPGSEPATSGS GCGCTACTCCTGAATCTGGCCCAGGT
ETPGTSESATPESGP ACTTCTACTGAACCGTCCGAGGGCAG
GSPAGSPTSTEEGSP CGCACCAGGTAGCCCTGCTGGCTCTC
AGSPTSTEEGTSTEPS CAACCTCCACCGAAGAAGGTACCTCT
EGSAPGTSESATPES GAAAGCGCAACCCCTGAATCCGGCCC
GPGTSESATPESGPG AGGTAGCGAACCGGCAACCTCCGGTT
TSESATPESGPGSEP CTGAAACCCCAGGTACTTCTGAAAGC
ATSGSETPGSEPATS GCTACTCCTGAGTCCGGCCCAGGTAG
GSETPGSPAGSPTST CCCGGCTGGCTCTCCGACTTCCACCGA
EEGTSTEPSEGSAPG GGAAGGTAGCCCGGCTGGCTCTCCAA
TSTEPSEGSAPGSEP CTTCTACTGAAGAAGGTACTTCTACCG
ATSGSETPGTSESAT AACCTTCCGAGGGCAGCGCACCAGGT
PESGPGTSTEPSEGS ACTTCTGAAAGCGCTACCCCTGAGTC
APGFPTIPLSRLFDNA CGGCCCAGGTACTTCTGAAAGCGCTA
MLRAHRLHQLAFDT CTCCTGAATCCGGTCCAGGTACTTCTG
YQEFEEAYIPKEQKY AAAGCGCTACCCCGGAATCTGGCCCA
SFLQNPQTSLCFSESI GGTAGCGAACCGGCTACTTCTGGTTCT
PTPSNREETQQKSNL GAAACCCCAGGTAGCGAACCGGCTAC
ELLRISLLLIQSWLEP CTCCGGTTCTGAAACTCCAGGTAGCC
VQFLRSVFANSLVY CAGCAGGCTCTCCGACTTCCACTGAG
GASDSNVYDLLKDL GAAGGTACTTCTACTGAACCTTCCGA
EEGIQTLMGRLEDGS AGGCAGCGCACCAGGTACCTCTACTG
PRTGQIFKQTYSKFD AACCTTCTGAGGGCAGCGCTCCAGGT
TNSHNDDALLKNYG AGCGAACCTGCAACCTCTGGCTCTGA
LLYCFRKDMDKVET AACCCCAGGTACCTCTGAAAGCGCTA
FLRIVQCRSVEGSCG CTCCTGAATCTGGCCCAGGTACTTCTA
FGGSEPATSGSETPG CTGAACCGTCCGAGGGCAGCGCACCA
TSESATPESGPGSEP GGTTTTCCGACTATTCCGCTGTCTCGT
ATSGSETPGSPAGSP CTGTTTGATAATGCTATGCTGCGTGCG
TSTEEGTSTEPSEGS CACCGTCTGCACCAGCTGGCCTTTGAT
APGSEPATSGSETPG ACTTACCAGGAATTTGAAGAAGCcTA
SEPATSGSETPGSEP CATTCCTAAAGAGCAGAAGTACTCTT
ATSGSETPGTSTEPSE TCCTGCAAAACCCACAGACTTCTCTCT
GSAPGTSESATPESG GCTTCAGCGAATCTATTCCGACGCCTT
PGSEPATSGSETPGT CCAATCGCGAGGAAACTCAGCAAAAG
STEPSEGSAP TCCAATCTGGAACTACTCCGCATTTCT
CTGCTTCTGATTCAGAGCTGGCTAGA
ACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTG
AAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCT
CTCCGCGTACTGGTCAGATCTTCAAGC
AGACTTACTCTAAATTTGATACTAACA
GCCACAATGACGATGCGCTTCTAAAA
AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTAGCGAACCGGCAACTTCCGGCTCT
GAAACCCCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCTGGCCCAGGTAGCG
AACCTGCTACCTCTGGCTCTGAAACCC
CAGGTAGCCCGGCAGGCTCTCCGACT
TCCACCGAGGAAGGTACCTCTACTGA
ACCTTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCTGGCTCTGAA
ACCCCAGGTAGCGAACCTGCTACCTC
CGGCTCTGAAACTCCAGGTAGCGAAC
CGGCTACTTCCGGTTCTGAAACTCCAG
GTACCTCTACCGAACCTTCCGAAGGC
AGCGCACCAGGTACTTCTGAAAGCGC
AACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTC
CAGGTACTTCTACCGAACCGTCCGAA
GGTAGCGCACCA
AF144- GTSTPESGSASPGTSP 737 GGTACTTCTACTCCGGAAAGCGGTTC 738
hGH- SGESSTAPGTSPSGES CGCATCTCCAGGTACTTCTCCTAGCGG
AE144 STAPGSTSSTAESPGP TGAATCTTCTACTGCTCCAGGTACCTC
GSTSESPSGTAPGSTS TCCTAGCGGCGAATCTTCTACTGCTCC
STAESPGPGTSPSGES AGGTTCTACCAGCTCTACCGCTGAATC
STAPGTSTPESGSASP TCCTGGCCCAGGTTCTACCAGCGAAT
GSTSSTAESPGPGTSP CCCCGTCTGGCACCGCACCAGGTTCT
SGESSTAPGTSPSGES ACTAGCTCTACCGCAGAATCTCCGGG
STAPGTSPSGESSTAP TCCAGGTACTTCCCCTAGCGGTGAATC
GFPTIPLSRLFDNAM TTCTACTGCTCCAGGTACCTCTACTCC
LRAHRLHQLAFDTY GGAAAGCGGCTCCGCATCTCCAGGTT
QEFEEAYIPKEQKYS CTACTAGCTCTACTGCTGAATCTCCTG
FLQNPQTSLCFSESIP GTCCAGGTACCTCCCCTAGCGGCGAA
TPSNREETQQKSNLE TCTTCTACTGCTCCAGGTACCTCTCCT
LLRISLLLIQSWLEPV AGCGGCGAATCTTCTACCGCTCCAGG
QFLRSVFANSLVYG TACCTCCCCTAGCGGTGAATCTTCTAC
ASDSNVYDLLKDLE CGCACCAGGTTTTCCGACTATTCCGCT
EGIQTLMGRLEDGSP GTCTCGTCTGTTTGATAATGCTATGCT
RTGQIFKQTYSKFDT GCGTGCGCACCGTCTGCACCAGCTGG
NSHNDDALLKNYGL CCTTTGATACTTACCAGGAATTTGAAG
LYCFRKDMDKVETF AAGCcTACATTCCTAAAGAGCAGAAG
LRIVQCRSVEGSCGF TACTCTTTCCTGCAAAACCCACAGACT
GGSEPATSGSETPGT TCTCTCTGCTTCAGCGAATCTATTCCG
SESATPESGPGSEPA ACGCCTTCCAATCGCGAGGAAACTCA
TSGSETPGSPAGSPTS GCAAAAGTCCAATCTGGAACTACTCC
TEEGTSTEPSEGSAP GCATTTCTCTGCTTCTGATTCAGAGCT
GSEPATSGSETPGSE GGCTAGAACCAGTGCAATTTCTGCGT
PATSGSETPGSEPAT TCCGTCTTCGCCAATAGCCTAGTTTAT
SGSETPGTSTEPSEGS GGCGCATCCGACAGCAACGTATACGA
APGTSESATPESGPG TCTCCTGAAAGATCTCGAGGAAGGCA
SEPATSGSETPGTSTE TTCAGACCCTGATGGGTCGTCTCGAG
PSEGSAP GATGGCTCTCCGCGTACTGGTCAGAT
CTTCAAGCAGACTTACTCTAAATTTGA
TACTAACAGCCACAATGACGATGCGC
TTCTAAAAAACTATGGTCTGCTGTATT
GTTTTCGTAAAGATATGGACAAAGTT
GAAACCTTCCTGCGTATTGTTCAGTGT
CGTTCCGTTGAGGGCAGCTGTGGTTTC
TAAGGTGGTAGCGAACCGGCAACTTC
CGGCTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCTGGCTCT
GAAACCCCAGGTAGCCCGGCAGGCTC
TCCGACTTCCACCGAGGAAGGTACCT
CTACTGAACCTTCTGAGGGTAGCGCT
CCAGGTAGCGAACCGGCAACCTCTGG
CTCTGAAACCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAAACTCCAGGT
AGCGAACCGGCTACTTCCGGTTCTGA
AACTCCAGGTACCTCTACCGAACCTTC
CGAAGGCAGCGCACCAGGTACTTCTG
AAAGCGCAACCCCTGAATCCGGTCCA
GGTAGCGAACCGGCTACTTCTGGCTC
TGAGACTCCAGGTACTTCTACCGAAC
CGTCCGAAGGTAGCGCACCA
AD576- GSSESGSSEGGPGSG 739 GGTTCCTCTGAAAGCGGTTCTTCCGAA 740
hGH- GEPSESGSSGSSESGS GGTGGTCCAGGTTCCTCTGAAAGCGG
AE144 SEGGPGSSESGSSEG TTCTTCTGAGGGTGGTCCAGGTGAATC
GPGSSESGSSEGGPG TCCGGGTGGCTCCAGCGGTTCCGAGT
SSESGSSEGGPGSSES CAGGTTCTGGTGGCGAACCTTCCGAG
GSSEGGPGESPGGSS TCTGGTAGCTCAGGTGAATCTCCGGG
GSESGSEGSSGPGES TGGTTCTAGCGGTTCCGAGTCAGGTG
SGSSESGSSEGGPGS AATCTCCGGGTGGTTCCAGCGGTTCTG
SESGSSEGGPGSSES AGTCAGGTTCCTCCGAAAGCGGTTCTT
GSSEGGPGSGGEPSE CTGAGGGCGGTCCAGGTTCCTCCGAA
SGSSGESPGGSSGSE AGCGGTTCTTCCGAGGGCGGTCCAGG
SGESPGGSSGSESGS TTCTTCTGAAAGCGGTTCTTCCGAGGG
GGEPSESGSSGSSES CGGTCCAGGTGAATCTCCTGGTGGTTC
GSSEGGPGSGGEPSE CAGCGGTTCCGAGTCAGGTGAATCTC
SGSSGSGGEPSESGS CAGGTGGCTCTAGCGGTTCCGAGTCA
SGSEGSSGPGESSGE GGTGAATCTCCTGGTGGTTCTAGCGGT
SPGGSSGSESGSGGE TCTGAATCAGGTTCCTCCGAAAGCGG
PSESGSSGSGGEPSES TTCTTCTGAGGGCGGTCCAGGTTCCTC
GSSGSGGEPSESGSS CGAAAGCGGTTCTTCCGAGGGCGGTC
GSSESGSSEGGPGES CAGGTTCTTCTGAAAGCGGTTCTTCCG
PGGSSGSESGESPGG AGGGCGGTCCAGGTTCCTCTGAAAGC
SSGSESGESPGGSSG GGTTCTTCTGAGGGCGGTCCAGGTTCT
SESGESPGGSSGSES TCCGAAAGCGGTTCTTCCGAGGGCGG
GESPGGSSGSESGSS TCCAGGTTCTTCCGAAAGCGGTTCTTC
ESGSSEGGPGSGGEP TGAAGGCGGTCCAGGTTCTGGTGGCG
SESGSSGSEGSSGPG AACCGTCCGAGTCTGGTAGCTCAGGT
ESSGSSESGSSEGGP GAATCTCCGGGTGGCTCTAGCGGTTC
GSGGEPSESGSSGSS CGAGTCAGGTGAATCTCCTGGTGGTT
ESGSSEGGPGSGGEP CCAGCGGTTCCGAGTCAGGTTCCGGT
SESGSSGESPGGSSG GGCGAACCGTCCGAATCTGGTAGCTC
SESGESPGGSSGSES AGGTAGCGAAGGTTCTTCTGGTCCAG
GSSESGSSEGGPGSG GCGAATCTTCAGGTTCCTCTGAAAGC
GEPSESGSSGSSESGS GGTTCTTCTGAGGGCGGTCCAGGTTCC
SEGGPGSGGEPSESG GGTGGCGAACCGTCCGAATCTGGTAG
SSGSGGEPSESGSSG CTCAGGTAGCGAAGGTTCTTCTGGTCC
ESPGGSSGSESGSEG AGGCGAATCTTCAGGTTCCTCTGAAA
SSGPGESSGSSESGSS GCGGTTCTTCTGAGGGCGGTCCAGGT
EGGPGSEGSSGPGES TCCGGTGGCGAACCTTCCGAATCTGG
SGFPTIPLSRLFDNA TAGCTCAGGTGAATCTCCGGGTGGTT
MLRAHRLHQLAFDT CTAGCGGTTCTGAGTCAGGTTCTGGTG
YQEFEEAYIPKEQKY GTGAACCTTCCGAGTCTGGTAGCTCA
SFLQNPQTSLCFSESI GGTTCTGGTGGCGAACCATCCGAGTC
PTPSNREETQQKSNL TGGTAGCTCAGGTTCTTCCGAAAGCG
ELLRISLLLIQSWLEP GTTCTTCCGAAGGCGGTCCAGGTTCTG
VQFLRSVFANSLVY GTGGTGAACCGTCCGAATCTGGTAGC
GASDSNVYDLLKDL TCAGGTTCTGGTGGCGAACCATCCGA
EEGIQTLMGRLEDGS ATCTGGTAGCTCAGGTAGCGAAGGTT
PRTGQIFKQTYSKFD CTTCTGGTCCTGGCGAATCTTCAGGTG
TNSHNDDALLKNYG AATCTCCAGGTGGCTCTAGCGGTTCC
LLYCFRKDMDKVET GAATCAGGTAGCGAAGGTTCTTCCGG
FLRIVQCRSVEGSCG TCCAGGTGAATCTTCAGGTAGCGAAG
FGGSEPATSGSETPG GTTCTTCTGGTCCTGGTGAATCCTCAG
TSESATPESGPGSEP GTTCCGGTGGCGAACCATCTGAATCT
ATSGSETPGSPAGSP GGTAGCTCAGGTTCCTCTGAAAGCGG
TSTEEGTSTEPSEGS TTCTTCCGAAGGTGGTCCAGGTTCCTC
APGSEPATSGSETPG TGAAAGCGGTTCTTCTGAGGGTGGTC
SEPATSGSETPGSEP CAGGTGAATCTCCGGGTGGCTCCAGC
ATSGSETPGTSTEPSE GGTTCCGAGTCAGGTTCTGGTGGCGA
GSAPGTSESATPESG ACCATCCGAATCTGGTAGCTCAGGTA
PGSEPATSGSETPGT GCGAAGGTTCTTCTGGTCCTGGCGAA
STEPSEGSAP TCTTCAGGTGAATCTCCAGGTGGCTCT
AGCGGTTCCGAATCAGGTAGCGAAGG
TTCTTCCGGTCCTGGTGAGTCTTCAGG
TGAATCTCCAGGTGGCTCTAGCGGTTC
CGAGTCAGGTAGCGAAGGTTCTTCTG
GTCCTGGCGAGTCCTCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAG
GAATTTGAAGAAGCcTACATTCCTAAA
GAGCAGAAGTACTCTTTCCTGCAAAA
CCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGA
GGAAACTCAGCAAAAGTCCAATCTGG
AACTACTCCGCATTTCTCTGCTTCTGA
TTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTCTTCGCCAATAGC
CTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCG
AGGAAGGCATTCAGACCCTGATGGGT
CGTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AE576- GSPAGSPTSTEEGTS 741 GGTAGCCCGGCTGGCTCTCCTACCTCT 742
hGH- ESATPESGPGTSTEPS ACTGAGGAAGGTACTTCTGAAAGCGC
AE144 EGSAPGSPAGSPTST TACTCCTGAGTCTGGTCCAGGTACCTC
EEGTSTEPSEGSAPG TACTGAACCGTCCGAAGGTAGCGCTC
TSTEPSEGSAPGTSES CAGGTAGCCCAGCAGGCTCTCCGACT
ATPESGPGSEPATSG TCCACTGAGGAAGGTACTTCTACTGA
SETPGSEPATSGSETP ACCTTCCGAAGGCAGCGCACCAGGTA
GSPAGSPTSTEEGTS CCTCTACTGAACCTTCTGAGGGCAGC
ESATPESGPGTSTEPS GCTCCAGGTACTTCTGAAAGCGCTAC
EGSAPGTSTEPSEGS CCCGGAATCTGGCCCAGGTAGCGAAC
APGSPAGSPTSTEEG CGGCTACTTCTGGTTCTGAAACCCCAG
TSTEPSEGSAPGTSTE GTAGCGAACCGGCTACCTCCGGTTCT
PSEGSAPGTSESATP GAAACTCCAGGTAGCCCGGCAGGCTC
ESGPGTSTEPSEGSA TCCGACCTCTACTGAGGAAGGTACTT
PGTSESATPESGPGS CTGAAAGCGCAACCCCGGAGTCCGGC
EPATSGSETPGTSTEP CCAGGTACCTCTACCGAACCGTCTGA
SEGSAPGTSTEPSEG GGGCAGCGCACCAGGTACTTCTACCG
SAPGTSESATPESGP AACCGTCCGAGGGTAGCGCACCAGGT
GTSESATPESGPGSP AGCCCAGCAGGTTCTCCTACCTCCACC
AGSPTSTEEGTSESA GAGGAAGGTACTTCTACCGAACCGTC
TPESGPGSEPATSGS CGAGGGTAGCGCACCAGGTACCTCTA
ETPGTSESATPESGP CTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACC
EGSAPGTSTEPSEGS GTCCGAAGGTAGCGCACCAGGTACTT
APGTSTEPSEGSAPG CTGAAAGCGCAACCCCTGAATCCGGT
TSTEPSEGSAPGSPA CCAGGTAGCGAACCGGCTACTTCTGG
GSPTSTEEGTSTEPSE CTCTGAGACTCCAGGTACTTCTACCGA
GSAPGTSESATPESG ACCGTCCGAAGGTAGCGCACCAGGTA
PGSEPATSGSETPGT CTTCTACTGAACCGTCTGAAGGTAGC
SESATPESGPGSEPA GCACCAGGTACTTCTGAAAGCGCAAC
TSGSETPGTSESATPE CCCGGAATCCGGCCCAGGTACCTCTG
SGPGTSTEPSEGSAP AAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSP GGTAGCCCTGCTGGCTCTCCAACCTCC
AGSPTSTEEGSPAGS ACCGAAGAAGGTACCTCTGAAAGCGC
PTSTEEGSPAGSPTST AACCCCTGAATCCGGCCCAGGTAGCG
EEGTSESATPESGPG AACCGGCAACCTCCGGTTCTGAAACC
TSTEPSEGSAPGFPTI CCAGGTACCTCTGAAAGCGCTACTCC
PLSRLFDNAMLRAH GGAGTCTGGCCCAGGTACCTCTACTG
RLHQLAFDTYQEFEE AACCGTCTGAGGGTAGCGCTCCAGGT
AYIPKEQKYSFLQNP ACTTCTACTGAACCGTCCGAAGGTAG
QTSLCFSESIPTPSNR CGCACCAGGTACTTCTACCGAACCGT
EETQQKSNLELLRIS CCGAAGGCAGCGCTCCAGGTACCTCT
LLLIQSWLEPVQFLR ACTGAACCTTCCGAGGGCAGCGCTCC
SVFANSLVYGASDS AGGTACCTCTACCGAACCTTCTGAAG
NVYDLLKDLEEGIQT GTAGCGCACCAGGTACTTCTACCGAA
LMGRLEDGSPRTGQI CCGTCCGAGGGTAGCGCACCAGGTAG
FKQTYSKFDTNSHN CCCAGCAGGTTCTCCTACCTCCACCGA
DDALLKNYGLLYCF GGAAGGTACTTCTACCGAACCGTCCG
RKDMDKVETFLRIV AGGGTAGCGCACCAGGTACCTCTGAA
QCRSVEGSCGFGGSE AGCGCAACTCCTGAGTCTGGCCCAGG
PATSGSETPGTSESA TAGCGAACCTGCTACCTCCGGCTCTG
TPESGPGSEPATSGS AGACTCCAGGTACCTCTGAAAGCGCA
ETPGSPAGSPTSTEE ACCCCGGAATCTGGTCCAGGTAGCGA
GTSTEPSEGSAPGSE ACCTGCAACCTCTGGCTCTGAAACCC
PATSGSETPGSEPAT CAGGTACCTCTGAAAGCGCTACTCCT
SGSETPGSEPATSGS GAATCTGGCCCAGGTACTTCTACTGA
ETPGTSTEPSEGSAP ACCGTCCGAGGGCAGCGCACCAGGTA
GTSESATPESGPGSE CTTCTGAAAGCGCTACTCCTGAGTCCG
PATSGSETPGTSTEPS GCCCAGGTAGCCCGGCTGGCTCTCCG
EGSAP ACTTCCACCGAGGAAGGTAGCCCGGC
TGGCTCTCCAACTTCTACTGAAGAAG
GTAGCCCGGCAGGCTCTCCGACCTCT
ACTGAGGAAGGTACTTCTGAAAGCGC
AACCCCGGAGTCCGGCCCAGGTACCT
CTACCGAACCGTCTGAGGGCAGCGCA
CCAGGTTTTCCGACTATTCCGCTGTCT
CGTCTGTTTGATAATGCTATGCTGCGT
GCGCACCGTCTGCACCAGCTGGCCTTT
GATACTTACCAGGAATTTGAAGAAGC
cTACATTCCTAAAGAGCAGAAGTACTC
TTTCCTGCAAAACCCACAGACTTCTCT
CTGCTTCAGCGAATCTATTCCGACGCC
TTCCAATCGCGAGGAAACTCAGCAAA
AGTCCAATCTGGAACTACTCCGCATTT
CTCTGCTTCTGATTCAGAGCTGGCTAG
AACCAGTGCAATTTCTGCGTTCCGTCT
TCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTG
AAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCT
CTCCGCGTACTGGTCAGATCTTCAAGC
AGACTTACTCTAAATTTGATACTAACA
GCCACAATGACGATGCGCTTCTAAAA
AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTAGCGAACCGGCAACTTCCGGCTCT
GAAACCCCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCTGGCCCAGGTAGCG
AACCTGCTACCTCTGGCTCTGAAACCC
CAGGTAGCCCGGCAGGCTCTCCGACT
TCCACCGAGGAAGGTACCTCTACTGA
ACCTTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCTGGCTCTGAA
ACCCCAGGTAGCGAACCTGCTACCTC
CGGCTCTGAAACTCCAGGTAGCGAAC
CGGCTACTTCCGGTTCTGAAACTCCAG
GTACCTCTACCGAACCTTCCGAAGGC
AGCGCACCAGGTACTTCTGAAAGCGC
AACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTC
CAGGTACTTCTACCGAACCGTCCGAA
GGTAGCGCACCA
AF576- GSTSSTAESPGPGSTS 743 GGTTCTACTAGCTCTACCGCTGAATCT 744
hGH- STAESPGPGSTSESPS CCTGGCCCAGGTTCCACTAGCTCTACC
AE144 GTAPGSTSSTAESPG GCAGAATCTCCGGGCCCAGGTTCTAC
PGSTSSTAESPGPGTS TAGCGAATCCCCTTCTGGTACCGCTCC
TPESGSASPGSTSESP AGGTTCTACTAGCTCTACCGCTGAATC
SGTAPGTSPSGESST TCCGGGTCCAGGTTCTACCAGCTCTAC
APGSTSESPSGTAPG TGCAGAATCTCCTGGCCCAGGTACTTC
STSESPSGTAPGTSPS TACTCCGGAAAGCGGTTCCGCTTCTCC
GESSTAPGSTSESPSG AGGTTCTACCAGCGAATCTCCTTCTGG
TAPGSTSESPSGTAP CACCGCTCCAGGTACCTCTCCTAGCG
GTSPSGESSTAPGSTS GCGAATCTTCTACCGCTCCAGGTTCTA
ESPSGTAPGSTSESPS CTAGCGAATCTCCTTCTGGCACTGCAC
GTAPGSTSESPSGTA CAGGTTCTACCAGCGAATCTCCTTCTG
PGTSTPESGSASPGST GCACCGCTCCAGGTACCTCTCCTAGC
SESPSGTAPGTSTPES GGCGAATCTTCTACCGCTCCAGGTTCT
GSASPGSTSSTAESP ACTAGCGAATCTCCTTCTGGCACTGCA
GPGSTSSTAESPGPG CCAGGTTCTACCAGCGAATCTCCTTCT
TSTPESGSASPGTSTP GGCACCGCTCCAGGTACCTCTCCTAG
ESGSASPGSTSESPSG CGGCGAATCTTCTACCGCTCCAGGTTC
TAPGTSTPESGSASP TACTAGCGAATCTCCTTCTGGCACTGC
GTSTPESGSASPGSTS ACCAGGTTCTACTAGCGAATCTCCTTC
ESPSGTAPGSTSESPS TGGCACTGCACCAGGTTCTACCAGCG
GTAPGSTSESPSGTA AATCTCCGTCTGGCACTGCACCAGGT
PGSTSSTAESPGPGTS ACCTCTACCCCTGAAAGCGGTTCCGCT
TPESGSASPGTSTPES TCTCCAGGTTCTACTAGCGAATCTCCT
GSASPGSTSESPSGT TCTGGTACCGCTCCAGGTACTTCTACC
APGSTSESPSGTAPG CCTGAAAGCGGCTCCGCTTCTCCAGG
TSTPESGSASPGSTSE TTCCACTAGCTCTACCGCTGAATCTCC
SPSGTAPGSTSESPSG GGGTCCAGGTTCTACTAGCTCTACTGC
TAPGTSTPESGSASP AGAATCTCCTGGCCCAGGTACCTCTA
GTSPSGESSTAPGSTS CTCCGGAAAGCGGCTCTGCATCTCCA
STAESPGPGTSPSGES GGTACTTCTACCCCTGAAAGCGGTTCT
STAPGSTSSTAESPGP GCATCTCCAGGTTCTACTAGCGAATCC
GTSTPESGSASPGSTS CCGTCTGGTACCGCACCAGGTACTTCT
ESPSGTAPGSTSSTA ACCCCGGAAAGCGGCTCTGCTTCTCC
ESPGPGTSTPESGSAS AGGTACTTCTACCCCGGAAAGCGGCT
PGTSTPESGSASPGFP CCGCATCTCCAGGTTCTACTAGCGAAT
TIPLSRLFDNAMLRA CTCCTTCTGGTACCGCTCCAGGTTCTA
HRLHQLAFDTYQEF CCAGCGAATCCCCGTCTGGTACTGCTC
EEAYIPKEQKYSFLQ CAGGTTCTACCAGCGAATCTCCTTCTG
NPQTSLCFSESIPTPS GTACTGCACCAGGTTCTACTAGCTCTA
NREETQQKSNLELLR CTGCAGAATCTCCTGGCCCAGGTACC
ISLLLIQSWLEPVQFL TCTACTCCGGAAAGCGGCTCTGCATCT
RSVFANSLVYGASD CCAGGTACTTCTACCCCTGAAAGCGG
SNVYDLLKDLEEGIQ TTCTGCATCTCCAGGTTCTACTAGCGA
TLMGRLEDGSPRTG ATCTCCTTCTGGCACTGCACCAGGTTC
QIFKQTYSKFDTNSH TACCAGCGAATCTCCGTCTGGCACTG
NDDALLKNYGLLYC CACCAGGTACCTCTACCCCTGAAAGC
FRKDMDKVETFLRI GGTTCCGCTTCTCCAGGTTCTACTAGC
VQCRSVEGSCGFGG GAATCTCCTTCTGGCACTGCACCAGGT
SEPATSGSETPGTSES TCTACCAGCGAATCTCCGTCTGGCACT
ATPESGPGSEPATSG GCACCAGGTACCTCTACCCCTGAAAG
SETPGSPAGSPTSTEE CGGTTCCGCTTCTCCAGGTACTTCTCC
GTSTEPSEGSAPGSE GAGCGGTGAATCTTCTACCGCACCAG
PATSGSETPGSEPAT GTTCTACTAGCTCTACCGCTGAATCTC
SGSETPGSEPATSGS CGGGCCCAGGTACTTCTCCGAGCGGT
ETPGTSTEPSEGSAP GAATCTTCTACTGCTCCAGGTTCCACT
GTSESATPESGPGSE AGCTCTACTGCTGAATCTCCTGGCCCA
PATSGSETPGTSTEPS GGTACTTCTACTCCGGAAAGCGGTTC
EGSAP CGCTTCTCCAGGTTCTACTAGCGAATC
TCCGTCTGGCACCGCACCAGGTTCTAC
TAGCTCTACTGCAGAATCTCCTGGCCC
AGGTACCTCTACTCCGGAAAGCGGCT
CTGCATCTCCAGGTACTTCTACCCCTG
AAAGCGGTTCTGCATCTCCAGGTTTTC
CGACTATTCCGCTGTCTCGTCTGTTTG
ATAATGCTATGCTGCGTGCGCACCGT
CTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCT
AAAGAGCAGAAGTACTCTTTCCTGCA
AAACCCACAGACTTCTCTCTGCTTCAG
CGAATCTATTCCGACGCCTTCCAATCG
CGAGGAAACTCAGCAAAAGTCCAATC
TGGAACTACTCCGCATTTCTCTGCTTC
TGATTCAGAGCTGGCTAGAACCAGTG
CAATTTCTGCGTTCCGTCTTCGCCAAT
AGCCTAGTTTATGGCGCATCCGACAG
CAACGTATACGATCTCCTGAAAGATC
TCGAGGAAGGCATTCAGACCCTGATG
GGTCGTCTCGAGGATGGCTCTCCGCG
TACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCAC
AATGACGATGCGCTTCTAAAAAACTA
TGGTCTGCTGTATTGTTTTCGTAAAGA
TATGGACAAAGTTGAAACCTTCCTGC
GTATTGTTCAGTGTCGTTCCGTTGAGG
GCAGCTGTGGTTTCTAAGGTGGTAGC
GAACCGGCAACTTCCGGCTCTGAAAC
CCCAGGTACTTCTGAAAGCGCTACTC
CTGAGTCTGGCCCAGGTAGCGAACCT
GCTACCTCTGGCTCTGAAACCCCAGG
TAGCCCGGCAGGCTCTCCGACTTCCA
CCGAGGAAGGTACCTCTACTGAACCT
TCTGAGGGTAGCGCTCCAGGTAGCGA
ACCGGCAACCTCTGGCTCTGAAACCC
CAGGTAGCGAACCTGCTACCTCCGGC
TCTGAAACTCCAGGTAGCGAACCGGC
TACTTCCGGTTCTGAAACTCCAGGTAC
CTCTACCGAACCTTCCGAAGGCAGCG
CACCAGGTACTTCTGAAAGCGCAACC
CCTGAATCCGGTCCAGGTAGCGAACC
GGCTACTTCTGGCTCTGAGACTCCAG
GTACTTCTACCGAACCGTCCGAAGGT
AGCGCACCA
AE624- MAEPAGSPTSTEEGT 745 ATGGCTGAACCTGCTGGCTCTCCAAC 746
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE144 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGSPAGSPTSTEE GCTCTACCCCTTCTGGTGCAACCGGCT
GTSESATPESGPGTS CTCCAGGTGCTTCTCCGGGCACCAGCT
TEPSEGSAPGSPAGS CTACCGGTTCTCCAGGTAGCCCGGCT
PTSTEEGTSTEPSEGS GGCTCTCCTACCTCTACTGAGGAAGG
APGTSTEPSEGSAPG TACTTCTGAAAGCGCTACTCCTGAGTC
TSESATPESGPGSEP TGGTCCAGGTACCTCTACTGAACCGTC
ATSGSETPGSEPATS CGAAGGTAGCGCTCCAGGTAGCCCAG
GSETPGSPAGSPTST CAGGCTCTCCGACTTCCACTGAGGAA
EEGTSESATPESGPG GGTACTTCTACTGAACCTTCCGAAGG
TSTEPSEGSAPGTSTE CAGCGCACCAGGTACCTCTACTGAAC
PSEGSAPGSPAGSPT CTTCTGAGGGCAGCGCTCCAGGTACT
STEEGTSTEPSEGSAP TCTGAAAGCGCTACCCCGGAATCTGG
GTSTEPSEGSAPGTS CCCAGGTAGCGAACCGGCTACTTCTG
ESATPESGPGTSTEPS GTTCTGAAACCCCAGGTAGCGAACCG
EGSAPGTSESATPES GCTACCTCCGGTTCTGAAACTCCAGGT
GPGSEPATSGSETPG AGCCCGGCAGGCTCTCCGACCTCTAC
TSTEPSEGSAPGTSTE TGAGGAAGGTACTTCTGAAAGCGCAA
PSEGSAPGTSESATP CCCCGGAGTCCGGCCCAGGTACCTCT
ESGPGTSESATPESG ACCGAACCGTCTGAGGGCAGCGCACC
PGSPAGSPTSTEEGT AGGTACTTCTACCGAACCGTCCGAGG
SESATPESGPGSEPA GTAGCGCACCAGGTAGCCCAGCAGGT
TSGSETPGTSESATPE TCTCCTACCTCCACCGAGGAAGGTAC
SGPGTSTEPSEGSAP TTCTACCGAACCGTCCGAGGGTAGCG
GTSTEPSEGSAPGTS CACCAGGTACCTCTACTGAACCTTCTG
TEPSEGSAPGTSTEPS AGGGCAGCGCTCCAGGTACTTCTGAA
EGSAPGTSTEPSEGS AGCGCTACCCCGGAGTCCGGTCCAGG
APGTSTEPSEGSAPG TACTTCTACTGAACCGTCCGAAGGTA
SPAGSPTSTEEGTSTE GCGCACCAGGTACTTCTGAAAGCGCA
PSEGSAPGTSESATP ACCCCTGAATCCGGTCCAGGTAGCGA
ESGPGSEPATSGSET ACCGGCTACTTCTGGCTCTGAGACTCC
PGTSESATPESGPGS AGGTACTTCTACCGAACCGTCCGAAG
EPATSGSETPGTSES GTAGCGCACCAGGTACTTCTACTGAA
ATPESGPGTSTEPSE CCGTCTGAAGGTAGCGCACCAGGTAC
GSAPGTSESATPESG TTCTGAAAGCGCAACCCCGGAATCCG
PGSPAGSPTSTEEGSP GCCCAGGTACCTCTGAAAGCGCAACC
AGSPTSTEEGSPAGS CCGGAGTCCGGCCCAGGTAGCCCTGC
PTSTEEGTSESATPES TGGCTCTCCAACCTCCACCGAAGAAG
GPGTSTEPSEGSAPG GTACCTCTGAAAGCGCAACCCCTGAA
FPTIPLSRLFDNAML TCCGGCCCAGGTAGCGAACCGGCAAC
RAHRLHQLAFDTYQ CTCCGGTTCTGAAACCCCAGGTACCTC
EFEEAYIPKEQKYSF TGAAAGCGCTACTCCGGAGTCTGGCC
LQNPQTSLCFSESIPT CAGGTACCTCTACTGAACCGTCTGAG
PSNREETQQKSNLEL GGTAGCGCTCCAGGTACTTCTACTGA
LRISLLLIQSWLEPVQ ACCGTCCGAAGGTAGCGCACCAGGTA
FLRSVFANSLVYGAS CTTCTACCGAACCGTCCGAAGGCAGC
DSNVYDLLKDLEEGI GCTCCAGGTACCTCTACTGAACCTTCC
QTLMGRLEDGSPRT GAGGGCAGCGCTCCAGGTACCTCTAC
GQIFKQTYSKFDTNS CGAACCTTCTGAAGGTAGCGCACCAG
HNDDALLKNYGLLY GTACTTCTACCGAACCGTCCGAGGGT
CFRKDMDKVETFLRI AGCGCACCAGGTAGCCCAGCAGGTTC
VQCRSVEGSCGFGG TCCTACCTCCACCGAGGAAGGTACTT
SEPATSGSETPGTSES CTACCGAACCGTCCGAGGGTAGCGCA
ATPESGPGSEPATSG CCAGGTACCTCTGAAAGCGCAACTCC
SETPGSPAGSPTSTEE TGAGTCTGGCCCAGGTAGCGAACCTG
GTSTEPSEGSAPGSE CTACCTCCGGCTCTGAGACTCCAGGT
PATSGSETPGSEPAT ACCTCTGAAAGCGCAACCCCGGAATC
SGSETPGSEPATSGS TGGTCCAGGTAGCGAACCTGCAACCT
ETPGTSTEPSEGSAP CTGGCTCTGAAACCCCAGGTACCTCT
GTSESATPESGPGSE GAAAGCGCTACTCCTGAATCTGGCCC
PATSGSETPGTSTEPS AGGTACTTCTACTGAACCGTCCGAGG
EGSAP GCAGCGCACCAGGTACTTCTGAAAGC
GCTACTCCTGAGTCCGGCCCAGGTAG
CCCGGCTGGCTCTCCGACTTCCACCGA
GGAAGGTAGCCCGGCTGGCTCTCCAA
CTTCTACTGAAGAAGGTAGCCCGGCA
GGCTCTCCGACCTCTACTGAGGAAGG
TACTTCTGAAAGCGCAACCCCGGAGT
CCGGCCCAGGTACCTCTACCGAACCG
TCTGAGGGCAGCGCACCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGA
TAATGCTATGCTGCGTGCGCACCGTCT
GCACCAGCTGGCCTTTGATACTTACCA
GGAATTTGAAGAAGCcTACATTCCTAA
AGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCG
AATCTATTCCGACGCCTTCCAATCGCG
AGGAAACTCAGCAAAAGTCCAATCTG
GAACTACTCCGCATTTCTCTGCTTCTG
ATTCAGAGCTGGCTAGAACCAGTGCA
ATTTCTGCGTTCCGTCTTCGCCAATAG
CCTAGTTTATGGCGCATCCGACAGCA
ACGTATACGATCTCCTGAAAGATCTC
GAGGAAGGCATTCAGACCCTGATGGG
TCGTCTCGAGGATGGCTCTCCGCGTAC
TGGTCAGATCTTCAAGCAGACTTACTC
TAAATTTGATACTAACAGCCACAATG
ACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATG
GACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AD836- GSSESGSSEGGPGSS 747 GGTTCCTCTGAAAGCGGTTCTTCCGAA 748
hGH- ESGSSEGGPGESPGG GGTGGTCCAGGTTCCTCTGAAAGCGG
AE144 SSGSESGSGGEPSES TTCTTCTGAGGGTGGTCCAGGTGAATC
GSSGESPGGSSGSES TCCGGGTGGCTCCAGCGGTTCCGAGT
GESPGGSSGSESGSS CAGGTTCTGGTGGCGAACCTTCCGAG
ESGSSEGGPGSSESG TCTGGTAGCTCAGGTGAATCTCCGGG
SSEGGPGSSESGSSE TGGTTCTAGCGGTTCCGAGTCAGGTG
GGPGESPGGSSGSES AATCTCCGGGTGGTTCCAGCGGTTCTG
GESPGGSSGSESGES AGTCAGGTTCCTCCGAAAGCGGTTCTT
PGGSSGSESGSSESG CTGAGGGCGGTCCAGGTTCCTCCGAA
SSEGGPGSSESGSSE AGCGGTTCTTCCGAGGGCGGTCCAGG
GGPGSSESGSSEGGP TTCTTCTGAAAGCGGTTCTTCCGAGGG
GSSESGSSEGGPGSS CGGTCCAGGTGAATCTCCTGGTGGTTC
ESGSSEGGPGSSESG CAGCGGTTCCGAGTCAGGTGAATCTC
SSEGGPGSGGEPSES CAGGTGGCTCTAGCGGTTCCGAGTCA
GSSGESPGGSSGSES GGTGAATCTCCTGGTGGTTCTAGCGGT
GESPGGSSGSESGSG TCTGAATCAGGTTCCTCCGAAAGCGG
GEPSESGSSGSEGSS TTCTTCTGAGGGCGGTCCAGGTTCCTC
GPGESSGSSESGSSE CGAAAGCGGTTCTTCCGAGGGCGGTC
GGPGSGGEPSESGSS CAGGTTCTTCTGAAAGCGGTTCTTCCG
GSEGSSGPGESSGSS AGGGCGGTCCAGGTTCCTCTGAAAGC
ESGSSEGGPGSGGEP GGTTCTTCTGAGGGCGGTCCAGGTTCT
SESGSSGESPGGSSG TCCGAAAGCGGTTCTTCCGAGGGCGG
SESGSGGEPSESGSS TCCAGGTTCTTCCGAAAGCGGTTCTTC
GSGGEPSESGSSGSS TGAAGGCGGTCCAGGTTCTGGTGGCG
ESGSSEGGPGSGGEP AACCGTCCGAGTCTGGTAGCTCAGGT
SESGSSGSGGEPSES GAATCTCCGGGTGGCTCTAGCGGTTC
GSSGSEGSSGPGESS CGAGTCAGGTGAATCTCCTGGTGGTT
GESPGGSSGSESGSE CCAGCGGTTCCGAGTCAGGTTCCGGT
GSSGPGESSGSEGSS GGCGAACCGTCCGAATCTGGTAGCTC
GPGESSGSGGEPSES AGGTAGCGAAGGTTCTTCTGGTCCAG
GSSGSSESGSSEGGP GCGAATCTTCAGGTTCCTCTGAAAGC
GSSESGSSEGGPGES GGTTCTTCTGAGGGCGGTCCAGGTTCC
PGGSSGSESGSGGEP GGTGGCGAACCGTCCGAATCTGGTAG
SESGSSGSEGSSGPG CTCAGGTAGCGAAGGTTCTTCTGGTCC
ESSGESPGGSSGSES AGGCGAATCTTCAGGTTCCTCTGAAA
GSEGSSGPGSSESGS GCGGTTCTTCTGAGGGCGGTCCAGGT
SEGGPGSGGEPSESG TCCGGTGGCGAACCTTCCGAATCTGG
SSGSEGSSGPGESSG TAGCTCAGGTGAATCTCCGGGTGGTT
SEGSSGPGESSGSEG CTAGCGGTTCTGAGTCAGGTTCTGGTG
SSGPGESSGSGGEPS GTGAACCTTCCGAGTCTGGTAGCTCA
ESGSSGSGGEPSESG GGTTCTGGTGGCGAACCATCCGAGTC
SSGESPGGSSGSESG TGGTAGCTCAGGTTCTTCCGAAAGCG
ESPGGSSGSESGSGG GTTCTTCCGAAGGCGGTCCAGGTTCTG
EPSESGSSGSEGSSGP GTGGTGAACCGTCCGAATCTGGTAGC
GESSGESPGGSSGSE TCAGGTTCTGGTGGCGAACCATCCGA
SGSSESGSSEGGPGS ATCTGGTAGCTCAGGTAGCGAAGGTT
SESGSSEGGPGSSES CTTCTGGTCCTGGCGAATCTTCAGGTG
GSSEGGPGSGGEPSE AATCTCCAGGTGGCTCTAGCGGTTCC
SGSSGSSESGSSEGG GAATCAGGTAGCGAAGGTTCTTCCGG
PGESPGGSSGSESGS TCCAGGTGAATCTTCAGGTAGCGAAG
GGEPSESGSSGSSES GTTCTTCTGGTCCTGGTGAATCCTCAG
GSSEGGPGESPGGSS GTTCCGGTGGCGAACCATCTGAATCT
GSESGSGGEPSESGS GGTAGCTCAGGTTCCTCTGAAAGCGG
SGESPGGSSGSESGS TTCTTCCGAAGGTGGTCCAGGTTCCTC
GGEPSESGSSGFPTIP TGAAAGCGGTTCTTCTGAGGGTGGTC
LSRLFDNAMLRAHR CAGGTGAATCTCCGGGTGGCTCCAGC
LHQLAFDTYQEFEE GGTTCCGAGTCAGGTTCTGGTGGCGA
AYIPKEQKYSFLQNP ACCATCCGAATCTGGTAGCTCAGGTA
QTSLCFSESIPTPSNR GCGAAGGTTCTTCTGGTCCTGGCGAA
EETQQKSNLELLRIS TCTTCAGGTGAATCTCCAGGTGGCTCT
LLLIQSWLEPVQFLR AGCGGTTCCGAATCAGGTAGCGAAGG
SVFANSLVYGASDS TTCTTCCGGTCCaGGTTCCTCTGAAAG
NVYDLLKDLEEGIQT CGGTTCTTCTGAGGGCGGTCCAGGTTC
LMGRLEDGSPRTGQI TGGTGGCGAACCATCTGAATCTGGTA
FKQTYSKFDTNSHN GCTCAGGTAGCGAAGGTTCTTCCGGT
DDALLKNYGLLYCF CCGGGTGAATCTTCAGGTAGCGAAGG
RKDMDKVETFLRIV TTCTTCCGGTCCAGGTGAATCTTCAGG
QCRSVEGSCGFGGSE TAGCGAAGGTTCTTCTGGTCCTGGTGA
PATSGSETPGTSESA ATCCTCAGGTTCCGGTGGCGAACCAT
TPESGPGSEPATSGS CTGAATCTGGTAGCTCAGGTTCTGGTG
ETPGSPAGSPTSTEE GCGAACCATCCGAATCTGGTAGCTCA
GTSTEPSEGSAPGSE GGTGAATCTCCGGGTGGCTCCAGCGG
PATSGSETPGSEPAT TTCTGAATCAGGTGAATCTCCTGGTGG
SGSETPGSEPATSGS CTCCAGCGGTTCTGAGTCAGGTTCTGG
ETPGTSTEPSEGSAP TGGCGAACCATCCGAATCTGGTAGCT
GTSESATPESGPGSE CAGGTAGCGAAGGTTCTTCTGGTCCT
PATSGSETPGTSTEPS GGCGAATCTTCAGGTGAATCTCCAGG
EGSAP TGGCTCTAGCGGTTCCGAATCAGGTTC
CTCTGAAAGCGGTTCTTCTGAGGGCG
GTCCAGGTTCTTCCGAAAGCGGTTCTT
CCGAGGGCGGTCCAGGTTCTTCCGAA
AGCGGTTCTTCTGAAGGCGGTCCAGG
TTCTGGTGGCGAACCGTCCGAATCTG
GTAGCTCAGGTTCCTCCGAAAGCGGT
TCTTCTGAAGGTGGTCCAGGTGAATCT
CCAGGTGGTTCTAGCGGTTCTGAATC
AGGTTCTGGTGGCGAACCGTCCGAAT
CTGGTAGCTCAGGTTCCTCCGAAAGC
GGTTCTTCTGAAGGTGGTCCAGGTGA
ATCTCCAGGTGGTTCTAGCGGTTCTGA
ATCAGGTTCTGGTGGCGAACCGTCCG
AATCTGGTAGCTCAGGTGAATCTCCT
GGTGGTTCCAGCGGTTCCGAGTCAGG
TTCTGGTGGCGAACCTTCCGAATCTGG
TAGCTCAGGTTTTCCGACTATTCCGCT
GTCTCGTCTGTTTGATAATGCTATGCT
GCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAG
AAGCcTACATTCCTAAAGAGCAGAAG
TACTCTTTCCTGCAAAACCCACAGACT
TCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCA
GCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCT
GGCTAGAACCAGTGCAATTTCTGCGT
TCCGTCTTCGCCAATAGCCTAGTTTAT
GGCGCATCCGACAGCAACGTATACGA
TCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGAT
CTTCAAGCAGACTTACTCTAAATTTGA
TACTAACAGCCACAATGACGATGCGC
TTCTAAAAAACTATGGTCTGCTGTATT
GTTTTCGTAAAGATATGGACAAAGTT
GAAACCTTCCTGCGTATTGTTCAGTGT
CGTTCCGTTGAGGGCAGCTGTGGTTTC
TAAGGTGGTAGCGAACCGGCAACTTC
CGGCTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCTGGCTCT
GAAACCCCAGGTAGCCCGGCAGGCTC
TCCGACTTCCACCGAGGAAGGTACCT
CTACTGAACCTTCTGAGGGTAGCGCT
CCAGGTAGCGAACCGGCAACCTCTGG
CTCTGAAACCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAAACTCCAGGT
AGCGAACCGGCTACTTCCGGTTCTGA
AACTCCAGGTACCTCTACCGAACCTTC
CGAAGGCAGCGCACCAGGTACTTCTG
AAAGCGCAACCCCTGAATCCGGTCCA
GGTAGCGAACCGGCTACTTCTGGCTC
TGAGACTCCAGGTACTTCTACCGAAC
CGTCCGAAGGTAGCGCACCA
AE864- GSPAGSPTSTEEGTS 749 GGTAGCCCGGCTGGCTCTCCTACCTCT 750
hGH- ESATPESGPGTSTEPS ACTGAGGAAGGTACTTCTGAAAGCGC
AE144 EGSAPGSPAGSPTST TACTCCTGAGTCTGGTCCAGGTACCTC
EEGTSTEPSEGSAPG TACTGAACCGTCCGAAGGTAGCGCTC
TSTEPSEGSAPGTSES CAGGTAGCCCAGCAGGCTCTCCGACT
ATPESGPGSEPATSG TCCACTGAGGAAGGTACTTCTACTGA
SETPGSEPATSGSETP ACCTTCCGAAGGCAGCGCACCAGGTA
GSPAGSPTSTEEGTS CCTCTACTGAACCTTCTGAGGGCAGC
ESATPESGPGTSTEPS GCTCCAGGTACTTCTGAAAGCGCTAC
EGSAPGTSTEPSEGS CCCGGAATCTGGCCCAGGTAGCGAAC
APGSPAGSPTSTEEG CGGCTACTTCTGGTTCTGAAACCCCAG
TSTEPSEGSAPGTSTE GTAGCGAACCGGCTACCTCCGGTTCT
PSEGSAPGTSESATP GAAACTCCAGGTAGCCCGGCAGGCTC
ESGPGTSTEPSEGSA TCCGACCTCTACTGAGGAAGGTACTT
PGTSESATPESGPGS CTGAAAGCGCAACCCCGGAGTCCGGC
EPATSGSETPGTSTEP CCAGGTACCTCTACCGAACCGTCTGA
SEGSAPGTSTEPSEG GGGCAGCGCACCAGGTACTTCTACCG
SAPGTSESATPESGP AACCGTCCGAGGGTAGCGCACCAGGT
GTSESATPESGPGSP AGCCCAGCAGGTTCTCCTACCTCCACC
AGSPTSTEEGTSESA GAGGAAGGTACTTCTACCGAACCGTC
TPESGPGSEPATSGS CGAGGGTAGCGCACCAGGTACCTCTA
ETPGTSESATPESGP CTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACC
EGSAPGTSTEPSEGS GTCCGAAGGTAGCGCACCAGGTACTT
APGTSTEPSEGSAPG CTGAAAGCGCAACCCCTGAATCCGGT
TSTEPSEGSAPGSPA CCAGGTAGCGAACCGGCTACTTCTGG
GSPTSTEEGTSTEPSE CTCTGAGACTCCAGGTACTTCTACCGA
GSAPGTSESATPESG ACCGTCCGAAGGTAGCGCACCAGGTA
PGSEPATSGSETPGT CTTCTACTGAACCGTCTGAAGGTAGC
SESATPESGPGSEPA GCACCAGGTACTTCTGAAAGCGCAAC
TSGSETPGTSESATPE CCCGGAATCCGGCCCAGGTACCTCTG
SGPGTSTEPSEGSAP AAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSP GGTAGCCCTGCTGGCTCTCCAACCTCC
AGSPTSTEEGSPAGS ACCGAAGAAGGTACCTCTGAAAGCGC
PTSTEEGSPAGSPTST AACCCCTGAATCCGGCCCAGGTAGCG
EEGTSESATPESGPG AACCGGCAACCTCCGGTTCTGAAACC
TSTEPSEGSAPGTSES CCAGGTACCTCTGAAAGCGCTACTCC
ATPESGPGSEPATSG GGAGTCTGGCCCAGGTACCTCTACTG
SETPGTSESATPESGP AACCGTCTGAGGGTAGCGCTCCAGGT
GSEPATSGSETPGTS ACTTCTACTGAACCGTCCGAAGGTAG
ESATPESGPGTSTEPS CGCACCAGGTACTTCTACCGAACCGT
EGSAPGSPAGSPTST CCGAAGGCAGCGCTCCAGGTACCTCT
EEGTSESATPESGPG ACTGAACCTTCCGAGGGCAGCGCTCC
SEPATSGSETPGTSES AGGTACCTCTACCGAACCTTCTGAAG
ATPESGPGSPAGSPT GTAGCGCACCAGGTACTTCTACCGAA
STEEGSPAGSPTSTEE CCGTCCGAGGGTAGCGCACCAGGTAG
GTSTEPSEGSAPGTS CCCAGCAGGTTCTCCTACCTCCACCGA
ESATPESGPGTSESA GGAAGGTACTTCTACCGAACCGTCCG
TPESGPGTSESATPES AGGGTAGCGCACCAGGTACCTCTGAA
GPGSEPATSGSETPG AGCGCAACTCCTGAGTCTGGCCCAGG
SEPATSGSETPGSPA TAGCGAACCTGCTACCTCCGGCTCTG
GSPTSTEEGTSTEPSE AGACTCCAGGTACCTCTGAAAGCGCA
GSAPGTSTEPSEGSA ACCCCGGAATCTGGTCCAGGTAGCGA
PGSEPATSGSETPGT ACCTGCAACCTCTGGCTCTGAAACCC
SESATPESGPGTSTEP CAGGTACCTCTGAAAGCGCTACTCCT
SEGSAPGFPTIPLSRL GAATCTGGCCCAGGTACTTCTACTGA
FDNAMLRAHRLHQL ACCGTCCGAGGGCAGCGCACCAGGTA
AFDTYQEFEEAYIPK CTTCTGAAAGCGCTACTCCTGAGTCCG
EQKYSFLQNPQTSLC GCCCAGGTAGCCCGGCTGGCTCTCCG
FSESIPTPSNREETQQ ACTTCCACCGAGGAAGGTAGCCCGGC
KSNLELLRISLLLIQS TGGCTCTCCAACTTCTACTGAAGAAG
WLEPVQFLRSVFAN GTAGCCCGGCAGGCTCTCCGACCTCT
SLVYGASDSNVYDL ACTGAGGAAGGTACTTCTGAAAGCGC
LKDLEEGIQTLMGRL AACCCCGGAGTCCGGCCCAGGTACCT
EDGSPRTGQIFKQTY CTACCGAACCGTCTGAGGGCAGCGCA
SKFDTNSHNDDALL CCAGGTACCTCTGAAAGCGCAACTCC
KNYGLLYCFRKDMD TGAGTCTGGCCCAGGTAGCGAACCTG
KVETFLRIVQCRSVE CTACCTCCGGCTCTGAGACTCCAGGT
GSCGFGGSEPATSGS ACCTCTGAAAGCGCAACCCCGGAATC
ETPGTSESATPESGP TGGTCCAGGTAGCGAACCTGCAACCT
GSEPATSGSETPGSP CTGGCTCTGAAACCCCAGGTACCTCT
AGSPTSTEEGTSTEPS GAAAGCGCTACTCCTGAATCTGGCCC
EGSAPGSEPATSGSE AGGTACTTCTACTGAACCGTCCGAGG
TPGSEPATSGSETPG GCAGCGCACCAGGTAGCCCTGCTGGC
SEPATSGSETPGTSTE TCTCCAACCTCCACCGAAGAAGGTAC
PSEGSAPGTSESATP CTCTGAAAGCGCAACCCCTGAATCCG
ESGPGSEPATSGSET GCCCAGGTAGCGAACCGGCAACCTCC
PGTSTEPSEGSAP GGTTCTGAAACCCCAGGTACTTCTGA
AAGCGCTACTCCTGAGTCCGGCCCAG
GTAGCCCGGCTGGCTCTCCGACTTCCA
CCGAGGAAGGTAGCCCGGCTGGCTCT
CCAACTTCTACTGAAGAAGGTACTTCT
ACCGAACCTTCCGAGGGCAGCGCACC
AGGTACTTCTGAAAGCGCTACCCCTG
AGTCCGGCCCAGGTACTTCTGAAAGC
GCTACTCCTGAATCCGGTCCAGGTACT
TCTGAAAGCGCTACCCCGGAATCTGG
CCCAGGTAGCGAACCGGCTACTTCTG
GTTCTGAAACCCCAGGTAGCGAACCG
GCTACCTCCGGTTCTGAAACTCCAGGT
AGCCCAGCAGGCTCTCCGACTTCCAC
TGAGGAAGGTACTTCTACTGAACCTT
CCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCC
AGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGC
ACCAGGTTTTCCGACTATTCCGCTGTC
TCGTCTGTTTGATAATGCTATGCTGCG
TGCGCACCGTCTGCACCAGCTGGCCTT
TGATACTTACCAGGAATTTGAAGAAG
CcTACATTCCTAAAGAGCAGAAGTACT
CTTTCCTGCAAAACCCACAGACTTCTC
TCTGCTTCAGCGAATCTATTCCGACGC
CTTCCAATCGCGAGGAAACTCAGCAA
AAGTCCAATCTGGAACTACTCCGCAT
TTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGT
CTTCGCCAATAGCCTAGTTTATGGCGC
ATCCGACAGCAACGTATACGATCTCC
TGAAAGATCTCGAGGAAGGCATTCAG
ACCCTGATGGGTCGTCTCGAGGATGG
CTCTCCGCGTACTGGTCAGATCTTCAA
GCAGACTTACTCTAAATTTGATACTAA
CAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTC
GTAAAGATATGGACAAAGTTGAAACC
TTCCTGCGTATTGTTCAGTGTCGTTCC
GTTGAGGGCAGCTGTGGTTTCTAAGG
TGGTAGCGAACCGGCAACTTCCGGCT
CTGAAACCCCAGGTACTTCTGAAAGC
GCTACTCCTGAGTCTGGCCCAGGTAG
CGAACCTGCTACCTCTGGCTCTGAAA
CCCCAGGTAGCCCGGCAGGCTCTCCG
ACTTCCACCGAGGAAGGTACCTCTAC
TGAACCTTCTGAGGGTAGCGCTCCAG
GTAGCGAACCGGCAACCTCTGGCTCT
GAAACCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAAACTCCAGGTAGCG
AACCGGCTACTTCCGGTTCTGAAACTC
CAGGTACCTCTACCGAACCTTCCGAA
GGCAGCGCACCAGGTACTTCTGAAAG
CGCAACCCCTGAATCCGGTCCAGGTA
GCGAACCGGCTACTTCTGGCTCTGAG
ACTCCAGGTACTTCTACCGAACCGTCC
GAAGGTAGCGCACCA
AF864- GSTSESPSGTAPGTSP 751 GGTTCTACCAGCGAATCTCCTTCTGGC 752
hGH- SGESSTAPGSTSESPS ACCGCTCCAGGTACCTCTCCTAGCGG
AE144 GTAPGSTSESPSGTA CGAATCTTCTACCGCTCCAGGTTCTAC
PGTSTPESGSASPGTS TAGCGAATCTCCTTCTGGCACTGCACC
TPESGSASPGSTSESP AGGTTCTACTAGCGAATCCCCGTCTG
SGTAPGSTSESPSGT GTACTGCTCCAGGTACTTCTACTCCTG
APGTSPSGESSTAPG AAAGCGGTTCCGCTTCTCCAGGTACCT
STSESPSGTAPGTSPS CTACTCCGGAAAGCGGTTCTGCATCTC
GESSTAPGTSPSGESS CAGGTTCTACCAGCGAATCTCCTTCTG
TAPGSTSSTAESPGP GCACCGCTCCAGGTTCTACTAGCGAA
GTSPSGESSTAPGTSP TCCCCGTCTGGTACCGCACCAGGTACT
SGESSTAPGSTSSTA TCTCCTAGCGGCGAATCTTCTACCGCA
ESPGPGTSTPESGSAS CCAGGTTCTACTAGCGAATCTCCGTCT
PGTSTPESGSASPGST GGCACTGCTCCAGGTACTTCTCCTAGC
SESPSGTAPGSTSESP GGTGAATCTTCTACCGCTCCAGGTACT
SGTAPGTSTPESGSA TCCCCTAGCGGCGAATCTTCTACCGCT
SPGSTSSTAESPGPGT CCAGGTTCTACTAGCTCTACTGCAGA
STPESGSASPGSTSES ATCTCCGGGCCCAGGTACCTCTCCTAG
PSGTAPGTSPSGESST CGGTGAATCTTCTACCGCTCCAGGTAC
APGSTSSTAESPGPG TTCTCCGAGCGGTGAATCTTCTACCGC
TSPSGESSTAPGTSTP TCCAGGTTCTACTAGCTCTACTGCAGA
ESGSASPGSTSSTAES ATCTCCTGGCCCAGGTACCTCTACTCC
PGPGSTSSTAESPGP GGAAAGCGGCTCTGCATCTCCAGGTA
GSTSSTAESPGPGSTS CTTCTACCCCTGAAAGCGGTTCTGCAT
STAESPGPGTSPSGES CTCCAGGTTCTACTAGCGAATCTCCTT
STAPGSTSESPSGTAP CTGGCACTGCACCAGGTTCTACCAGC
GSTSESPSGTAPGTS GAATCTCCGTCTGGCACTGCACCAGG
TPESGPXXXGASASG TACCTCTACCCCTGAAAGCGGTTCCGC
APSTXXXXSESPSGT TTCTCCAGGTTCTACCAGCTCTACCGC
APGSTSESPSGTAPG AGAATCTCCTGGTCCAGGTACCTCTAC
STSESPSGTAPGSTSE TCCGGAAAGCGGCTCTGCATCTCCAG
SPSGTAPGSTSESPSG GTTCTACTAGCGAATCTCCTTCTGGCA
TAPGSTSESPSGTAP CTGCACCAGGTACTTCTCCGAGCGGT
GTSTPESGSASPGTSP GAATCTTCTACCGCACCAGGTTCTACT
SGESSTAPGTSPSGES AGCTCTACCGCTGAATCTCCGGGCCC
STAPGSTSSTAESPGP AGGTACTTCTCCGAGCGGTGAATCTTC
GTSPSGESSTAPGTS TACTGCTCCAGGTACCTCTACTCCTGA
TPESGSASPGSTSESP AAGCGGTTCTGCATCTCCAGGTTCCAC
SGTAPGSTSESPSGT TAGCTCTACCGCAGAATCTCCGGGCC
APGTSPSGESSTAPG CAGGTTCTACTAGCTCTACTGCTGAAT
STSESPSGTAPGTSTP CTCCTGGCCCAGGTTCTACTAGCTCTA
ESGSASPGTSTPESGS CTGCTGAATCTCCGGGTCCAGGTTCTA
ASPGSTSESPSGTAP CCAGCTCTACTGCTGAATCTCCTGGTC
GTSTPESGSASPGSTS CAGGTACCTCCCCGAGCGGTGAATCT
STAESPGPGSTSESPS TCTACTGCACCAGGTTCTACTAGCGA
GTAPGSTSESPSGTA ATCTCCTTCTGGCACTGCACCAGGTTC
PGTSPSGESSTAPGST TACCAGCGAATCTCCGTCTGGCACTG
SSTAESPGPGTSPSGE CACCAGGTACCTCTACCCCTGAAAGC
SSTAPGTSTPESGSAS GGTCCXXXXXXXXXXXXTGCAAGCG
PGTSPSGESSTAPGTS CAAGCGGCGCGCCAAGCACGGGAXX
PSGESSTAPGTSPSGE XXXXXXTAGCGAATCTCCTTCTGGTA
SSTAPGSTSSTAESPG CCGCTCCAGGTTCTACCAGCGAATCC
PGSTSSTAESPGPGTS CCGTCTGGTACTGCTCCAGGTTCTACC
PSGESSTAPGSSPSAS AGCGAATCTCCTTCTGGTACTGCACCA
TGTGPGSSTPSGATG GGTTCTACTAGCGAATCTCCTTCTGGT
SPGSSTPSGATGSPG ACCGCTCCAGGTTCTACCAGCGAATC
FPTIPLSRLFDNAML CCCGTCTGGTACTGCTCCAGGTTCTAC
RAHRLHQLAFDTYQ CAGCGAATCTCCTTCTGGTACTGCACC
EFEEAYIPKEQKYSF AGGTACTTCTACTCCGGAAAGCGGTT
LQNPQTSLCFSESIPT CCGCATCTCCAGGTACTTCTCCTAGCG
PSNREETQQKSNLEL GTGAATCTTCTACTGCTCCAGGTACCT
LRISLLLIQSWLEPVQ CTCCTAGCGGCGAATCTTCTACTGCTC
FLRSVFANSLVYGAS CAGGTTCTACCAGCTCTACTGCTGAAT
DSNVYDLLKDLEEGI CTCCGGGTCCAGGTACTTCCCCGAGC
QTLMGRLEDGSPRT GGTGAATCTTCTACTGCACCAGGTACT
GQIFKQTYSKFDTNS TCTACTCCGGAAAGCGGTTCCGCTTCT
HNDDALLKNYGLLY CCAGGTTCTACCAGCGAATCTCCTTCT
CFRKDMDKVETFLRI GGCACCGCTCCAGGTTCTACTAGCGA
VQCRSVEGSCGFGG ATCCCCGTCTGGTACCGCACCAGGTA
SEPATSGSETPGTSES CTTCTCCTAGCGGCGAATCTTCTACCG
ATPESGPGSEPATSG CACCAGGTTCTACTAGCGAATCCCCG
SETPGSPAGSPTSTEE TCTGGTACCGCACCAGGTACTTCTACC
GTSTEPSEGSAPGSE CCGGAAAGCGGCTCTGCTTCTCCAGG
PATSGSETPGSEPAT TACTTCTACCCCGGAAAGCGGCTCCG
SGSETPGSEPATSGS CATCTCCAGGTTCTACTAGCGAATCTC
ETPGTSTEPSEGSAP CTTCTGGTACCGCTCCAGGTACTTCTA
GTSESATPESGPGSE CCCCTGAAAGCGGCTCCGCTTCTCCA
PATSGSETPGTSTEPS GGTTCCACTAGCTCTACCGCTGAATCT
EGSAP CCGGGTCCAGGTTCTACCAGCGAATC
TCCTTCTGGCACCGCTCCAGGTTCTAC
TAGCGAATCCCCGTCTGGTACCGCAC
CAGGTACTTCTCCTAGCGGCGAATCTT
CTACCGCACCAGGTTCTACCAGCTCTA
CTGCTGAATCTCCGGGTCCAGGTACTT
CCCCGAGCGGTGAATCTTCTACTGCA
CCAGGTACTTCTACTCCGGAAAGCGG
TTCCGCTTCTCCAGGTACCTCCCCTAG
CGGCGAATCTTCTACTGCTCCAGGTAC
CTCTCCTAGCGGCGAATCTTCTACCGC
TCCAGGTACCTCCCCTAGCGGTGAAT
CTTCTACCGCACCAGGTTCTACTAGCT
CTACTGCTGAATCTCCGGGTCCAGGTT
CTACCAGCTCTACTGCTGAATCTCCTG
GTCCAGGTACCTCCCCGAGCGGTGAA
TCTTCTACTGCACCAGGTTCTAGCCCT
TCTGCTTCCACCGGTACCGGCCCAGGT
AGCTCTACTCCGTCTGGTGCAACTGGC
TCTCCAGGTAGCTCTACTCCGTCTGGT
GCAACCGGCTCCCCAGGTTTTCCGACT
ATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCA
CCAGCTGGCCTTTGATACTTACCAGG
AATTTGAAGAAGCcTACATTCCTAAAG
AGCAGAAGTACTCTTTCCTGCAAAAC
CCACAGACTTCTCTCTGCTTCAGCGAA
TCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGA
ACTACTCCGCATTTCTCTGCTTCTGAT
TCAGAGCTGGCTAGAACCAGTGCAAT
TTCTGCGTTCCGTCTTCGCCAATAGCC
TAGTTTATGGCGCATCCGACAGCAAC
GTATACGATCTCCTGAAAGATCTCGA
GGAAGGCATTCAGACCCTGATGGGTC
GTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AG864- GASPGTSSTGSPGSS 753 GGTGCTTCCCCGGGCACCAGCTCTACT 754
hGH- PSASTGTGPGSSPSA GGTTCTCCAGGTTCTAGCCCGTCTGCT
AE144 STGTGPGTPGSGTAS TCTACTGGTACTGGTCCAGGTTCTAGC
SSPGSSTPSGATGSP CCTTCTGCTTCCACTGGTACTGGTCCA
GSNPSASTGTGPGAS GGTACCCCGGGTAGCGGTACCGCTTC
PGTSSTGSPGTPGSG TTCTTCTCCAGGTAGCTCTACTCCGTC
TASSSPGSSTPSGAT TGGTGCTACCGGCTCTCCAGGTTCTAA
GSPGTPGSGTASSSP CCCTTCTGCATCCACCGGTACCGGCCC
GASPGTSSTGSPGAS AGGTGCTTCTCCGGGCACCAGCTCTA
PGTSSTGSPGTPGSG CTGGTTCTCCAGGTACCCCGGGCAGC
TASSSPGSSTPSGAT GGTACCGCATCTTCTTCTCCAGGTAGC
GSPGASPGTSSTGSP TCTACTCCTTCTGGTGCAACTGGTTCT
GTPGSGTASSSPGSS CCAGGTACTCCTGGCAGCGGTACCGC
TPSGATGSPGSNPSA TTCTTCTTCTCCAGGTGCTTCTCCTGG
STGTGPGSSPSASTG TACTAGCTCTACTGGTTCTCCAGGTGC
TGPGSSTPSGATGSP TTCTCCGGGCACTAGCTCTACTGGTTC
GSSTPSGATGSPGAS TCCAGGTACCCCGGGTAGCGGTACTG
PGTSSTGSPGASPGT CTTCTTCCTCTCCAGGTAGCTCTACCC
SSTGSPGASPGTSST CTTCTGGTGCAACCGGCTCTCCAGGTG
GSPGTPGSGTASSSP CTTCTCCGGGCACCAGCTCTACCGGTT
GASPGTSSTGSPGAS CTCCAGGTACCCCGGGTAGCGGTACC
PGTSSTGSPGASPGT GCTTCTTCTTCTCCAGGTAGCTCTACT
SSTGSPGSSPSASTGT CCGTCTGGTGCTACCGGCTCTCCAGGT
GPGTPGSGTASSSPG TCTAACCCTTCTGCATCCACCGGTACC
ASPGTSSTGSPGASP GGCCCAGGTTCTAGCCCTTCTGCTTCC
GTSSTGSPGASPGTS ACCGGTACTGGCCCAGGTAGCTCTAC
STGSPGSSTPSGATG CCCTTCTGGTGCTACCGGCTCCCCAGG
SPGSSTPSGATGSPG TAGCTCTACTCCTTCTGGTGCAACTGG
ASPGTSSTGSPGTPG CTCTCCAGGTGCATCTCCGGGCACTA
SGTASSSPGSSTPSG GCTCTACTGGTTCTCCAGGTGCATCCC
ATGSPGSSTPSGATG CTGGCACTAGCTCTACTGGTTCTCCAG
SPGSSTPSGATGSPG GTGCTTCTCCTGGTACCAGCTCTACTG
SSPSASTGTGPGASP GTTCTCCAGGTACTCCTGGCAGCGGT
GTSSTGSPGASPGTS ACCGCTTCTTCTTCTCCAGGTGCTTCT
STGSPGTPGSGTASS CCTGGTACTAGCTCTACTGGTTCTCCA
SPGASPGTSSTGSPG GGTGCTTCTCCGGGCACTAGCTCTACT
ASPGTSSTGSPGASP GGTTCTCCAGGTGCTTCCCCGGGCACT
GTSSTGSPGASPGTS AGCTCTACCGGTTCTCCAGGTTCTAGC
STGSPGTPGSGTASS CCTTCTGCATCTACTGGTACTGGCCCA
SPGSSTPSGATGSPG GGTACTCCGGGCAGCGGTACTGCTTC
TPGSGTASSSPGSSTP TTCCTCTCCAGGTGCATCTCCGGGCAC
SGATGSPGTPGSGTA TAGCTCTACTGGTTCTCCAGGTGCATC
SSSPGSSTPSGATGSP CCCTGGCACTAGCTCTACTGGTTCTCC
GSSTPSGATGSPGSS AGGTGCTTCTCCTGGTACCAGCTCTAC
PSASTGTGPGSSPSA TGGTTCTCCAGGTAGCTCTACTCCGTC
STGTGPGASPGTSST TGGTGCAACCGGTTCCCCAGGTAGCT
GSPGTPGSGTASSSP CTACTCCTTCTGGTGCTACTGGCTCCC
GSSTPSGATGSPGSS CAGGTGCATCCCCTGGCACCAGCTCT
PSASTGTGPGSSPSA ACCGGTTCTCCAGGTACCCCGGGCAG
STGTGPGASPGTSST CGGTACCGCATCTTCCTCTCCAGGTAG
GSPGASPGTSSTGSP CTCTACCCCGTCTGGTGCTACCGGTTC
GSSTPSGATGSPGSS CCCAGGTAGCTCTACCCCGTCTGGTGC
PSASTGTGPGASPGT AACCGGCTCCCCAGGTAGCTCTACTC
SSTGSPGSSPSASTGT CGTCTGGTGCAACCGGCTCCCCAGGT
GPGTPGSGTASSSPG TCTAGCCCGTCTGCTTCCACTGGTACT
SSTPSGATGSPGSSTP GGCCCAGGTGCTTCCCCGGGCACCAG
SGATGSPGASPGTSS CTCTACTGGTTCTCCAGGTGCATCCCC
TGSPGFPTIPLSRLFD GGGTACCAGCTCTACCGGTTCTCCAG
NAMLRAHRLHQLAF GTACTCCTGGCAGCGGTACTGCATCTT
DTYQEFEEAYIPKEQ CCTCTCCAGGTGCTTCTCCGGGCACCA
KYSFLQNPQTSLCFS GCTCTACTGGTTCTCCAGGTGCATCTC
ESIPTPSNREETQQKS CGGGCACTAGCTCTACTGGTTCTCCAG
NLELLRISLLLIQSWL GTGCATCCCCTGGCACTAGCTCTACTG
EPVQFLRSVFANSLV GTTCTCCAGGTGCTTCTCCTGGTACCA
YGASDSNVYDLLKD GCTCTACTGGTTCTCCAGGTACCCCTG
LEEGIQTLMGRLEDG GTAGCGGTACTGCTTCTTCCTCTCCAG
SPRTGQIFKQTYSKF GTAGCTCTACTCCGTCTGGTGCTACCG
DTNSHNDDALLKNY GTTCTCCAGGTACCCCGGGTAGCGGT
GLLYCFRKDMDKVE ACCGCATCTTCTTCTCCAGGTAGCTCT
TFLRIVQCRSVEGSC ACCCCGTCTGGTGCTACTGGTTCTCCA
GFGGSEPATSGSETP GGTACTCCGGGCAGCGGTACTGCTTC
GTSESATPESGPGSE TTCCTCTCCAGGTAGCTCTACCCCTTC
PATSGSETPGSPAGS TGGTGCTACTGGCTCTCCAGGTAGCTC
PTSTEEGTSTEPSEGS TACCCCGTCTGGTGCTACTGGCTCCCC
APGSEPATSGSETPG AGGTTCTAGCCCTTCTGCATCCACCGG
SEPATSGSETPGSEP TACCGGTCCAGGTTCTAGCCCGTCTGC
ATSGSETPGTSTEPSE ATCTACTGGTACTGGTCCAGGTGCATC
GSAPGTSESATPESG CCCGGGCACTAGCTCTACCGGTTCTCC
PGSEPATSGSETPGT AGGTACTCCTGGTAGCGGTACTGCTTC
STEPSEGSAP TTCTTCTCCAGGTAGCTCTACTCCTTC
TGGTGCTACTGGTTCTCCAGGTTCTAG
CCCTTCTGCATCCACCGGTACCGGCCC
AGGTTCTAGCCCGTCTGCTTCTACCGG
TACTGGTCCAGGTGCTTCTCCGGGTAC
TAGCTCTACTGGTTCTCCAGGTGCATC
TCCTGGTACTAGCTCTACTGGTTCTCC
AGGTAGCTCTACTCCGTCTGGTGCAA
CCGGCTCTCCAGGTTCTAGCCCTTCTG
CATCTACCGGTACTGGTCCAGGTGCA
TCCCCTGGTACCAGCTCTACCGGTTCT
CCAGGTTCTAGCCCTTCTGCTTCTACC
GGTACCGGTCCAGGTACCCCTGGCAG
CGGTACCGCATCTTCCTCTCCAGGTAG
CTCTACTCCGTCTGGTGCAACCGGTTC
CCCAGGTAGCTCTACTCCTTCTGGTGC
TACTGGCTCCCCAGGTGCATCCCCTGG
CACCAGCTCTACCGGTTCTCCAGGTTT
TCCGACTATTCCGCTGTCTCGTCTGTT
TGATAATGCTATGCTGCGTGCGCACC
GTCTGCACCAGCTGGCCTTTGATACTT
ACCAGGAATTTGAAGAAGCcTACATT
CCTAAAGAGCAGAAGTACTCTTTCCT
GCAAAACCCACAGACTTCTCTCTGCTT
CAGCGAATCTATTCCGACGCCTTCCA
ATCGCGAGGAAACTCAGCAAAAGTCC
AATCTGGAACTACTCCGCATTTCTCTG
CTTCTGATTCAGAGCTGGCTAGAACC
AGTGCAATTTCTGCGTTCCGTCTTCGC
CAATAGCCTAGTTTATGGCGCATCCG
ACAGCAACGTATACGATCTCCTGAAA
GATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTC
CGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGC
CACAATGACGATGCGCTTCTAAAAAA
CTATGGTCTGCTGTATTGTTTTCGTAA
AGATATGGACAAAGTTGAAACCTTCC
TGCGTATTGTTCAGTGTCGTTCCGTTG
AGGGCAGCTGTGGTTTCTAAGGTGGT
AGCGAACCGGCAACTTCCGGCTCTGA
AACCCCAGGTACTTCTGAAAGCGCTA
CTCCTGAGTCTGGCCCAGGTAGCGAA
CCTGCTACCTCTGGCTCTGAAACCCCA
GGTAGCCCGGCAGGCTCTCCGACTTC
CACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGC
GAACCGGCAACCTCTGGCTCTGAAAC
CCCAGGTAGCGAACCTGCTACCTCCG
GCTCTGAAACTCCAGGTAGCGAACCG
GCTACTTCCGGTTCTGAAACTCCAGGT
ACCTCTACCGAACCTTCCGAAGGCAG
CGCACCAGGTACTTCTGAAAGCGCAA
CCCCTGAATCCGGTCCAGGTAGCGAA
CCGGCTACTTCTGGCTCTGAGACTCCA
GGTACTTCTACCGAACCGTCCGAAGG
TAGCGCACCA
AM875- GTSTEPSEGSAPGSE 755 GGTACTTCTACTGAACCGTCTGAAGG 756
hGH- PATSGSETPGSPAGS CAGCGCACCAGGTAGCGAACCGGCTA
AE144 PTSTEEGSTSSTAESP CTTCCGGTTCTGAAACCCCAGGTAGC
GPGTSTPESGSASPG CCAGCAGGTTCTCCAACTTCTACTGAA
STSESPSGTAPGSTSE GAAGGTTCTACCAGCTCTACCGCAGA
SPSGTAPGTSTPESGS ATCTCCTGGTCCAGGTACCTCTACTCC
ASPGTSTPESGSASP GGAAAGCGGCTCTGCATCTCCAGGTT
GSEPATSGSETPGTS CTACTAGCGAATCTCCTTCTGGCACTG
ESATPESGPGSPAGS CACCAGGTTCTACTAGCGAATCCCCG
PTSTEEGTSTEPSEGS TCTGGTACTGCTCCAGGTACTTCTACT
APGTSESATPESGPG CCTGAAAGCGGTTCCGCTTCTCCAGGT
TSTEPSEGSAPGTSTE ACCTCTACTCCGGAAAGCGGTTCTGC
PSEGSAPGSPAGSPT ATCTCCAGGTAGCGAACCGGCAACCT
STEEGTSTEPSEGSAP CCGGCTCTGAAACCCCAGGTACCTCT
GTSTEPSEGSAPGTS GAAAGCGCTACTCCTGAATCCGGCCC
ESATPESGPGTSESA AGGTAGCCCGGCAGGTTCTCCGACTT
TPESGPGTSTEPSEGS CCACTGAGGAAGGTACCTCTACTGAA
APGTSTEPSEGSAPG CCTTCTGAGGGCAGCGCTCCAGGTAC
TSESATPESGPGTSTE TTCTGAAAGCGCTACCCCGGAGTCCG
PSEGSAPGSEPATSG GTCCAGGTACTTCTACTGAACCGTCCG
SETPGSPAGSPTSTEE AAGGTAGCGCACCAGGTACTTCTACC
GSSTPSGATGSPGTP GAACCGTCCGAGGGTAGCGCACCAGG
GSGTASSSPGSSTPS TAGCCCAGCAGGTTCTCCTACCTCCAC
GATGSPGTSTEPSEG CGAGGAAGGTACTTCTACCGAACCGT
SAPGTSTEPSEGSAP CCGAGGGTAGCGCACCAGGTACTTCT
GSEPATSGSETPGSP ACCGAACCTTCCGAGGGCAGCGCACC
AGSPTSTEEGSPAGS AGGTACTTCTGAAAGCGCTACCCCTG
PTSTEEGTSTEPSEGS AGTCCGGCCCAGGTACTTCTGAAAGC
APGASASGAPSTGGT GCTACTCCTGAATCCGGTCCAGGTAC
SESATPESGPGSPAG CTCTACTGAACCTTCCGAAGGCAGCG
SPTSTEEGSPAGSPTS CTCCAGGTACCTCTACCGAACCGTCC
TEEGSTSSTAESPGP GAGGGCAGCGCACCAGGTACTTCTGA
GSTSESPSGTAPGTSP AAGCGCAACCCCTGAATCCGGTCCAG
SGESSTAPGTPGSGT GTACTTCTACTGAACCTTCCGAAGGTA
ASSSPGSSTPSGATG GCGCTCCAGGTAGCGAACCTGCTACT
SPGSSPSASTGTGPG TCTGGTTCTGAAACCCCAGGTAGCCC
SEPATSGSETPGTSES GGCTGGCTCTCCGACCTCCACCGAGG
ATPESGPGSEPATSG AAGGTAGCTCTACCCCGTCTGGTGCT
SETPGSTSSTAESPGP ACTGGTTCTCCAGGTACTCCGGGCAG
GSTSSTAESPGPGTSP CGGTACTGCTTCTTCCTCTCCAGGTAG
SGESSTAPGSEPATS CTCTACCCCTTCTGGTGCTACTGGCTC
GSETPGSEPATSGSE TCCAGGTACCTCTACCGAACCGTCCG
TPGTSTEPSEGSAPG AGGGTAGCGCACCAGGTACCTCTACT
STSSTAESPGPGTSTP GAACCGTCTGAGGGTAGCGCTCCAGG
ESGSASPGSTSESPSG TAGCGAACCGGCAACCTCCGGTTCTG
TAPGTSTEPSEGSAP AAACTCCAGGTAGCCCTGCTGGCTCT
GTSTEPSEGSAPGTS CCGACTTCTACTGAGGAAGGTAGCCC
TEPSEGSAPGSSTPSG GGCTGGTTCTCCGACTTCTACTGAGGA
ATGSPGSSPSASTGT AGGTACTTCTACCGAACCTTCCGAAG
GPGASPGTSSTGSPG GTAGCGCTCCAGGTGCAAGCGCAAGC
SEPATSGSETPGTSES GGCGCGCCAAGCACGGGAGGTACTTC
ATPESGPGSPAGSPT TGAAAGCGCTACTCCTGAGTCCGGCC
STEEGSSTPSGATGS CAGGTAGCCCGGCTGGCTCTCCGACT
PGSSPSASTGTGPGA TCCACCGAGGAAGGTAGCCCGGCTGG
SPGTSSTGSPGTSESA CTCTCCAACTTCTACTGAAGAAGGTTC
TPESGPGTSTEPSEGS TACCAGCTCTACCGCTGAATCTCCTGG
APGTSTEPSEGSAPG CCCAGGTTCTACTAGCGAATCTCCGTC
FPTIPLSRLFDNAML TGGCACCGCACCAGGTACTTCCCCTA
RAHRLHQLAFDTYQ GCGGTGAATCTTCTACTGCACCAGGT
EFEEAYIPKEQKYSF ACCCCTGGCAGCGGTACCGCTTCTTCC
LQNPQTSLCFSESIPT TCTCCAGGTAGCTCTACCCCGTCTGGT
PSNREETQQKSNLEL GCTACTGGCTCTCCAGGTTCTAGCCCG
LRISLLLIQSWLEPVQ TCTGCATCTACCGGTACCGGCCCAGG
FLRSVFANSLVYGAS TAGCGAACCGGCAACCTCCGGCTCTG
DSNVYDLLKDLEEGI AAACTCCAGGTACTTCTGAAAGCGCT
QTLMGRLEDGSPRT ACTCCGGAATCCGGCCCAGGTAGCGA
GQIFKQTYSKFDTNS ACCGGCTACTTCCGGCTCTGAAACCC
HNDDALLKNYGLLY CAGGTTCCACCAGCTCTACTGCAGAA
CFRKDMDKVETFLRI TCTCCGGGCCCAGGTTCTACTAGCTCT
VQCRSVEGSCGFGG ACTGCAGAATCTCCGGGTCCAGGTAC
SEPATSGSETPGTSES TTCTCCTAGCGGCGAATCTTCTACCGC
ATPESGPGSEPATSG TCCAGGTAGCGAACCGGCAACCTCTG
SETPGSPAGSPTSTEE GCTCTGAAACTCCAGGTAGCGAACCT
GTSTEPSEGSAPGSE GCAACCTCCGGCTCTGAAACCCCAGG
PATSGSETPGSEPAT TACTTCTACTGAACCTTCTGAGGGCAG
SGSETPGSEPATSGS CGCACCAGGTTCTACCAGCTCTACCG
ETPGTSTEPSEGSAP CAGAATCTCCTGGTCCAGGTACCTCTA
GTSESATPESGPGSE CTCCGGAAAGCGGCTCTGCATCTCCA
PATSGSETPGTSTEPS GGTTCTACTAGCGAATCTCCTTCTGGC
EGSAP ACTGCACCAGGTACTTCTACCGAACC
GTCCGAAGGCAGCGCTCCAGGTACCT
CTACTGAACCTTCCGAGGGCAGCGCT
CCAGGTACCTCTACCGAACCTTCTGA
AGGTAGCGCACCAGGTAGCTCTACTC
CGTCTGGTGCAACCGGCTCCCCAGGT
TCTAGCCCGTCTGCTTCCACTGGTACT
GGCCCAGGTGCTTCCCCGGGCACCAG
CTCTACTGGTTCTCCAGGTAGCGAACC
TGCTACCTCCGGTTCTGAAACCCCAG
GTACCTCTGAAAGCGCAACTCCGGAG
TCTGGTCCAGGTAGCCCTGCAGGTTCT
CCTACCTCCACTGAGGAAGGTAGCTC
TACTCCGTCTGGTGCAACCGGCTCCCC
AGGTTCTAGCCCGTCTGCTTCCACTGG
TACTGGCCCAGGTGCTTCCCCGGGCA
CCAGCTCTACTGGTTCTCCAGGTACCT
CTGAAAGCGCTACTCCGGAGTCTGGC
CCAGGTACCTCTACTGAACCGTCTGA
GGGTAGCGCTCCAGGTACTTCTACTG
AACCGTCCGAAGGTAGCGCACCAGGT
TTTCCGACTATTCCGCTGTCTCGTCTG
TTTGATAATGCTATGCTGCGTGCGCAC
CGTCTGCACCAGCTGGCCTTTGATACT
TACCAGGAATTTGAAGAAGCcTACATT
CCTAAAGAGCAGAAGTACTCTTTCCT
GCAAAACCCACAGACTTCTCTCTGCTT
CAGCGAATCTATTCCGACGCCTTCCA
ATCGCGAGGAAACTCAGCAAAAGTCC
AATCTGGAACTACTCCGCATTTCTCTG
CTTCTGATTCAGAGCTGGCTAGAACC
AGTGCAATTTCTGCGTTCCGTCTTCGC
CAATAGCCTAGTTTATGGCGCATCCG
ACAGCAACGTATACGATCTCCTGAAA
GATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTC
CGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGC
CACAATGACGATGCGCTTCTAAAAAA
CTATGGTCTGCTGTATTGTTTTCGTAA
AGATATGGACAAAGTTGAAACCTTCC
TGCGTATTGTTCAGTGTCGTTCCGTTG
AGGGCAGCTGTGGTTTCTAAGGTGGT
AGCGAACCGGCAACTTCCGGCTCTGA
AACCCCAGGTACTTCTGAAAGCGCTA
CTCCTGAGTCTGGCCCAGGTAGCGAA
CCTGCTACCTCTGGCTCTGAAACCCCA
GGTAGCCCGGCAGGCTCTCCGACTTC
CACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGC
GAACCGGCAACCTCTGGCTCTGAAAC
CCCAGGTAGCGAACCTGCTACCTCCG
GCTCTGAAACTCCAGGTAGCGAACCG
GCTACTTCCGGTTCTGAAACTCCAGGT
ACCTCTACCGAACCTTCCGAAGGCAG
CGCACCAGGTACTTCTGAAAGCGCAA
CCCCTGAATCCGGTCCAGGTAGCGAA
CCGGCTACTTCTGGCTCTGAGACTCCA
GGTACTTCTACCGAACCGTCCGAAGG
TAGCGCACCA
AE912- MAEPAGSPTSTEEGT 757 ATGGCTGAACCTGCTGGCTCTCCAAC 758
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE144 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGSPAGSPTSTEE GCTCTACCCCTTCTGGTGCAACCGGCT
GTSESATPESGPGTS CTCCAGGTGCTTCTCCGGGCACCAGCT
TEPSEGSAPGSPAGS CTACCGGTTCTCCAGGTAGCCCGGCT
PTSTEEGTSTEPSEGS GGCTCTCCTACCTCTACTGAGGAAGG
APGTSTEPSEGSAPG TACTTCTGAAAGCGCTACTCCTGAGTC
TSESATPESGPGSEP TGGTCCAGGTACCTCTACTGAACCGTC
ATSGSETPGSEPATS CGAAGGTAGCGCTCCAGGTAGCCCAG
GSETPGSPAGSPTST CAGGCTCTCCGACTTCCACTGAGGAA
EEGTSESATPESGPG GGTACTTCTACTGAACCTTCCGAAGG
TSTEPSEGSAPGTSTE CAGCGCACCAGGTACCTCTACTGAAC
PSEGSAPGSPAGSPT CTTCTGAGGGCAGCGCTCCAGGTACT
STEEGTSTEPSEGSAP TCTGAAAGCGCTACCCCGGAATCTGG
GTSTEPSEGSAPGTS CCCAGGTAGCGAACCGGCTACTTCTG
ESATPESGPGTSTEPS GTTCTGAAACCCCAGGTAGCGAACCG
EGSAPGTSESATPES GCTACCTCCGGTTCTGAAACTCCAGGT
GPGSEPATSGSETPG AGCCCGGCAGGCTCTCCGACCTCTAC
TSTEPSEGSAPGTSTE TGAGGAAGGTACTTCTGAAAGCGCAA
PSEGSAPGTSESATP CCCCGGAGTCCGGCCCAGGTACCTCT
ESGPGTSESATPESG ACCGAACCGTCTGAGGGCAGCGCACC
PGSPAGSPTSTEEGT AGGTACTTCTACCGAACCGTCCGAGG
SESATPESGPGSEPA GTAGCGCACCAGGTAGCCCAGCAGGT
TSGSETPGTSESATPE TCTCCTACCTCCACCGAGGAAGGTAC
SGPGTSTEPSEGSAP TTCTACCGAACCGTCCGAGGGTAGCG
GTSTEPSEGSAPGTS CACCAGGTACCTCTACTGAACCTTCTG
TEPSEGSAPGTSTEPS AGGGCAGCGCTCCAGGTACTTCTGAA
EGSAPGTSTEPSEGS AGCGCTACCCCGGAGTCCGGTCCAGG
APGTSTEPSEGSAPG TACTTCTACTGAACCGTCCGAAGGTA
SPAGSPTSTEEGTSTE GCGCACCAGGTACTTCTGAAAGCGCA
PSEGSAPGTSESATP ACCCCTGAATCCGGTCCAGGTAGCGA
ESGPGSEPATSGSET ACCGGCTACTTCTGGCTCTGAGACTCC
PGTSESATPESGPGS AGGTACTTCTACCGAACCGTCCGAAG
EPATSGSETPGTSES GTAGCGCACCAGGTACTTCTACTGAA
ATPESGPGTSTEPSE CCGTCTGAAGGTAGCGCACCAGGTAC
GSAPGTSESATPESG TTCTGAAAGCGCAACCCCGGAATCCG
PGSPAGSPTSTEEGSP GCCCAGGTACCTCTGAAAGCGCAACC
AGSPTSTEEGSPAGS CCGGAGTCCGGCCCAGGTAGCCCTGC
PTSTEEGTSESATPES TGGCTCTCCAACCTCCACCGAAGAAG
GPGTSTEPSEGSAPG GTACCTCTGAAAGCGCAACCCCTGAA
TSESATPESGPGSEP TCCGGCCCAGGTAGCGAACCGGCAAC
ATSGSETPGTSESAT CTCCGGTTCTGAAACCCCAGGTACCTC
PESGPGSEPATSGSE TGAAAGCGCTACTCCGGAGTCTGGCC
TPGTSESATPESGPG CAGGTACCTCTACTGAACCGTCTGAG
TSTEPSEGSAPGSPA GGTAGCGCTCCAGGTACTTCTACTGA
GSPTSTEEGTSESATP ACCGTCCGAAGGTAGCGCACCAGGTA
ESGPGSEPATSGSET CTTCTACCGAACCGTCCGAAGGCAGC
PGTSESATPESGPGSP GCTCCAGGTACCTCTACTGAACCTTCC
AGSPTSTEEGSPAGS GAGGGCAGCGCTCCAGGTACCTCTAC
PTSTEEGTSTEPSEGS CGAACCTTCTGAAGGTAGCGCACCAG
APGTSESATPESGPG GTACTTCTACCGAACCGTCCGAGGGT
TSESATPESGPGTSES AGCGCACCAGGTAGCCCAGCAGGTTC
ATPESGPGSEPATSG TCCTACCTCCACCGAGGAAGGTACTT
SETPGSEPATSGSETP CTACCGAACCGTCCGAGGGTAGCGCA
GSPAGSPTSTEEGTS CCAGGTACCTCTGAAAGCGCAACTCC
TEPSEGSAPGTSTEPS TGAGTCTGGCCCAGGTAGCGAACCTG
EGSAPGSEPATSGSE CTACCTCCGGCTCTGAGACTCCAGGT
TPGTSESATPESGPG ACCTCTGAAAGCGCAACCCCGGAATC
TSTEPSEGSAPGFPTI TGGTCCAGGTAGCGAACCTGCAACCT
PLSRLFDNAMLRAH CTGGCTCTGAAACCCCAGGTACCTCT
RLHQLAFDTYQEFEE GAAAGCGCTACTCCTGAATCTGGCCC
AYIPKEQKYSFLQNP AGGTACTTCTACTGAACCGTCCGAGG
QTSLCFSESIPTPSNR GCAGCGCACCAGGTACTTCTGAAAGC
EETQQKSNLELLRIS GCTACTCCTGAGTCCGGCCCAGGTAG
LLLIQSWLEPVQFLR CCCGGCTGGCTCTCCGACTTCCACCGA
SVFANSLVYGASDS GGAAGGTAGCCCGGCTGGCTCTCCAA
NVYDLLKDLEEGIQT CTTCTACTGAAGAAGGTAGCCCGGCA
LMGRLEDGSPRTGQI GGCTCTCCGACCTCTACTGAGGAAGG
FKQTYSKFDTNSHN TACTTCTGAAAGCGCAACCCCGGAGT
DDALLKNYGLLYCF CCGGCCCAGGTACCTCTACCGAACCG
RKDMDKVETFLRIV TCTGAGGGCAGCGCACCAGGTACCTC
QCRSVEGSCGFGGTS TGAAAGCGCAACTCCTGAGTCTGGCC
ESATPESGPGTSTEPS CAGGTAGCGAACCTGCTACCTCCGGC
EGSAPGTSTEPSEGS TCTGAGACTCCAGGTACCTCTGAAAG
APGTSESATPESGPG CGCAACCCCGGAATCTGGTCCAGGTA
TSTEPSEGSAPGTSTE GCGAACCTGCAACCTCTGGCTCTGAA
PSEGSAPGTSESATP ACCCCAGGTACCTCTGAAAGCGCTAC
ESGPGTSTEPSEGSA TCCTGAATCTGGCCCAGGTACTTCTAC
PGTSTEPSEGSAPGT TGAACCGTCCGAGGGCAGCGCACCAG
STEPSEGSAPGSPAG GTAGCCCTGCTGGCTCTCCAACCTCCA
SPTSTEEGTSTEPSEG CCGAAGAAGGTACCTCTGAAAGCGCA
SAPG ACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCC
CAGGTACTTCTGAAAGCGCTACTCCT
GAGTCCGGCCCAGGTAGCCCGGCTGG
CTCTCCGACTTCCACCGAGGAAGGTA
GCCCGGCTGGCTCTCCAACTTCTACTG
AAGAAGGTACTTCTACCGAACCTTCC
GAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAAT
CCGGTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAATCTGGCCCAGGTAGCGA
ACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTT
CTGAAACTCCAGGTAGCCCAGCAGGC
TCTCCGACTTCCACTGAGGAAGGTAC
TTCTACTGAACCTTCCGAAGGCAGCG
CACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATC
TGGCCCAGGTACTTCTACTGAACCGTC
CGAGGGCAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAG
GAATTTGAAGAAGCcTACATTCCTAAA
GAGCAGAAGTACTCTTTCCTGCAAAA
CCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGA
GGAAACTCAGCAAAAGTCCAATCTGG
AACTACTCCGCATTTCTCTGCTTCTGA
TTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTCTTCGCCAATAGC
CTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCG
AGGAAGGCATTCAGACCCTGATGGGT
CGTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTAGCGAAC
CGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGA
GTCTGGCCCAGGTAGCGAACCTGCTA
CCTCTGGCTCTGAAACCCCAGGTAGC
CCGGCAGGCTCTCCGACTTCCACCGA
GGAAGGTACCTCTACTGAACCTTCTG
AGGGTAGCGCTCCAGGTAGCGAACCG
GCAACCTCTGGCTCTGAAACCCCAGG
TAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACT
TCCGGTTCTGAAACTCCAGGTACCTCT
ACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTG
AATCCGGTCCAGGTAGCGAACCGGCT
ACTTCTGGCTCTGAGACTCCAGGTACT
TCTACCGAACCGTCCGAAGGTAGCGC
ACCA
AM923- MAEPAGSPTSTEEGA 759 ATGGCTGAACCTGCTGGCTCTCCAAC 760
hGH- SPGTSSTGSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE144 GATGSPGSSTPSGAT GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGTSTEPSEGSAP GCTCTACCCCTTCTGGTGCAACCGGCT
GSEPATSGSETPGSP CTCCAGGTGCTTCTCCGGGCACCAGCT
AGSPTSTEEGSTSST CTACCGGTTCTCCAGGTAGCCCGGCT
AESPGPGTSTPESGS GGCTCTCCTACCTCTACTGAGGAAGG
ASPGSTSESPSGTAP TACTTCTGAAAGCGCTACTCCTGAGTC
GSTSESPSGTAPGTS TGGTCCAGGTACCTCTACTGAACCGTC
TPESGSASPGTSTPES CGAAGGTAGCGCTCCAGGTAGCCCAG
GSASPGSEPATSGSE CAGGCTCTCCGACTTCCACTGAGGAA
TPGTSESATPESGPG GGTACTTCTACTGAACCTTCCGAAGG
SPAGSPTSTEEGTSTE CAGCGCACCAGGTACCTCTACTGAAC
PSEGSAPGTSESATP CTTCTGAGGGCAGCGCTCCAGGTACT
ESGPGTSTEPSEGSA TCTGAAAGCGCTACCCCGGAATCTGG
PGTSTEPSEGSAPGSP CCCAGGTAGCGAACCGGCTACTTCTG
AGSPTSTEEGTSTEPS GTTCTGAAACCCCAGGTAGCGAACCG
EGSAPGTSTEPSEGS GCTACCTCCGGTTCTGAAACTCCAGGT
APGTSESATPESGPG AGCCCGGCAGGCTCTCCGACCTCTAC
TSESATPESGPGTSTE TGAGGAAGGTACTTCTGAAAGCGCAA
PSEGSAPGTSTEPSE CCCCGGAGTCCGGCCCAGGTACCTCT
GSAPGTSESATPESG ACCGAACCGTCTGAGGGCAGCGCACC
PGTSTEPSEGSAPGS AGGTACTTCTACCGAACCGTCCGAGG
EPATSGSETPGSPAG GTAGCGCACCAGGTAGCCCAGCAGGT
SPTSTEEGSSTPSGAT TCTCCTACCTCCACCGAGGAAGGTAC
GSPGTPGSGTASSSP TTCTACCGAACCGTCCGAGGGTAGCG
GSSTPSGATGSPGTS CACCAGGTACCTCTACTGAACCTTCTG
TEPSEGSAPGTSTEPS AGGGCAGCGCTCCAGGTACTTCTGAA
EGSAPGSEPATSGSE AGCGCTACCCCGGAGTCCGGTCCAGG
TPGSPAGSPTSTEEG TACTTCTACTGAACCGTCCGAAGGTA
SPAGSPTSTEEGTSTE GCGCACCAGGTACTTCTGAAAGCGCA
PSEGSAPGASASGAP ACCCCTGAATCCGGTCCAGGTAGCGA
STGGTSESATPESGP ACCGGCTACTTCTGGCTCTGAGACTCC
GSPAGSPTSTEEGSP AGGTACTTCTACCGAACCGTCCGAAG
AGSPTSTEEGSTSST GTAGCGCACCAGGTACTTCTACTGAA
AESPGPGSTSESPSGT CCGTCTGAAGGTAGCGCACCAGGTAC
APGTSPSGESSTAPG TTCTGAAAGCGCAACCCCGGAATCCG
TPGSGTASSSPGSSTP GCCCAGGTACCTCTGAAAGCGCAACC
SGATGSPGSSPSAST CCGGAGTCCGGCCCAGGTAGCCCTGC
GTGPGSEPATSGSET TGGCTCTCCAACCTCCACCGAAGAAG
PGTSESATPESGPGS GTACCTCTGAAAGCGCAACCCCTGAA
EPATSGSETPGSTSST TCCGGCCCAGGTAGCGAACCGGCAAC
AESPGPGSTSSTAESP CTCCGGTTCTGAAACCCCAGGTACCTC
GPGTSPSGESSTAPG TGAAAGCGCTACTCCGGAGTCTGGCC
SEPATSGSETPGSEP CAGGTACCTCTACTGAACCGTCTGAG
ATSGSETPGTSTEPSE GGTAGCGCTCCAGGTACTTCTACTGA
GSAPGSTSSTAESPG ACCGTCCGAAGGTAGCGCACCAGGTA
PGTSTPESGSASPGST CTTCTACCGAACCGTCCGAAGGCAGC
SESPSGTAPGTSTEPS GCTCCAGGTACCTCTACTGAACCTTCC
EGSAPGTSTEPSEGS GAGGGCAGCGCTCCAGGTACCTCTAC
APGTSTEPSEGSAPG CGAACCTTCTGAAGGTAGCGCACCAG
SSTPSGATGSPGSSPS GTACTTCTACCGAACCGTCCGAGGGT
ASTGTGPGASPGTSS AGCGCACCAGGTAGCCCAGCAGGTTC
TGSPGSEPATSGSET TCCTACCTCCACCGAGGAAGGTACTT
PGTSESATPESGPGSP CTACCGAACCGTCCGAGGGTAGCGCA
AGSPTSTEEGSSTPS CCAGGTACCTCTGAAAGCGCAACTCC
GATGSPGSSPSASTG TGAGTCTGGCCCAGGTAGCGAACCTG
TGPGASPGTSSTGSP CTACCTCCGGCTCTGAGACTCCAGGT
GTSESATPESGPGTS ACCTCTGAAAGCGCAACCCCGGAATC
TEPSEGSAPGTSTEPS TGGTCCAGGTAGCGAACCTGCAACCT
EGSAPGFPTIPLSRLF CTGGCTCTGAAACCCCAGGTACCTCT
DNAMLRAHRLHQL GAAAGCGCTACTCCTGAATCTGGCCC
AFDTYQEFEEAYIPK AGGTACTTCTACTGAACCGTCCGAGG
EQKYSFLQNPQTSLC GCAGCGCACCAGGTACTTCTGAAAGC
FSESIPTPSNREETQQ GCTACTCCTGAGTCCGGCCCAGGTAG
KSNLELLRISLLLIQS CCCGGCTGGCTCTCCGACTTCCACCGA
WLEPVQFLRSVFAN GGAAGGTAGCCCGGCTGGCTCTCCAA
SLVYGASDSNVYDL CTTCTACTGAAGAAGGTAGCCCGGCA
LKDLEEGIQTLMGRL GGCTCTCCGACCTCTACTGAGGAAGG
EDGSPRTGQIFKQTY TACTTCTGAAAGCGCAACCCCGGAGT
SKFDTNSHNDDALL CCGGCCCAGGTACCTCTACCGAACCG
KNYGLLYCFRKDMD TCTGAGGGCAGCGCACCAGGTACCTC
KVETFLRIVQCRSVE TGAAAGCGCAACTCCTGAGTCTGGCC
GSCGFGGSEPATSGS CAGGTAGCGAACCTGCTACCTCCGGC
ETPGTSESATPESGP TCTGAGACTCCAGGTACCTCTGAAAG
GSEPATSGSETPGSP CGCAACCCCGGAATCTGGTCCAGGTA
AGSPTSTEEGTSTEPS GCGAACCTGCAACCTCTGGCTCTGAA
EGSAPGSEPATSGSE ACCCCAGGTACCTCTGAAAGCGCTAC
TPGSEPATSGSETPG TCCTGAATCTGGCCCAGGTACTTCTAC
SEPATSGSETPGTSTE TGAACCGTCCGAGGGCAGCGCACCAG
PSEGSAPGTSESATP GTAGCCCTGCTGGCTCTCCAACCTCCA
ESGPGSEPATSGSET CCGAAGAAGGTACCTCTGAAAGCGCA
PGTSTEPSEGSAP ACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCC
CAGGTACTTCTGAAAGCGCTACTCCT
GAGTCCGGCCCAGGTAGCCCGGCTGG
CTCTCCGACTTCCACCGAGGAAGGTA
GCCCGGCTGGCTCTCCAACTTCTACTG
AAGAAGGTACTTCTACCGAACCTTCC
GAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAAT
CCGGTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAATCTGGCCCAGGTAGCGA
ACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTT
CTGAAACTCCAGGTAGCCCAGCAGGC
TCTCCGACTTCCACTGAGGAAGGTAC
TTCTACTGAACCTTCCGAAGGCAGCG
CACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATC
TGGCCCAGGTACTTCTACTGAACCGTC
CGAGGGCAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAG
GAATTTGAAGAAGCcTACATTCCTAAA
GAGCAGAAGTACTCTTTCCTGCAAAA
CCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGA
GGAAACTCAGCAAAAGTCCAATCTGG
AACTACTCCGCATTTCTCTGCTTCTGA
TTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTgTTCGCCAATAGC
CTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCG
AGGAAGGCATTCAGACCCTGATGGGT
CGTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCGGAGGTACTTCTGAAA
GCGCTACTCCGGAGTCCGGTCCAGGT
ACCTCTACCGAACCGTCCGAAGGCAG
CGCTCCAGGTACTTCTACTGAACCTTC
TGAGGGTAGCGCTCCAGGTACTTCTG
AAAGCGCTACTCCGGAGTCCGGTCCA
GGTACCTCTACCGAACCGTCCGAAGG
CAGCGCTCCAGGTACTTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGG
CCCAGGTACCTCTACTGAACCGTCTG
AGGGTAGCGCTCCAGGTACTTCTACT
GAACCGTCCGAAGGTAGCGCACCAGG
TACTTCTACCGAACCGTCCGAGGGTA
GCGCACCAGGTAGCCCAGCAGGTTCT
CCTACCTCCACCGAGGAAGGTACTTC
TACCGAACCGTCCGAGGGTAGCGCAC
CAGGTTAA
AM1318- GTSTEPSEGSAPGSE 761 GGTACTTCTACTGAACCGTCTGAAGG 762
hGH- PATSGSETPGSPAGS CAGCGCACCAGGTAGCGAACCGGCTA
AE144 PTSTEEGSTSSTAESP CTTCCGGTTCTGAAACCCCAGGTAGC
GPGTSTPESGSASPG CCAGCAGGTTCTCCAACTTCTACTGAA
STSESPSGTAPGSTSE GAAGGTTCTACCAGCTCTACCGCAGA
SPSGTAPGTSTPESGS ATCTCCTGGTCCAGGTACCTCTACTCC
ASPGTSTPESGSASP GGAAAGCGGCTCTGCATCTCCAGGTT
GSEPATSGSETPGTS CTACTAGCGAATCTCCTTCTGGCACTG
ESATPESGPGSPAGS CACCAGGTTCTACTAGCGAATCCCCG
PTSTEEGTSTEPSEGS TCTGGTACTGCTCCAGGTACTTCTACT
APGTSESATPESGPG CCTGAAAGCGGTTCCGCTTCTCCAGGT
TSTEPSEGSAPGTSTE ACCTCTACTCCGGAAAGCGGTTCTGC
PSEGSAPGSPAGSPT ATCTCCAGGTAGCGAACCGGCAACCT
STEEGTSTEPSEGSAP CCGGCTCTGAAACCCCAGGTACCTCT
GTSTEPSEGSAPGTS GAAAGCGCTACTCCTGAATCCGGCCC
ESATPESGPGTSESA AGGTAGCCCGGCAGGTTCTCCGACTT
TPESGPGTSTEPSEGS CCACTGAGGAAGGTACCTCTACTGAA
APGTSTEPSEGSAPG CCTTCTGAGGGCAGCGCTCCAGGTAC
TSESATPESGPGTSTE TTCTGAAAGCGCTACCCCGGAGTCCG
PSEGSAPGSEPATSG GTCCAGGTACTTCTACTGAACCGTCCG
SETPGSPAGSPTSTEE AAGGTAGCGCACCAGGTACTTCTACC
GSSTPSGATGSPGTP GAACCGTCCGAGGGTAGCGCACCAGG
GSGTASSSPGSSTPS TAGCCCAGCAGGTTCTCCTACCTCCAC
GATGSPGTSTEPSEG CGAGGAAGGTACTTCTACCGAACCGT
SAPGTSTEPSEGSAP CCGAGGGTAGCGCACCAGGTACTTCT
GSEPATSGSETPGSP ACCGAACCTTCCGAGGGCAGCGCACC
AGSPTSTEEGSPAGS AGGTACTTCTGAAAGCGCTACCCCTG
PTSTEEGTSTEPSEGS AGTCCGGCCCAGGTACTTCTGAAAGC
APGPEPTGPAPSGGS GCTACTCCTGAATCCGGTCCAGGTAC
EPATSGSETPGTSES CTCTACTGAACCTTCCGAAGGCAGCG
ATPESGPGSPAGSPT CTCCAGGTACCTCTACCGAACCGTCC
STEEGTSESATPESGP GAGGGCAGCGCACCAGGTACTTCTGA
GSPAGSPTSTEEGSP AAGCGCAACCCCTGAATCCGGTCCAG
AGSPTSTEEGTSESA GTACTTCTACTGAACCTTCCGAAGGTA
TPESGPGSPAGSPTST GCGCTCCAGGTAGCGAACCTGCTACT
EEGSPAGSPTSTEEG TCTGGTTCTGAAACCCCAGGTAGCCC
STSSTAESPGPGSTSE GGCTGGCTCTCCGACCTCCACCGAGG
SPSGTAPGTSPSGESS AAGGTAGCTCTACCCCGTCTGGTGCT
TAPGSTSESPSGTAP ACTGGTTCTCCAGGTACTCCGGGCAG
GSTSESPSGTAPGTSP CGGTACTGCTTCTTCCTCTCCAGGTAG
SGESSTAPGTSTEPSE CTCTACCCCTTCTGGTGCTACTGGCTC
GSAPGTSESATPESG TCCAGGTACCTCTACCGAACCGTCCG
PGTSESATPESGPGS AGGGTAGCGCACCAGGTACCTCTACT
EPATSGSETPGTSES GAACCGTCTGAGGGTAGCGCTCCAGG
ATPESGPGTSESATP TAGCGAACCGGCAACCTCCGGTTCTG
ESGPGTSTEPSEGSA AAACTCCAGGTAGCCCTGCTGGCTCT
PGTSESATPESGPGT CCGACTTCTACTGAGGAAGGTAGCCC
STEPSEGSAPGTSPSG GGCTGGTTCTCCGACTTCTACTGAGGA
ESSTAPGTSPSGESST AGGTACTTCTACCGAACCTTCCGAAG
APGTSPSGESSTAPG GTAGCGCTCCAGGTCCAGAACCAACG
TSTEPSEGSAPGSPA GGGCCGGCCCCAAGCGGAGGTAGCGA
GSPTSTEEGTSTEPSE ACCGGCAACCTCCGGCTCTGAAACCC
GSAPGSSPSASTGTG CAGGTACCTCTGAAAGCGCTACTCCT
PGSSTPSGATGSPGS GAATCCGGCCCAGGTAGCCCGGCAGG
STPSGATGSPGSSTPS TTCTCCGACTTCCACTGAGGAAGGTA
GATGSPGSSTPSGAT CTTCTGAAAGCGCTACTCCTGAGTCCG
GSPGASPGTSSTGSP GCCCAGGTAGCCCGGCTGGCTCTCCG
GASASGAPSTGGTSP ACTTCCACCGAGGAAGGTAGCCCGGC
SGESSTAPGSTSSTA TGGCTCTCCAACTTCTACTGAAGAAG
ESPGPGTSPSGESSTA GTACTTCTGAAAGCGCTACTCCTGAGT
PGTSESATPESGPGT CCGGCCCAGGTAGCCCGGCTGGCTCT
STEPSEGSAPGTSTEP CCGACTTCCACCGAGGAAGGTAGCCC
SEGSAPGSSPSASTG GGCTGGCTCTCCAACTTCTACTGAAG
TGPGSSTPSGATGSP AAGGTTCTACCAGCTCTACCGCTGAA
GASPGTSSTGSPGTS TCTCCTGGCCCAGGTTCTACTAGCGAA
TPESGSASPGTSPSGE TCTCCGTCTGGCACCGCACCAGGTACT
SSTAPGTSPSGESSTA TCCCCTAGCGGTGAATCTTCTACTGCA
PGTSESATPESGPGS CCAGGTTCTACCAGCGAATCTCCTTCT
EPATSGSETPGTSTEP GGCACCGCTCCAGGTTCTACTAGCGA
SEGSAPGSTSESPSGT ATCCCCGTCTGGTACCGCACCAGGTA
APGSTSESPSGTAPG CTTCTCCTAGCGGCGAATCTTCTACCG
TSTPESGSASPGSPA CACCAGGTACTTCTACCGAACCTTCCG
GSPTSTEEGTSESATP AGGGCAGCGCACCAGGTACTTCTGAA
ESGPGTSTEPSEGSA AGCGCTACCCCTGAGTCCGGCCCAGG
PGSPAGSPTSTEEGT TACTTCTGAAAGCGCTACTCCTGAATC
SESATPESGPGSEPA CGGTCCAGGTAGCGAACCGGCAACCT
TSGSETPGSSTPSGA CTGGCTCTGAAACCCCAGGTACCTCT
TGSPGASPGTSSTGS GAAAGCGCTACTCCGGAATCTGGTCC
PGSSTPSGATGSPGS AGGTACTTCTGAAAGCGCTACTCCGG
TSESPSGTAPGTSPSG AATCCGGTCCAGGTACCTCTACTGAA
ESSTAPGSTSSTAESP CCTTCTGAGGGCAGCGCTCCAGGTAC
GPGSSTPSGATGSPG TTCTGAAAGCGCTACCCCGGAGTCCG
ASPGTSSTGSPGTPG GTCCAGGTACTTCTACTGAACCGTCCG
SGTASSSPGSPAGSP AAGGTAGCGCACCAGGTACCTCCCCT
TSTEEGSPAGSPTSTE AGCGGCGAATCTTCTACTGCTCCAGG
EGTSTEPSEGSAPGF TACCTCTCCTAGCGGCGAATCTTCTAC
PTIPLSRLFDNAMLR CGCTCCAGGTACCTCCCCTAGCGGTG
AHRLHQLAFDTYQE AATCTTCTACCGCACCAGGTACTTCTA
FEEAYIPKEQKYSFL CCGAACCGTCCGAGGGTAGCGCACCA
QNPQTSLCFSESIPTP GGTAGCCCAGCAGGTTCTCCTACCTCC
SNREETQQKSNLELL ACCGAGGAAGGTACTTCTACCGAACC
RISLLLIQSWLEPVQF GTCCGAGGGTAGCGCACCAGGTTCTA
LRSVFANSLVYGAS GCCCTTCTGCTTCCACCGGTACCGGCC
DSNVYDLLKDLEEGI CAGGTAGCTCTACTCCGTCTGGTGCA
QTLMGRLEDGSPRT ACTGGCTCTCCAGGTAGCTCTACTCCG
GQIFKQTYSKFDTNS TCTGGTGCAACCGGCTCCCCAGGTAG
HNDDALLKNYGLLY CTCTACCCCGTCTGGTGCTACCGGCTC
CFRKDMDKVETFLRI TCCAGGTAGCTCTACCCCGTCTGGTGC
VQCRSVEGSCGFGG AACCGGCTCCCCAGGTGCATCCCCGG
SEPATSGSETPGTSES GTACTAGCTCTACCGGTTCTCCAGGTG
ATPESGPGSEPATSG CAAGCGCAAGCGGCGCGCCAAGCACG
SETPGSPAGSPTSTEE GGAGGTACTTCTCCGAGCGGTGAATC
GTSTEPSEGSAPGSE TTCTACCGCACCAGGTTCTACTAGCTC
PATSGSETPGSEPAT TACCGCTGAATCTCCGGGCCCAGGTA
SGSETPGSEPATSGS CTTCTCCGAGCGGTGAATCTTCTACTG
ETPGTSTEPSEGSAP CTCCAGGTACCTCTGAAAGCGCTACT
GTSESATPESGPGSE CCGGAGTCTGGCCCAGGTACCTCTAC
PATSGSETPGTSTEPS TGAACCGTCTGAGGGTAGCGCTCCAG
EGSAP GTACTTCTACTGAACCGTCCGAAGGT
AGCGCACCAGGTTCTAGCCCTTCTGC
ATCTACTGGTACTGGCCCAGGTAGCT
CTACTCCTTCTGGTGCTACCGGCTCTC
CAGGTGCTTCTCCGGGTACTAGCTCTA
CCGGTTCTCCAGGTACTTCTACTCCGG
AAAGCGGTTCCGCATCTCCAGGTACT
TCTCCTAGCGGTGAATCTTCTACTGCT
CCAGGTACCTCTCCTAGCGGCGAATC
TTCTACTGCTCCAGGTACTTCTGAAAG
CGCAACCCCTGAATCCGGTCCAGGTA
GCGAACCGGCTACTTCTGGCTCTGAG
ACTCCAGGTACTTCTACCGAACCGTCC
GAAGGTAGCGCACCAGGTTCTACCAG
CGAATCCCCTTCTGGTACTGCTCCAGG
TTCTACCAGCGAATCCCCTTCTGGCAC
CGCACCAGGTACTTCTACCCCTGAAA
GCGGCTCCGCTTCTCCAGGTAGCCCG
GCAGGCTCTCCGACCTCTACTGAGGA
AGGTACTTCTGAAAGCGCAACCCCGG
AGTCCGGCCCAGGTACCTCTACCGAA
CCGTCTGAGGGCAGCGCACCAGGTAG
CCCTGCTGGCTCTCCAACCTCCACCGA
AGAAGGTACCTCTGAAAGCGCAACCC
CTGAATCCGGCCCAGGTAGCGAACCG
GCAACCTCCGGTTCTGAAACCCCAGG
TAGCTCTACCCCGTCTGGTGCTACCGG
TTCCCCAGGTGCTTCTCCTGGTACTAG
CTCTACCGGTTCTCCAGGTAGCTCTAC
CCCGTCTGGTGCTACTGGCTCTCCAGG
TTCTACTAGCGAATCCCCGTCTGGTAC
TGCTCCAGGTACTTCCCCTAGCGGTGA
ATCTTCTACTGCTCCAGGTTCTACCAG
CTCTACCGCAGAATCTCCGGGTCCAG
GTAGCTCTACCCCTTCTGGTGCAACCG
GCTCTCCAGGTGCATCCCCGGGTACC
AGCTCTACCGGTTCTCCAGGTACTCCG
GGTAGCGGTACCGCTTCTTCCTCTCCA
GGTAGCCCTGCTGGCTCTCCGACTTCT
ACTGAGGAAGGTAGCCCGGCTGGTTC
TCCGACTTCTACTGAGGAAGGTACTTC
TACCGAACCTTCCGAAGGTAGCGCTC
CAGGTTTTCCGACTATTCCGCTGTCTC
GTCTGTTTGATAATGCTATGCTGCGTG
CGCACCGTCTGCACCAGCTGGCCTTTG
ATACTTACCAGGAATTTGAAGAAGCcT
ACATTCCTAAAGAGCAGAAGTACTCT
TTCCTGCAAAACCCACAGACTTCTCTC
TGCTTCAGCGAATCTATTCCGACGCCT
TCCAATCGCGAGGAAACTCAGCAAAA
GTCCAATCTGGAACTACTCCGCATTTC
TCTGCTTCTGATTCAGAGCTGGCTAGA
ACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTG
AAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCT
CTCCGCGTACTGGTCAGATCTTCAAGC
AGACTTACTCTAAATTTGATACTAACA
GCCACAATGACGATGCGCTTCTAAAA
AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTAGCGAACCGGCAACTTCCGGCTCT
GAAACCCCAGGTACTTCTGAAAGCGC
TACTCCTGAGTCTGGCCCAGGTAGCG
AACCTGCTACCTCTGGCTCTGAAACCC
CAGGTAGCCCGGCAGGCTCTCCGACT
TCCACCGAGGAAGGTACCTCTACTGA
ACCTTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCTGGCTCTGAA
ACCCCAGGTAGCGAACCTGCTACCTC
CGGCTCTGAAACTCCAGGTAGCGAAC
CGGCTACTTCCGGTTCTGAAACTCCAG
GTACCTCTACCGAACCTTCCGAAGGC
AGCGCACCAGGTACTTCTGAAAGCGC
AACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTC
CAGGTACTTCTACCGAACCGTCCGAA
GGTAGCGCACCA
AE48- MAEPAGSPTSTEEGT 763 ATGGCTGAACCTGCTGGCTCTCCAAC 764
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE288 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGFPTIPLSRLFDN GCTCTACCCCTTCTGGTGCAACCGGCT
AMLRAHRLHQLAFD CTCCAGGTGCTTCTCCGGGCACCAGCT
TYQEFEEAYIPKEQK CTACCGGTTCTCCAGGTTTTCCGACTA
YSFLQNPQTSLCFSE TTCCGCTGTCTCGTCTGTTTGATAATG
SIPTPSNREETQQKS CTATGCTGCGTGCGCACCGTCTGCACC
NLELLRISLLLIQSWL AGCTGGCCTTTGATACTTACCAGGAA
EPVQFLRSVFANSLV TTTGAAGAAGCcTACATTCCTAAAGAG
YGASDSNVYDLLKD CAGAAGTACTCTTTCCTGCAAAACCC
LEEGIQTLMGRLEDG ACAGACTTCTCTCTGCTTCAGCGAATC
SPRTGQIFKQTYSKF TATTCCGACGCCTTCCAATCGCGAGG
DTNSHNDDALLKNY AAACTCAGCAAAAGTCCAATCTGGAA
GLLYCFRKDMDKVE CTACTCCGCATTTCTCTGCTTCTGATT
TFLRIVQCRSVEGSC CAGAGCTGGCTAGAACCAGTGCAATT
GFGGTSESATPESGP TCTGCGTTCCGTCTTCGCCAATAGCCT
GSEPATSGSETPGTS AGTTTATGGCGCATCCGACAGCAACG
ESATPESGPGSEPAT TATACGATCTCCTGAAAGATCTCGAG
SGSETPGTSESATPES GAAGGCATTCAGACCCTGATGGGTCG
GPGTSTEPSEGSAPG TCTCGAGGATGGCTCTCCGCGTACTG
SPAGSPTSTEEGTSES GTCAGATCTTCAAGCAGACTTACTCTA
ATPESGPGSEPATSG AATTTGATACTAACAGCCACAATGAC
SETPGTSESATPESGP GATGCGCTTCTAAAAAACTATGGTCT
GSPAGSPTSTEEGSP GCTGTATTGTTTTCGTAAAGATATGGA
AGSPTSTEEGTSTEPS CAAAGTTGAAACCTTCCTGCGTATTGT
EGSAPGTSESATPES TCAGTGTCGTTCCGTTGAGGGCAGCT
GPGTSESATPESGPG GTGGTTTCTAAGGTGGTACCTCTGAA
TSESATPESGPGSEP AGCGCAACTCCTGAGTCTGGCCCAGG
ATSGSETPGSEPATS TAGCGAACCTGCTACCTCCGGCTCTG
GSETPGSPAGSPTST AGACTCCAGGTACCTCTGAAAGCGCA
EEGTSTEPSEGSAPG ACCCCGGAATCTGGTCCAGGTAGCGA
TSTEPSEGSAPGSEP ACCTGCAACCTCTGGCTCTGAAACCC
ATSGSETPGTSESAT CAGGTACCTCTGAAAGCGCTACTCCT
PESGPGTSTEPSEGS GAATCTGGCCCAGGTACTTCTACTGA
AP ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AM48- MAEPAGSPTSTEEGA 765 ATGGCTGAACCTGCTGGCTCTCCAAC 766
hGH- SPGTSSTGSPGSSTPS CTCCACTGAGGAAGGTGCATCCCCGG
AE288 GATGSPGSSTPSGAT GCACCAGCTCTACCGGTTCTCCAGGT
GSPGFPTIPLSRLFDN AGCTCTACCCCGTCTGGTGCTACCGGC
AMLRAHRLHQLAFD TCTCCAGGTAGCTCTACCCCGTCTGGT
TYQEFEEAYIPKEQK GCTACTGGCTCTCCAGGTTTTCCGACT
YSFLQNPQTSLCFSE ATTCCGCTGTCTCGTCTGTTTGATAAT
SIPTPSNREETQQKS GCTATGCTGCGTGCGCACCGTCTGCA
NLELLRISLLLIQSWL CCAGCTGGCCTTTGATACTTACCAGG
EPVQFLRSVFANSLV AATTTGAAGAAGCcTACATTCCTAAAG
YGASDSNVYDLLKD AGCAGAAGTACTCTTTCCTGCAAAAC
LEEGIQTLMGRLEDG CCACAGACTTCTCTCTGCTTCAGCGAA
SPRTGQIFKQTYSKF TCTATTCCGACGCCTTCCAATCGCGAG
DTNSHNDDALLKNY GAAACTCAGCAAAAGTCCAATCTGGA
GLLYCFRKDMDKVE ACTACTCCGCATTTCTCTGCTTCTGAT
TFLRIVQCRSVEGSC TCAGAGCTGGCTAGAACCAGTGCAAT
GFGGTSESATPESGP TTCTGCGTTCCGTCTTCGCCAATAGCC
GSEPATSGSETPGTS TAGTTTATGGCGCATCCGACAGCAAC
ESATPESGPGSEPAT GTATACGATCTCCTGAAAGATCTCGA
SGSETPGTSESATPES GGAAGGCATTCAGACCCTGATGGGTC
GPGTSTEPSEGSAPG GTCTCGAGGATGGCTCTCCGCGTACT
SPAGSPTSTEEGTSES GGTCAGATCTTCAAGCAGACTTACTCT
ATPESGPGSEPATSG AAATTTGATACTAACAGCCACAATGA
SETPGTSESATPESGP CGATGCGCTTCTAAAAAACTATGGTC
GSPAGSPTSTEEGSP TGCTGTATTGTTTTCGTAAAGATATGG
AGSPTSTEEGTSTEPS ACAAAGTTGAAACCTTCCTGCGTATT
EGSAPGTSESATPES GTTCAGTGTCGTTCCGTTGAGGGCAG
GPGTSESATPESGPG CTGTGGTTTCTAAGGTGGTACCTCTGA
TSESATPESGPGSEP AAGCGCAACTCCTGAGTCTGGCCCAG
ATSGSETPGSEPATS GTAGCGAACCTGCTACCTCCGGCTCT
GSETPGSPAGSPTST GAGACTCCAGGTACCTCTGAAAGCGC
EEGTSTEPSEGSAPG AACCCCGGAATCTGGTCCAGGTAGCG
TSTEPSEGSAPGSEP AACCTGCAACCTCTGGCTCTGAAACC
ATSGSETPGTSESAT CCAGGTACCTCTGAAAGCGCTACTCC
PESGPGTSTEPSEGS TGAATCTGGCCCAGGTACTTCTACTGA
AP ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AE144- GSEPATSGSETPGTS 767 GGTAGCGAACCGGCAACTTCCGGCTC 768
hGH- ESATPESGPGSEPAT TGAAACCCCAGGTACTTCTGAAAGCG
AE288 SGSETPGSPAGSPTST CTACTCCTGAGTCTGGCCCAGGTAGC
EEGTSTEPSEGSAPG GAACCTGCTACCTCTGGCTCTGAAAC
SEPATSGSETPGSEP CCCAGGTAGCCCGGCAGGCTCTCCGA
ATSGSETPGSEPATS CTTCCACCGAGGAAGGTACCTCTACT
GSETPGTSTEPSEGS GAACCTTCTGAGGGTAGCGCTCCAGG
APGTSESATPESGPG TAGCGAACCGGCAACCTCTGGCTCTG
SEPATSGSETPGTSTE AAACCCCAGGTAGCGAACCTGCTACC
PSEGSAPGFPTIPLSR TCCGGCTCTGAAACTCCAGGTAGCGA
LFDNAMLRAHRLHQ ACCGGCTACTTCCGGTTCTGAAACTCC
LAFDTYQEFEEAYIP AGGTACCTCTACCGAACCTTCCGAAG
KEQKYSFLQNPQTSL GCAGCGCACCAGGTACTTCTGAAAGC
CFSESIPTPSNREETQ GCAACCCCTGAATCCGGTCCAGGTAG
QKSNLELLRISLLLIQ CGAACCGGCTACTTCTGGCTCTGAGA
SWLEPVQFLRSVFA CTCCAGGTACTTCTACCGAACCGTCCG
NSLVYGASDSNVYD AAGGTAGCGCACCAGGTTTTCCGACT
LLKDLEEGIQTLMGR ATTCCGCTGTCTCGTCTGTTTGATAAT
LEDGSPRTGQIFKQT GCTATGCTGCGTGCGCACCGTCTGCA
YSKFDTNSHNDDAL CCAGCTGGCCTTTGATACTTACCAGG
LKNYGLLYCFRKDM AATTTGAAGAAGCcTACATTCCTAAAG
DKVETFLRIVQCRSV AGCAGAAGTACTCTTTCCTGCAAAAC
EGSCGFGGTSESATP CCACAGACTTCTCTCTGCTTCAGCGAA
ESGPGSEPATSGSET TCTATTCCGACGCCTTCCAATCGCGAG
PGTSESATPESGPGS GAAACTCAGCAAAAGTCCAATCTGGA
EPATSGSETPGTSES ACTACTCCGCATTTCTCTGCTTCTGAT
ATPESGPGTSTEPSE TCAGAGCTGGCTAGAACCAGTGCAAT
GSAPGSPAGSPTSTE TTCTGCGTTCCGTCTTCGCCAATAGCC
EGTSESATPESGPGS TAGTTTATGGCGCATCCGACAGCAAC
EPATSGSETPGTSES GTATACGATCTCCTGAAAGATCTCGA
ATPESGPGSPAGSPT GGAAGGCATTCAGACCCTGATGGGTC
STEEGSPAGSPTSTEE GTCTCGAGGATGGCTCTCCGCGTACT
GTSTEPSEGSAPGTS GGTCAGATCTTCAAGCAGACTTACTCT
ESATPESGPGTSESA AAATTTGATACTAACAGCCACAATGA
TPESGPGTSESATPES CGATGCGCTTCTAAAAAACTATGGTC
GPGSEPATSGSETPG TGCTGTATTGTTTTCGTAAAGATATGG
SEPATSGSETPGSPA ACAAAGTTGAAACCTTCCTGCGTATT
GSPTSTEEGTSTEPSE GTTCAGTGTCGTTCCGTTGAGGGCAG
GSAPGTSTEPSEGSA CTGTGGTTTCTAAGGTGGTACCTCTGA
PGSEPATSGSETPGT AAGCGCAACTCCTGAGTCTGGCCCAG
SESATPESGPGTSTEP GTAGCGAACCTGCTACCTCCGGCTCT
SEGSAP GAGACTCCAGGTACCTCTGAAAGCGC
AACCCCGGAATCTGGTCCAGGTAGCG
AACCTGCAACCTCTGGCTCTGAAACC
CCAGGTACCTCTGAAAGCGCTACTCC
TGAATCTGGCCCAGGTACTTCTACTGA
ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AE288- GTSESATPESGPGSE 769 GGTACCTCTGAAAGCGCAACTCCTGA 770
hGH- PATSGSETPGTSESA GTCTGGCCCAGGTAGCGAACCTGCTA
AE288 TPESGPGSEPATSGS CCTCCGGCTCTGAGACTCCAGGTACCT
ETPGTSESATPESGP CTGAAAGCGCAACCCCGGAATCTGGT
GTSTEPSEGSAPGSP CCAGGTAGCGAACCTGCAACCTCTGG
AGSPTSTEEGTSESA CTCTGAAACCCCAGGTACCTCTGAAA
TPESGPGSEPATSGS GCGCTACTCCTGAATCTGGCCCAGGT
ETPGTSESATPESGP ACTTCTACTGAACCGTCCGAGGGCAG
GSPAGSPTSTEEGSP CGCACCAGGTAGCCCTGCTGGCTCTC
AGSPTSTEEGTSTEPS CAACCTCCACCGAAGAAGGTACCTCT
EGSAPGTSESATPES GAAAGCGCAACCCCTGAATCCGGCCC
GPGTSESATPESGPG AGGTAGCGAACCGGCAACCTCCGGTT
TSESATPESGPGSEP CTGAAACCCCAGGTACTTCTGAAAGC
ATSGSETPGSEPATS GCTACTCCTGAGTCCGGCCCAGGTAG
GSETPGSPAGSPTST CCCGGCTGGCTCTCCGACTTCCACCGA
EEGTSTEPSEGSAPG GGAAGGTAGCCCGGCTGGCTCTCCAA
TSTEPSEGSAPGSEP CTTCTACTGAAGAAGGTACTTCTACCG
ATSGSETPGTSESAT AACCTTCCGAGGGCAGCGCACCAGGT
PESGPGTSTEPSEGS ACTTCTGAAAGCGCTACCCCTGAGTC
APGFPTIPLSRLFDNA CGGCCCAGGTACTTCTGAAAGCGCTA
MLRAHRLHQLAFDT CTCCTGAATCCGGTCCAGGTACTTCTG
YQEFEEAYIPKEQKY AAAGCGCTACCCCGGAATCTGGCCCA
SFLQNPQTSLCFSESI GGTAGCGAACCGGCTACTTCTGGTTCT
PTPSNREETQQKSNL GAAACCCCAGGTAGCGAACCGGCTAC
ELLRISLLLIQSWLEP CTCCGGTTCTGAAACTCCAGGTAGCC
VQFLRSVFANSLVY CAGCAGGCTCTCCGACTTCCACTGAG
GASDSNVYDLLKDL GAAGGTACTTCTACTGAACCTTCCGA
EEGIQTLMGRLEDGS AGGCAGCGCACCAGGTACCTCTACTG
PRTGQIFKQTYSKFD AACCTTCTGAGGGCAGCGCTCCAGGT
TNSHNDDALLKNYG AGCGAACCTGCAACCTCTGGCTCTGA
LLYCFRKDMDKVET AACCCCAGGTACCTCTGAAAGCGCTA
FLRIVQCRSVEGSCG CTCCTGAATCTGGCCCAGGTACTTCTA
FGGTSESATPESGPG CTGAACCGTCCGAGGGCAGCGCACCA
SEPATSGSETPGTSES GGTTTTCCGACTATTCCGCTGTCTCGT
ATPESGPGSEPATSG CTGTTTGATAATGCTATGCTGCGTGCG
SETPGTSESATPESGP CACCGTCTGCACCAGCTGGCCTTTGAT
GTSTEPSEGSAPGSP ACTTACCAGGAATTTGAAGAAGCcTA
AGSPTSTEEGTSESA CATTCCTAAAGAGCAGAAGTACTCTT
TPESGPGSEPATSGS TCCTGCAAAACCCACAGACTTCTCTCT
ETPGTSESATPESGP GCTTCAGCGAATCTATTCCGACGCCTT
GSPAGSPTSTEEGSP CCAATCGCGAGGAAACTCAGCAAAAG
AGSPTSTEEGTSTEPS TCCAATCTGGAACTACTCCGCATTTCT
EGSAPGTSESATPES CTGCTTCTGATTCAGAGCTGGCTAGA
GPGTSESATPESGPG ACCAGTGCAATTTCTGCGTTCCGTCTT
TSESATPESGPGSEP CGCCAATAGCCTAGTTTATGGCGCAT
ATSGSETPGSEPATS CCGACAGCAACGTATACGATCTCCTG
GSETPGSPAGSPTST AAAGATCTCGAGGAAGGCATTCAGAC
EEGTSTEPSEGSAPG CCTGATGGGTCGTCTCGAGGATGGCT
TSTEPSEGSAPGSEP CTCCGCGTACTGGTCAGATCTTCAAGC
ATSGSETPGTSESAT AGACTTACTCTAAATTTGATACTAACA
PESGPGTSTEPSEGS GCCACAATGACGATGCGCTTCTAAAA
AP AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTACCTCTGAAAGCGCAACTCCTGAG
TCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTC
TGAAAGCGCAACCCCGGAATCTGGTC
CAGGTAGCGAACCTGCAACCTCTGGC
TCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTA
CTTCTACTGAACCGTCCGAGGGCAGC
GCACCAGGTAGCCCTGCTGGCTCTCC
AACCTCCACCGAAGAAGGTACCTCTG
AAAGCGCAACCCCTGAATCCGGCCCA
GGTAGCGAACCGGCAACCTCCGGTTC
TGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGC
CCGGCTGGCTCTCCGACTTCCACCGA
GGAAGGTAGCCCGGCTGGCTCTCCAA
CTTCTACTGAAGAAGGTACTTCTACCG
AACCTTCCGAGGGCAGCGCACCAGGT
ACTTCTGAAAGCGCTACCCCTGAGTC
CGGCCCAGGTACTTCTGAAAGCGCTA
CTCCTGAATCCGGTCCAGGTACTTCTG
AAAGCGCTACCCCGGAATCTGGCCCA
GGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCC
CAGCAGGCTCTCCGACTTCCACTGAG
GAAGGTACTTCTACTGAACCTTCCGA
AGGCAGCGCACCAGGTACCTCTACTG
AACCTTCTGAGGGCAGCGCTCCAGGT
AGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCA
AF144- GTSTPESGSASPGTSP 771 GGTACTTCTACTCCGGAAAGCGGTTC 772
hGH- SGESSTAPGTSPSGES CGCATCTCCAGGTACTTCTCCTAGCGG
AE288 STAPGSTSSTAESPGP TGAATCTTCTACTGCTCCAGGTACCTC
GSTSESPSGTAPGSTS TCCTAGCGGCGAATCTTCTACTGCTCC
STAESPGPGTSPSGES AGGTTCTACCAGCTCTACCGCTGAATC
STAPGTSTPESGSASP TCCTGGCCCAGGTTCTACCAGCGAAT
GSTSSTAESPGPGTSP CCCCGTCTGGCACCGCACCAGGTTCT
SGESSTAPGTSPSGES ACTAGCTCTACCGCAGAATCTCCGGG
STAPGTSPSGESSTAP TCCAGGTACTTCCCCTAGCGGTGAATC
GFPTIPLSRLFDNAM TTCTACTGCTCCAGGTACCTCTACTCC
LRAHRLHQLAFDTY GGAAAGCGGCTCCGCATCTCCAGGTT
QEFEEAYIPKEQKYS CTACTAGCTCTACTGCTGAATCTCCTG
FLQNPQTSLCFSESIP GTCCAGGTACCTCCCCTAGCGGCGAA
TPSNREETQQKSNLE TCTTCTACTGCTCCAGGTACCTCTCCT
LLRISLLLIQSWLEPV AGCGGCGAATCTTCTACCGCTCCAGG
QFLRSVFANSLVYG TACCTCCCCTAGCGGTGAATCTTCTAC
ASDSNVYDLLKDLE CGCACCAGGTTTTCCGACTATTCCGCT
EGIQTLMGRLEDGSP GTCTCGTCTGTTTGATAATGCTATGCT
RTGQIFKQTYSKFDT GCGTGCGCACCGTCTGCACCAGCTGG
NSHNDDALLKNYGL CCTTTGATACTTACCAGGAATTTGAAG
LYCFRKDMDKVETF AAGCcTACATTCCTAAAGAGCAGAAG
LRIVQCRSVEGSCGF TACTCTTTCCTGCAAAACCCACAGACT
GGTSESATPESGPGS TCTCTCTGCTTCAGCGAATCTATTCCG
EPATSGSETPGTSES ACGCCTTCCAATCGCGAGGAAACTCA
ATPESGPGSEPATSG GCAAAAGTCCAATCTGGAACTACTCC
SETPGTSESATPESGP GCATTTCTCTGCTTCTGATTCAGAGCT
GTSTEPSEGSAPGSP GGCTAGAACCAGTGCAATTTCTGCGT
AGSPTSTEEGTSESA TCCGTCTTCGCCAATAGCCTAGTTTAT
TPESGPGSEPATSGS GGCGCATCCGACAGCAACGTATACGA
ETPGTSESATPESGP TCTCCTGAAAGATCTCGAGGAAGGCA
GSPAGSPTSTEEGSP TTCAGACCCTGATGGGTCGTCTCGAG
AGSPTSTEEGTSTEPS GATGGCTCTCCGCGTACTGGTCAGAT
EGSAPGTSESATPES CTTCAAGCAGACTTACTCTAAATTTGA
GPGTSESATPESGPG TACTAACAGCCACAATGACGATGCGC
TSESATPESGPGSEP TTCTAAAAAACTATGGTCTGCTGTATT
ATSGSETPGSEPATS GTTTTCGTAAAGATATGGACAAAGTT
GSETPGSPAGSPTST GAAACCTTCCTGCGTATTGTTCAGTGT
EEGTSTEPSEGSAPG CGTTCCGTTGAGGGCAGCTGTGGTTTC
TSTEPSEGSAPGSEP TAAGGTGGTACCTCTGAAAGCGCAAC
ATSGSETPGTSESAT TCCTGAGTCTGGCCCAGGTAGCGAAC
PESGPGTSTEPSEGS CTGCTACCTCCGGCTCTGAGACTCCAG
AP GTACCTCTGAAAGCGCAACCCCGGAA
TCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCTGAATCTGGCC
CAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCAGGTAGCCCTGCTGG
CTCTCCAACCTCCACCGAAGAAGGTA
CCTCTGAAAGCGCAACCCCTGAATCC
GGCCCAGGTAGCGAACCGGCAACCTC
CGGTTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCC
ACCGAGGAAGGTAGCCCGGCTGGCTC
TCCAACTTCTACTGAAGAAGGTACTTC
TACCGAACCTTCCGAGGGCAGCGCAC
CAGGTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTA
CTTCTGAAAGCGCTACCCCGGAATCT
GGCCCAGGTAGCGAACCGGCTACTTC
TGGTTCTGAAACCCCAGGTAGCGAAC
CGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACC
TCTACTGAACCTTCTGAGGGCAGCGC
TCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAA
AGCGCTACTCCTGAATCTGGCCCAGG
TACTTCTACTGAACCGTCCGAGGGCA
GCGCACCA
AD576- GSSESGSSEGGPGSG 773 GGTTCCTCTGAAAGCGGTTCTTCCGAA 774
hGH- GEPSESGSSGSSESGS GGTGGTCCAGGTTCCTCTGAAAGCGG
AE288 SEGGPGSSESGSSEG TTCTTCTGAGGGTGGTCCAGGTGAATC
GPGSSESGSSEGGPG TCCGGGTGGCTCCAGCGGTTCCGAGT
SSESGSSEGGPGSSES CAGGTTCTGGTGGCGAACCTTCCGAG
GSSEGGPGESPGGSS TCTGGTAGCTCAGGTGAATCTCCGGG
GSESGSEGSSGPGES TGGTTCTAGCGGTTCCGAGTCAGGTG
SGSSESGSSEGGPGS AATCTCCGGGTGGTTCCAGCGGTTCTG
SESGSSEGGPGSSES AGTCAGGTTCCTCCGAAAGCGGTTCTT
GSSEGGPGSGGEPSE CTGAGGGCGGTCCAGGTTCCTCCGAA
SGSSGESPGGSSGSE AGCGGTTCTTCCGAGGGCGGTCCAGG
SGESPGGSSGSESGS TTCTTCTGAAAGCGGTTCTTCCGAGGG
GGEPSESGSSGSSES CGGTCCAGGTGAATCTCCTGGTGGTTC
GSSEGGPGSGGEPSE CAGCGGTTCCGAGTCAGGTGAATCTC
SGSSGSGGEPSESGS CAGGTGGCTCTAGCGGTTCCGAGTCA
SGSEGSSGPGESSGE GGTGAATCTCCTGGTGGTTCTAGCGGT
SPGGSSGSESGSGGE TCTGAATCAGGTTCCTCCGAAAGCGG
PSESGSSGSGGEPSES TTCTTCTGAGGGCGGTCCAGGTTCCTC
GSSGSGGEPSESGSS CGAAAGCGGTTCTTCCGAGGGCGGTC
GSSESGSSEGGPGES CAGGTTCTTCTGAAAGCGGTTCTTCCG
PGGSSGSESGESPGG AGGGCGGTCCAGGTTCCTCTGAAAGC
SSGSESGESPGGSSG GGTTCTTCTGAGGGCGGTCCAGGTTCT
SESGESPGGSSGSES TCCGAAAGCGGTTCTTCCGAGGGCGG
GESPGGSSGSESGSS TCCAGGTTCTTCCGAAAGCGGTTCTTC
ESGSSEGGPGSGGEP TGAAGGCGGTCCAGGTTCTGGTGGCG
SESGSSGSEGSSGPG AACCGTCCGAGTCTGGTAGCTCAGGT
ESSGSSESGSSEGGP GAATCTCCGGGTGGCTCTAGCGGTTC
GSGGEPSESGSSGSS CGAGTCAGGTGAATCTCCTGGTGGTT
ESGSSEGGPGSGGEP CCAGCGGTTCCGAGTCAGGTTCCGGT
SESGSSGESPGGSSG GGCGAACCGTCCGAATCTGGTAGCTC
SESGESPGGSSGSES AGGTAGCGAAGGTTCTTCTGGTCCAG
GSSESGSSEGGPGSG GCGAATCTTCAGGTTCCTCTGAAAGC
GEPSESGSSGSSESGS GGTTCTTCTGAGGGCGGTCCAGGTTCC
SEGGPGSGGEPSESG GGTGGCGAACCGTCCGAATCTGGTAG
SSGSGGEPSESGSSG CTCAGGTAGCGAAGGTTCTTCTGGTCC
ESPGGSSGSESGSEG AGGCGAATCTTCAGGTTCCTCTGAAA
SSGPGESSGSSESGSS GCGGTTCTTCTGAGGGCGGTCCAGGT
EGGPGSEGSSGPGES TCCGGTGGCGAACCTTCCGAATCTGG
SGFPTIPLSRLFDNA TAGCTCAGGTGAATCTCCGGGTGGTT
MLRAHRLHQLAFDT CTAGCGGTTCTGAGTCAGGTTCTGGTG
YQEFEEAYIPKEQKY GTGAACCTTCCGAGTCTGGTAGCTCA
SFLQNPQTSLCFSESI GGTTCTGGTGGCGAACCATCCGAGTC
PTPSNREETQQKSNL TGGTAGCTCAGGTTCTTCCGAAAGCG
ELLRISLLLIQSWLEP GTTCTTCCGAAGGCGGTCCAGGTTCTG
VQFLRSVFANSLVY GTGGTGAACCGTCCGAATCTGGTAGC
GASDSNVYDLLKDL TCAGGTTCTGGTGGCGAACCATCCGA
EEGIQTLMGRLEDGS ATCTGGTAGCTCAGGTAGCGAAGGTT
PRTGQIFKQTYSKFD CTTCTGGTCCTGGCGAATCTTCAGGTG
TNSHNDDALLKNYG AATCTCCAGGTGGCTCTAGCGGTTCC
LLYCFRKDMDKVET GAATCAGGTAGCGAAGGTTCTTCCGG
FLRIVQCRSVEGSCG TCCAGGTGAATCTTCAGGTAGCGAAG
FGGTSESATPESGPG GTTCTTCTGGTCCTGGTGAATCCTCAG
SEPATSGSETPGTSES GTTCCGGTGGCGAACCATCTGAATCT
ATPESGPGSEPATSG GGTAGCTCAGGTTCCTCTGAAAGCGG
SETPGTSESATPESGP TTCTTCCGAAGGTGGTCCAGGTTCCTC
GTSTEPSEGSAPGSP TGAAAGCGGTTCTTCTGAGGGTGGTC
AGSPTSTEEGTSESA CAGGTGAATCTCCGGGTGGCTCCAGC
TPESGPGSEPATSGS GGTTCCGAGTCAGGTTCTGGTGGCGA
ETPGTSESATPESGP ACCATCCGAATCTGGTAGCTCAGGTA
GSPAGSPTSTEEGSP GCGAAGGTTCTTCTGGTCCTGGCGAA
AGSPTSTEEGTSTEPS TCTTCAGGTGAATCTCCAGGTGGCTCT
EGSAPGTSESATPES AGCGGTTCCGAATCAGGTAGCGAAGG
GPGTSESATPESGPG TTCTTCCGGTCCTGGTGAGTCTTCAGG
TSESATPESGPGSEP TGAATCTCCAGGTGGCTCTAGCGGTTC
ATSGSETPGSEPATS CGAGTCAGGTAGCGAAGGTTCTTCTG
GSETPGSPAGSPTST GTCCTGGCGAGTCCTCAGGTTTTCCGA
EEGTSTEPSEGSAPG CTATTCCGCTGTCTCGTCTGTTTGATA
TSTEPSEGSAPGSEP ATGCTATGCTGCGTGCGCACCGTCTGC
ATSGSETPGTSESAT ACCAGCTGGCCTTTGATACTTACCAG
PESGPGTSTEPSEGS GAATTTGAAGAAGCcTACATTCCTAAA
AP GAGCAGAAGTACTCTTTCCTGCAAAA
CCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGA
GGAAACTCAGCAAAAGTCCAATCTGG
AACTACTCCGCATTTCTCTGCTTCTGA
TTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTCTTCGCCAATAGC
CTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCG
AGGAAGGCATTCAGACCCTGATGGGT
CGTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTACCTCTGA
AAGCGCAACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCCGGCTCT
GAGACTCCAGGTACCTCTGAAAGCGC
AACCCCGGAATCTGGTCCAGGTAGCG
AACCTGCAACCTCTGGCTCTGAAACC
CCAGGTACCTCTGAAAGCGCTACTCC
TGAATCTGGCCCAGGTACTTCTACTGA
ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AE576- GSPAGSPTSTEEGTS 775 GGTAGCCCGGCTGGCTCTCCTACCTCT 776
hGH- ESATPESGPGTSTEPS ACTGAGGAAGGTACTTCTGAAAGCGC
AE288 EGSAPGSPAGSPTST TACTCCTGAGTCTGGTCCAGGTACCTC
EEGTSTEPSEGSAPG TACTGAACCGTCCGAAGGTAGCGCTC
TSTEPSEGSAPGTSES CAGGTAGCCCAGCAGGCTCTCCGACT
ATPESGPGSEPATSG TCCACTGAGGAAGGTACTTCTACTGA
SETPGSEPATSGSETP ACCTTCCGAAGGCAGCGCACCAGGTA
GSPAGSPTSTEEGTS CCTCTACTGAACCTTCTGAGGGCAGC
ESATPESGPGTSTEPS GCTCCAGGTACTTCTGAAAGCGCTAC
EGSAPGTSTEPSEGS CCCGGAATCTGGCCCAGGTAGCGAAC
APGSPAGSPTSTEEG CGGCTACTTCTGGTTCTGAAACCCCAG
TSTEPSEGSAPGTSTE GTAGCGAACCGGCTACCTCCGGTTCT
PSEGSAPGTSESATP GAAACTCCAGGTAGCCCGGCAGGCTC
ESGPGTSTEPSEGSA TCCGACCTCTACTGAGGAAGGTACTT
PGTSESATPESGPGS CTGAAAGCGCAACCCCGGAGTCCGGC
EPATSGSETPGTSTEP CCAGGTACCTCTACCGAACCGTCTGA
SEGSAPGTSTEPSEG GGGCAGCGCACCAGGTACTTCTACCG
SAPGTSESATPESGP AACCGTCCGAGGGTAGCGCACCAGGT
GTSESATPESGPGSP AGCCCAGCAGGTTCTCCTACCTCCACC
AGSPTSTEEGTSESA GAGGAAGGTACTTCTACCGAACCGTC
TPESGPGSEPATSGS CGAGGGTAGCGCACCAGGTACCTCTA
ETPGTSESATPESGP CTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACC
EGSAPGTSTEPSEGS GTCCGAAGGTAGCGCACCAGGTACTT
APGTSTEPSEGSAPG CTGAAAGCGCAACCCCTGAATCCGGT
TSTEPSEGSAPGSPA CCAGGTAGCGAACCGGCTACTTCTGG
GSPTSTEEGTSTEPSE CTCTGAGACTCCAGGTACTTCTACCGA
GSAPGTSESATPESG ACCGTCCGAAGGTAGCGCACCAGGTA
PGSEPATSGSETPGT CTTCTACTGAACCGTCTGAAGGTAGC
SESATPESGPGSEPA GCACCAGGTACTTCTGAAAGCGCAAC
TSGSETPGTSESATPE CCCGGAATCCGGCCCAGGTACCTCTG
SGPGTSTEPSEGSAP AAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSP GGTAGCCCTGCTGGCTCTCCAACCTCC
AGSPTSTEEGSPAGS ACCGAAGAAGGTACCTCTGAAAGCGC
PTSTEEGSPAGSPTST AACCCCTGAATCCGGCCCAGGTAGCG
EEGTSESATPESGPG AACCGGCAACCTCCGGTTCTGAAACC
TSTEPSEGSAPGFPTI CCAGGTACCTCTGAAAGCGCTACTCC
PLSRLFDNAMLRAH GGAGTCTGGCCCAGGTACCTCTACTG
RLHQLAFDTYQEFEE AACCGTCTGAGGGTAGCGCTCCAGGT
AYIPKEQKYSFLQNP ACTTCTACTGAACCGTCCGAAGGTAG
QTSLCFSESIPTPSNR CGCACCAGGTACTTCTACCGAACCGT
EETQQKSNLELLRIS CCGAAGGCAGCGCTCCAGGTACCTCT
LLLIQSWLEPVQFLR ACTGAACCTTCCGAGGGCAGCGCTCC
SVFANSLVYGASDS AGGTACCTCTACCGAACCTTCTGAAG
NVYDLLKDLEEGIQT GTAGCGCACCAGGTACTTCTACCGAA
LMGRLEDGSPRTGQI CCGTCCGAGGGTAGCGCACCAGGTAG
FKQTYSKFDTNSHN CCCAGCAGGTTCTCCTACCTCCACCGA
DDALLKNYGLLYCF GGAAGGTACTTCTACCGAACCGTCCG
RKDMDKVETFLRIV AGGGTAGCGCACCAGGTACCTCTGAA
QCRSVEGSCGFGGTS AGCGCAACTCCTGAGTCTGGCCCAGG
ESATPESGPGSEPAT TAGCGAACCTGCTACCTCCGGCTCTG
SGSETPGTSESATPES AGACTCCAGGTACCTCTGAAAGCGCA
GPGSEPATSGSETPG ACCCCGGAATCTGGTCCAGGTAGCGA
TSESATPESGPGTSTE ACCTGCAACCTCTGGCTCTGAAACCC
PSEGSAPGSPAGSPT CAGGTACCTCTGAAAGCGCTACTCCT
STEEGTSESATPESGP GAATCTGGCCCAGGTACTTCTACTGA
GSEPATSGSETPGTS ACCGTCCGAGGGCAGCGCACCAGGTA
ESATPESGPGSPAGS CTTCTGAAAGCGCTACTCCTGAGTCCG
PTSTEEGSPAGSPTST GCCCAGGTAGCCCGGCTGGCTCTCCG
EEGTSTEPSEGSAPG ACTTCCACCGAGGAAGGTAGCCCGGC
TSESATPESGPGTSES TGGCTCTCCAACTTCTACTGAAGAAG
ATPESGPGTSESATP GTAGCCCGGCAGGCTCTCCGACCTCT
ESGPGSEPATSGSET ACTGAGGAAGGTACTTCTGAAAGCGC
PGSEPATSGSETPGSP AACCCCGGAGTCCGGCCCAGGTACCT
AGSPTSTEEGTSTEPS CTACCGAACCGTCTGAGGGCAGCGCA
EGSAPGTSTEPSEGS CCAGGTTTTCCGACTATTCCGCTGTCT
APGSEPATSGSETPG CGTCTGTTTGATAATGCTATGCTGCGT
TSESATPESGPGTSTE GCGCACCGTCTGCACCAGCTGGCCTTT
PSEGSAP GATACTTACCAGGAATTTGAAGAAGC
cTACATTCCTAAAGAGCAGAAGTACTC
TTTCCTGCAAAACCCACAGACTTCTCT
CTGCTTCAGCGAATCTATTCCGACGCC
TTCCAATCGCGAGGAAACTCAGCAAA
AGTCCAATCTGGAACTACTCCGCATTT
CTCTGCTTCTGATTCAGAGCTGGCTAG
AACCAGTGCAATTTCTGCGTTCCGTCT
TCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTG
AAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCT
CTCCGCGTACTGGTCAGATCTTCAAGC
AGACTTACTCTAAATTTGATACTAACA
GCCACAATGACGATGCGCTTCTAAAA
AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTACCTCTGAAAGCGCAACTCCTGAG
TCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTC
TGAAAGCGCAACCCCGGAATCTGGTC
CAGGTAGCGAACCTGCAACCTCTGGC
TCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTA
CTTCTACTGAACCGTCCGAGGGCAGC
GCACCAGGTAGCCCTGCTGGCTCTCC
AACCTCCACCGAAGAAGGTACCTCTG
AAAGCGCAACCCCTGAATCCGGCCCA
GGTAGCGAACCGGCAACCTCCGGTTC
TGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGC
CCGGCTGGCTCTCCGACTTCCACCGA
GGAAGGTAGCCCGGCTGGCTCTCCAA
CTTCTACTGAAGAAGGTACTTCTACCG
AACCTTCCGAGGGCAGCGCACCAGGT
ACTTCTGAAAGCGCTACCCCTGAGTC
CGGCCCAGGTACTTCTGAAAGCGCTA
CTCCTGAATCCGGTCCAGGTACTTCTG
AAAGCGCTACCCCGGAATCTGGCCCA
GGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCC
CAGCAGGCTCTCCGACTTCCACTGAG
GAAGGTACTTCTACTGAACCTTCCGA
AGGCAGCGCACCAGGTACCTCTACTG
AACCTTCTGAGGGCAGCGCTCCAGGT
AGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCA
AF576- GSTSSTAESPGPGSTS 777 GGTTCTACTAGCTCTACCGCTGAATCT 778
hGH- STAESPGPGSTSESPS CCTGGCCCAGGTTCCACTAGCTCTACC
AE288 GTAPGSTSSTAESPG GCAGAATCTCCGGGCCCAGGTTCTAC
PGSTSSTAESPGPGTS TAGCGAATCCCCTTCTGGTACCGCTCC
TPESGSASPGSTSESP AGGTTCTACTAGCTCTACCGCTGAATC
SGTAPGTSPSGESST TCCGGGTCCAGGTTCTACCAGCTCTAC
APGSTSESPSGTAPG TGCAGAATCTCCTGGCCCAGGTACTTC
STSESPSGTAPGTSPS TACTCCGGAAAGCGGTTCCGCTTCTCC
GESSTAPGSTSESPSG AGGTTCTACCAGCGAATCTCCTTCTGG
TAPGSTSESPSGTAP CACCGCTCCAGGTACCTCTCCTAGCG
GTSPSGESSTAPGSTS GCGAATCTTCTACCGCTCCAGGTTCTA
ESPSGTAPGSTSESPS CTAGCGAATCTCCTTCTGGCACTGCAC
GTAPGSTSESPSGTA CAGGTTCTACCAGCGAATCTCCTTCTG
PGTSTPESGSASPGST GCACCGCTCCAGGTACCTCTCCTAGC
SESPSGTAPGTSTPES GGCGAATCTTCTACCGCTCCAGGTTCT
GSASPGSTSSTAESP ACTAGCGAATCTCCTTCTGGCACTGCA
GPGSTSSTAESPGPG CCAGGTTCTACCAGCGAATCTCCTTCT
TSTPESGSASPGTSTP GGCACCGCTCCAGGTACCTCTCCTAG
ESGSASPGSTSESPSG CGGCGAATCTTCTACCGCTCCAGGTTC
TAPGTSTPESGSASP TACTAGCGAATCTCCTTCTGGCACTGC
GTSTPESGSASPGSTS ACCAGGTTCTACTAGCGAATCTCCTTC
ESPSGTAPGSTSESPS TGGCACTGCACCAGGTTCTACCAGCG
GTAPGSTSESPSGTA AATCTCCGTCTGGCACTGCACCAGGT
PGSTSSTAESPGPGTS ACCTCTACCCCTGAAAGCGGTTCCGCT
TPESGSASPGTSTPES TCTCCAGGTTCTACTAGCGAATCTCCT
GSASPGSTSESPSGT TCTGGTACCGCTCCAGGTACTTCTACC
APGSTSESPSGTAPG CCTGAAAGCGGCTCCGCTTCTCCAGG
TSTPESGSASPGSTSE TTCCACTAGCTCTACCGCTGAATCTCC
SPSGTAPGSTSESPSG GGGTCCAGGTTCTACTAGCTCTACTGC
TAPGTSTPESGSASP AGAATCTCCTGGCCCAGGTACCTCTA
GTSPSGESSTAPGSTS CTCCGGAAAGCGGCTCTGCATCTCCA
STAESPGPGTSPSGES GGTACTTCTACCCCTGAAAGCGGTTCT
STAPGSTSSTAESPGP GCATCTCCAGGTTCTACTAGCGAATCC
GTSTPESGSASPGSTS CCGTCTGGTACCGCACCAGGTACTTCT
ESPSGTAPGSTSSTA ACCCCGGAAAGCGGCTCTGCTTCTCC
ESPGPGTSTPESGSAS AGGTACTTCTACCCCGGAAAGCGGCT
PGTSTPESGSASPGFP CCGCATCTCCAGGTTCTACTAGCGAAT
TIPLSRLFDNAMLRA CTCCTTCTGGTACCGCTCCAGGTTCTA
HRLHQLAFDTYQEF CCAGCGAATCCCCGTCTGGTACTGCTC
EEAYIPKEQKYSFLQ CAGGTTCTACCAGCGAATCTCCTTCTG
NPQTSLCFSESIPTPS GTACTGCACCAGGTTCTACTAGCTCTA
NREETQQKSNLELLR CTGCAGAATCTCCTGGCCCAGGTACC
ISLLLIQSWLEPVQFL TCTACTCCGGAAAGCGGCTCTGCATCT
RSVFANSLVYGASD CCAGGTACTTCTACCCCTGAAAGCGG
SNVYDLLKDLEEGIQ TTCTGCATCTCCAGGTTCTACTAGCGA
TLMGRLEDGSPRTG ATCTCCTTCTGGCACTGCACCAGGTTC
QIFKQTYSKFDTNSH TACCAGCGAATCTCCGTCTGGCACTG
NDDALLKNYGLLYC CACCAGGTACCTCTACCCCTGAAAGC
FRKDMDKVETFLRI GGTTCCGCTTCTCCAGGTTCTACTAGC
VQCRSVEGSCGFGG GAATCTCCTTCTGGCACTGCACCAGGT
TSESATPESGPGSEP TCTACCAGCGAATCTCCGTCTGGCACT
ATSGSETPGTSESAT GCACCAGGTACCTCTACCCCTGAAAG
PESGPGSEPATSGSE CGGTTCCGCTTCTCCAGGTACTTCTCC
TPGTSESATPESGPG GAGCGGTGAATCTTCTACCGCACCAG
TSTEPSEGSAPGSPA GTTCTACTAGCTCTACCGCTGAATCTC
GSPTSTEEGTSESATP CGGGCCCAGGTACTTCTCCGAGCGGT
ESGPGSEPATSGSET GAATCTTCTACTGCTCCAGGTTCCACT
PGTSESATPESGPGSP AGCTCTACTGCTGAATCTCCTGGCCCA
AGSPTSTEEGSPAGS GGTACTTCTACTCCGGAAAGCGGTTC
PTSTEEGTSTEPSEGS CGCTTCTCCAGGTTCTACTAGCGAATC
APGTSESATPESGPG TCCGTCTGGCACCGCACCAGGTTCTAC
TSESATPESGPGTSES TAGCTCTACTGCAGAATCTCCTGGCCC
ATPESGPGSEPATSG AGGTACCTCTACTCCGGAAAGCGGCT
SETPGSEPATSGSETP CTGCATCTCCAGGTACTTCTACCCCTG
GSPAGSPTSTEEGTS AAAGCGGTTCTGCATCTCCAGGTTTTC
TEPSEGSAPGTSTEPS CGACTATTCCGCTGTCTCGTCTGTTTG
EGSAPGSEPATSGSE ATAATGCTATGCTGCGTGCGCACCGT
TPGTSESATPESGPG CTGCACCAGCTGGCCTTTGATACTTAC
TSTEPSEGSAP CAGGAATTTGAAGAAGCcTACATTCCT
AAAGAGCAGAAGTACTCTTTCCTGCA
AAACCCACAGACTTCTCTCTGCTTCAG
CGAATCTATTCCGACGCCTTCCAATCG
CGAGGAAACTCAGCAAAAGTCCAATC
TGGAACTACTCCGCATTTCTCTGCTTC
TGATTCAGAGCTGGCTAGAACCAGTG
CAATTTCTGCGTTCCGTCTTCGCCAAT
AGCCTAGTTTATGGCGCATCCGACAG
CAACGTATACGATCTCCTGAAAGATC
TCGAGGAAGGCATTCAGACCCTGATG
GGTCGTCTCGAGGATGGCTCTCCGCG
TACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCAC
AATGACGATGCGCTTCTAAAAAACTA
TGGTCTGCTGTATTGTTTTCGTAAAGA
TATGGACAAAGTTGAAACCTTCCTGC
GTATTGTTCAGTGTCGTTCCGTTGAGG
GCAGCTGTGGTTTCTAAGGTGGTACCT
CTGAAAGCGCAACTCCTGAGTCTGGC
CCAGGTAGCGAACCTGCTACCTCCGG
CTCTGAGACTCCAGGTACCTCTGAAA
GCGCAACCCCGGAATCTGGTCCAGGT
AGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCA
GGTAGCCCTGCTGGCTCTCCAACCTCC
ACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCG
AACCGGCAACCTCCGGTTCTGAAACC
CCAGGTACTTCTGAAAGCGCTACTCCT
GAGTCCGGCCCAGGTAGCCCGGCTGG
CTCTCCGACTTCCACCGAGGAAGGTA
GCCCGGCTGGCTCTCCAACTTCTACTG
AAGAAGGTACTTCTACCGAACCTTCC
GAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAAT
CCGGTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAATCTGGCCCAGGTAGCGA
ACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTT
CTGAAACTCCAGGTAGCCCAGCAGGC
TCTCCGACTTCCACTGAGGAAGGTAC
TTCTACTGAACCTTCCGAAGGCAGCG
CACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATC
TGGCCCAGGTACTTCTACTGAACCGTC
CGAGGGCAGCGCACCA
AE624- MAEPAGSPTSTEEGT 779 ATGGCTGAACCTGCTGGCTCTCCAAC 780
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE288 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGSPAGSPTSTEE GCTCTACCCCTTCTGGTGCAACCGGCT
GTSESATPESGPGTS CTCCAGGTGCTTCTCCGGGCACCAGCT
TEPSEGSAPGSPAGS CTACCGGTTCTCCAGGTAGCCCGGCT
PTSTEEGTSTEPSEGS GGCTCTCCTACCTCTACTGAGGAAGG
APGTSTEPSEGSAPG TACTTCTGAAAGCGCTACTCCTGAGTC
TSESATPESGPGSEP TGGTCCAGGTACCTCTACTGAACCGTC
ATSGSETPGSEPATS CGAAGGTAGCGCTCCAGGTAGCCCAG
GSETPGSPAGSPTST CAGGCTCTCCGACTTCCACTGAGGAA
EEGTSESATPESGPG GGTACTTCTACTGAACCTTCCGAAGG
TSTEPSEGSAPGTSTE CAGCGCACCAGGTACCTCTACTGAAC
PSEGSAPGSPAGSPT CTTCTGAGGGCAGCGCTCCAGGTACT
STEEGTSTEPSEGSAP TCTGAAAGCGCTACCCCGGAATCTGG
GTSTEPSEGSAPGTS CCCAGGTAGCGAACCGGCTACTTCTG
ESATPESGPGTSTEPS GTTCTGAAACCCCAGGTAGCGAACCG
EGSAPGTSESATPES GCTACCTCCGGTTCTGAAACTCCAGGT
GPGSEPATSGSETPG AGCCCGGCAGGCTCTCCGACCTCTAC
TSTEPSEGSAPGTSTE TGAGGAAGGTACTTCTGAAAGCGCAA
PSEGSAPGTSESATP CCCCGGAGTCCGGCCCAGGTACCTCT
ESGPGTSESATPESG ACCGAACCGTCTGAGGGCAGCGCACC
PGSPAGSPTSTEEGT AGGTACTTCTACCGAACCGTCCGAGG
SESATPESGPGSEPA GTAGCGCACCAGGTAGCCCAGCAGGT
TSGSETPGTSESATPE TCTCCTACCTCCACCGAGGAAGGTAC
SGPGTSTEPSEGSAP TTCTACCGAACCGTCCGAGGGTAGCG
GTSTEPSEGSAPGTS CACCAGGTACCTCTACTGAACCTTCTG
TEPSEGSAPGTSTEPS AGGGCAGCGCTCCAGGTACTTCTGAA
EGSAPGTSTEPSEGS AGCGCTACCCCGGAGTCCGGTCCAGG
APGTSTEPSEGSAPG TACTTCTACTGAACCGTCCGAAGGTA
SPAGSPTSTEEGTSTE GCGCACCAGGTACTTCTGAAAGCGCA
PSEGSAPGTSESATP ACCCCTGAATCCGGTCCAGGTAGCGA
ESGPGSEPATSGSET ACCGGCTACTTCTGGCTCTGAGACTCC
PGTSESATPESGPGS AGGTACTTCTACCGAACCGTCCGAAG
EPATSGSETPGTSES GTAGCGCACCAGGTACTTCTACTGAA
ATPESGPGTSTEPSE CCGTCTGAAGGTAGCGCACCAGGTAC
GSAPGTSESATPESG TTCTGAAAGCGCAACCCCGGAATCCG
PGSPAGSPTSTEEGSP GCCCAGGTACCTCTGAAAGCGCAACC
AGSPTSTEEGSPAGS CCGGAGTCCGGCCCAGGTAGCCCTGC
PTSTEEGTSESATPES TGGCTCTCCAACCTCCACCGAAGAAG
GPGTSTEPSEGSAPG GTACCTCTGAAAGCGCAACCCCTGAA
FPTIPLSRLFDNAML TCCGGCCCAGGTAGCGAACCGGCAAC
RAHRLHQLAFDTYQ CTCCGGTTCTGAAACCCCAGGTACCTC
EFEEAYIPKEQKYSF TGAAAGCGCTACTCCGGAGTCTGGCC
LQNPQTSLCFSESIPT CAGGTACCTCTACTGAACCGTCTGAG
PSNREETQQKSNLEL GGTAGCGCTCCAGGTACTTCTACTGA
LRISLLLIQSWLEPVQ ACCGTCCGAAGGTAGCGCACCAGGTA
FLRSVFANSLVYGAS CTTCTACCGAACCGTCCGAAGGCAGC
DSNVYDLLKDLEEGI GCTCCAGGTACCTCTACTGAACCTTCC
QTLMGRLEDGSPRT GAGGGCAGCGCTCCAGGTACCTCTAC
GQIFKQTYSKFDTNS CGAACCTTCTGAAGGTAGCGCACCAG
HNDDALLKNYGLLY GTACTTCTACCGAACCGTCCGAGGGT
CFRKDMDKVETFLRI AGCGCACCAGGTAGCCCAGCAGGTTC
VQCRSVEGSCGFGG TCCTACCTCCACCGAGGAAGGTACTT
TSESATPESGPGSEP CTACCGAACCGTCCGAGGGTAGCGCA
ATSGSETPGTSESAT CCAGGTACCTCTGAAAGCGCAACTCC
PESGPGSEPATSGSE TGAGTCTGGCCCAGGTAGCGAACCTG
TPGTSESATPESGPG CTACCTCCGGCTCTGAGACTCCAGGT
TSTEPSEGSAPGSPA ACCTCTGAAAGCGCAACCCCGGAATC
GSPTSTEEGTSESATP TGGTCCAGGTAGCGAACCTGCAACCT
ESGPGSEPATSGSET CTGGCTCTGAAACCCCAGGTACCTCT
PGTSESATPESGPGSP GAAAGCGCTACTCCTGAATCTGGCCC
AGSPTSTEEGSPAGS AGGTACTTCTACTGAACCGTCCGAGG
PTSTEEGTSTEPSEGS GCAGCGCACCAGGTACTTCTGAAAGC
APGTSESATPESGPG GCTACTCCTGAGTCCGGCCCAGGTAG
TSESATPESGPGTSES CCCGGCTGGCTCTCCGACTTCCACCGA
ATPESGPGSEPATSG GGAAGGTAGCCCGGCTGGCTCTCCAA
SETPGSEPATSGSETP CTTCTACTGAAGAAGGTAGCCCGGCA
GSPAGSPTSTEEGTS GGCTCTCCGACCTCTACTGAGGAAGG
TEPSEGSAPGTSTEPS TACTTCTGAAAGCGCAACCCCGGAGT
EGSAPGSEPATSGSE CCGGCCCAGGTACCTCTACCGAACCG
TPGTSESATPESGPG TCTGAGGGCAGCGCACCAGGTTTTCC
TSTEPSEGSAP GACTATTCCGCTGTCTCGTCTGTTTGA
TAATGCTATGCTGCGTGCGCACCGTCT
GCACCAGCTGGCCTTTGATACTTACCA
GGAATTTGAAGAAGCcTACATTCCTAA
AGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCG
AATCTATTCCGACGCCTTCCAATCGCG
AGGAAACTCAGCAAAAGTCCAATCTG
GAACTACTCCGCATTTCTCTGCTTCTG
ATTCAGAGCTGGCTAGAACCAGTGCA
ATTTCTGCGTTCCGTCTTCGCCAATAG
CCTAGTTTATGGCGCATCCGACAGCA
ACGTATACGATCTCCTGAAAGATCTC
GAGGAAGGCATTCAGACCCTGATGGG
TCGTCTCGAGGATGGCTCTCCGCGTAC
TGGTCAGATCTTCAAGCAGACTTACTC
TAAATTTGATACTAACAGCCACAATG
ACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATG
GACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTACCTCTGA
AAGCGCAACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCCGGCTCT
GAGACTCCAGGTACCTCTGAAAGCGC
AACCCCGGAATCTGGTCCAGGTAGCG
AACCTGCAACCTCTGGCTCTGAAACC
CCAGGTACCTCTGAAAGCGCTACTCC
TGAATCTGGCCCAGGTACTTCTACTGA
ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AD836- GSSESGSSEGGPGSS 781 GGTTCCTCTGAAAGCGGTTCTTCCGAA 782
hGH- ESGSSEGGPGESPGG GGTGGTCCAGGTTCCTCTGAAAGCGG
AE288 SSGSESGSGGEPSES TTCTTCTGAGGGTGGTCCAGGTGAATC
GSSGESPGGSSGSES TCCGGGTGGCTCCAGCGGTTCCGAGT
GESPGGSSGSESGSS CAGGTTCTGGTGGCGAACCTTCCGAG
ESGSSEGGPGSSESG TCTGGTAGCTCAGGTGAATCTCCGGG
SSEGGPGSSESGSSE TGGTTCTAGCGGTTCCGAGTCAGGTG
GGPGESPGGSSGSES AATCTCCGGGTGGTTCCAGCGGTTCTG
GESPGGSSGSESGES AGTCAGGTTCCTCCGAAAGCGGTTCTT
PGGSSGSESGSSESG CTGAGGGCGGTCCAGGTTCCTCCGAA
SSEGGPGSSESGSSE AGCGGTTCTTCCGAGGGCGGTCCAGG
GGPGSSESGSSEGGP TTCTTCTGAAAGCGGTTCTTCCGAGGG
GSSESGSSEGGPGSS CGGTCCAGGTGAATCTCCTGGTGGTTC
ESGSSEGGPGSSESG CAGCGGTTCCGAGTCAGGTGAATCTC
SSEGGPGSGGEPSES CAGGTGGCTCTAGCGGTTCCGAGTCA
GSSGESPGGSSGSES GGTGAATCTCCTGGTGGTTCTAGCGGT
GESPGGSSGSESGSG TCTGAATCAGGTTCCTCCGAAAGCGG
GEPSESGSSGSEGSS TTCTTCTGAGGGCGGTCCAGGTTCCTC
GPGESSGSSESGSSE CGAAAGCGGTTCTTCCGAGGGCGGTC
GGPGSGGEPSESGSS CAGGTTCTTCTGAAAGCGGTTCTTCCG
GSEGSSGPGESSGSS AGGGCGGTCCAGGTTCCTCTGAAAGC
ESGSSEGGPGSGGEP GGTTCTTCTGAGGGCGGTCCAGGTTCT
SESGSSGESPGGSSG TCCGAAAGCGGTTCTTCCGAGGGCGG
SESGSGGEPSESGSS TCCAGGTTCTTCCGAAAGCGGTTCTTC
GSGGEPSESGSSGSS TGAAGGCGGTCCAGGTTCTGGTGGCG
ESGSSEGGPGSGGEP AACCGTCCGAGTCTGGTAGCTCAGGT
SESGSSGSGGEPSES GAATCTCCGGGTGGCTCTAGCGGTTC
GSSGSEGSSGPGESS CGAGTCAGGTGAATCTCCTGGTGGTT
GESPGGSSGSESGSE CCAGCGGTTCCGAGTCAGGTTCCGGT
GSSGPGESSGSEGSS GGCGAACCGTCCGAATCTGGTAGCTC
GPGESSGSGGEPSES AGGTAGCGAAGGTTCTTCTGGTCCAG
GSSGSSESGSSEGGP GCGAATCTTCAGGTTCCTCTGAAAGC
GSSESGSSEGGPGES GGTTCTTCTGAGGGCGGTCCAGGTTCC
PGGSSGSESGSGGEP GGTGGCGAACCGTCCGAATCTGGTAG
SESGSSGSEGSSGPG CTCAGGTAGCGAAGGTTCTTCTGGTCC
ESSGESPGGSSGSES AGGCGAATCTTCAGGTTCCTCTGAAA
GSEGSSGPGSSESGS GCGGTTCTTCTGAGGGCGGTCCAGGT
SEGGPGSGGEPSESG TCCGGTGGCGAACCTTCCGAATCTGG
SSGSEGSSGPGESSG TAGCTCAGGTGAATCTCCGGGTGGTT
SEGSSGPGESSGSEG CTAGCGGTTCTGAGTCAGGTTCTGGTG
SSGPGESSGSGGEPS GTGAACCTTCCGAGTCTGGTAGCTCA
ESGSSGSGGEPSESG GGTTCTGGTGGCGAACCATCCGAGTC
SSGESPGGSSGSESG TGGTAGCTCAGGTTCTTCCGAAAGCG
ESPGGSSGSESGSGG GTTCTTCCGAAGGCGGTCCAGGTTCTG
EPSESGSSGSEGSSGP GTGGTGAACCGTCCGAATCTGGTAGC
GESSGESPGGSSGSE TCAGGTTCTGGTGGCGAACCATCCGA
SGSSESGSSEGGPGS ATCTGGTAGCTCAGGTAGCGAAGGTT
SESGSSEGGPGSSES CTTCTGGTCCTGGCGAATCTTCAGGTG
GSSEGGPGSGGEPSE AATCTCCAGGTGGCTCTAGCGGTTCC
SGSSGSSESGSSEGG GAATCAGGTAGCGAAGGTTCTTCCGG
PGESPGGSSGSESGS TCCAGGTGAATCTTCAGGTAGCGAAG
GGEPSESGSSGSSES GTTCTTCTGGTCCTGGTGAATCCTCAG
GSSEGGPGESPGGSS GTTCCGGTGGCGAACCATCTGAATCT
GSESGSGGEPSESGS GGTAGCTCAGGTTCCTCTGAAAGCGG
SGESPGGSSGSESGS TTCTTCCGAAGGTGGTCCAGGTTCCTC
GGEPSESGSSGFPTIP TGAAAGCGGTTCTTCTGAGGGTGGTC
LSRLFDNAMLRAHR CAGGTGAATCTCCGGGTGGCTCCAGC
LHQLAFDTYQEFEE GGTTCCGAGTCAGGTTCTGGTGGCGA
AYIPKEQKYSFLQNP ACCATCCGAATCTGGTAGCTCAGGTA
QTSLCFSESIPTPSNR GCGAAGGTTCTTCTGGTCCTGGCGAA
EETQQKSNLELLRIS TCTTCAGGTGAATCTCCAGGTGGCTCT
LLLIQSWLEPVQFLR AGCGGTTCCGAATCAGGTAGCGAAGG
SVFANSLVYGASDS TTCTTCCGGTCCaGGTTCCTCTGAAAG
NVYDLLKDLEEGIQT CGGTTCTTCTGAGGGCGGTCCAGGTTC
LMGRLEDGSPRTGQI TGGTGGCGAACCATCTGAATCTGGTA
FKQTYSKFDTNSHN GCTCAGGTAGCGAAGGTTCTTCCGGT
DDALLKNYGLLYCF CCGGGTGAATCTTCAGGTAGCGAAGG
RKDMDKVETFLRIV TTCTTCCGGTCCAGGTGAATCTTCAGG
QCRSVEGSCGFGGTS TAGCGAAGGTTCTTCTGGTCCTGGTGA
ESATPESGPGSEPAT ATCCTCAGGTTCCGGTGGCGAACCAT
SGSETPGTSESATPES CTGAATCTGGTAGCTCAGGTTCTGGTG
GPGSEPATSGSETPG GCGAACCATCCGAATCTGGTAGCTCA
TSESATPESGPGTSTE GGTGAATCTCCGGGTGGCTCCAGCGG
PSEGSAPGSPAGSPT TTCTGAATCAGGTGAATCTCCTGGTGG
STEEGTSESATPESGP CTCCAGCGGTTCTGAGTCAGGTTCTGG
GSEPATSGSETPGTS TGGCGAACCATCCGAATCTGGTAGCT
ESATPESGPGSPAGS CAGGTAGCGAAGGTTCTTCTGGTCCT
PTSTEEGSPAGSPTST GGCGAATCTTCAGGTGAATCTCCAGG
EEGTSTEPSEGSAPG TGGCTCTAGCGGTTCCGAATCAGGTTC
TSESATPESGPGTSES CTCTGAAAGCGGTTCTTCTGAGGGCG
ATPESGPGTSESATP GTCCAGGTTCTTCCGAAAGCGGTTCTT
ESGPGSEPATSGSET CCGAGGGCGGTCCAGGTTCTTCCGAA
PGSEPATSGSETPGSP AGCGGTTCTTCTGAAGGCGGTCCAGG
AGSPTSTEEGTSTEPS TTCTGGTGGCGAACCGTCCGAATCTG
EGSAPGTSTEPSEGS GTAGCTCAGGTTCCTCCGAAAGCGGT
APGSEPATSGSETPG TCTTCTGAAGGTGGTCCAGGTGAATCT
TSESATPESGPGTSTE CCAGGTGGTTCTAGCGGTTCTGAATC
PSEGSAP AGGTTCTGGTGGCGAACCGTCCGAAT
CTGGTAGCTCAGGTTCCTCCGAAAGC
GGTTCTTCTGAAGGTGGTCCAGGTGA
ATCTCCAGGTGGTTCTAGCGGTTCTGA
ATCAGGTTCTGGTGGCGAACCGTCCG
AATCTGGTAGCTCAGGTGAATCTCCT
GGTGGTTCCAGCGGTTCCGAGTCAGG
TTCTGGTGGCGAACCTTCCGAATCTGG
TAGCTCAGGTTTTCCGACTATTCCGCT
GTCTCGTCTGTTTGATAATGCTATGCT
GCGTGCGCACCGTCTGCACCAGCTGG
CCTTTGATACTTACCAGGAATTTGAAG
AAGCcTACATTCCTAAAGAGCAGAAG
TACTCTTTCCTGCAAAACCCACAGACT
TCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCA
GCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCT
GGCTAGAACCAGTGCAATTTCTGCGT
TCCGTCTTCGCCAATAGCCTAGTTTAT
GGCGCATCCGACAGCAACGTATACGA
TCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGAT
CTTCAAGCAGACTTACTCTAAATTTGA
TACTAACAGCCACAATGACGATGCGC
TTCTAAAAAACTATGGTCTGCTGTATT
GTTTTCGTAAAGATATGGACAAAGTT
GAAACCTTCCTGCGTATTGTTCAGTGT
CGTTCCGTTGAGGGCAGCTGTGGTTTC
TAAGGTGGTACCTCTGAAAGCGCAAC
TCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAG
GTACCTCTGAAAGCGCAACCCCGGAA
TCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCTGAATCTGGCC
CAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCAGGTAGCCCTGCTGG
CTCTCCAACCTCCACCGAAGAAGGTA
CCTCTGAAAGCGCAACCCCTGAATCC
GGCCCAGGTAGCGAACCGGCAACCTC
CGGTTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCC
ACCGAGGAAGGTAGCCCGGCTGGCTC
TCCAACTTCTACTGAAGAAGGTACTTC
TACCGAACCTTCCGAGGGCAGCGCAC
CAGGTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTA
CTTCTGAAAGCGCTACCCCGGAATCT
GGCCCAGGTAGCGAACCGGCTACTTC
TGGTTCTGAAACCCCAGGTAGCGAAC
CGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACC
TCTACTGAACCTTCTGAGGGCAGCGC
TCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAA
AGCGCTACTCCTGAATCTGGCCCAGG
TACTTCTACTGAACCGTCCGAGGGCA
GCGCACCA
AE864- GSPAGSPTSTEEGTS 783 GGTAGCCCGGCTGGCTCTCCTACCTCT 784
hGH- ESATPESGPGTSTEPS ACTGAGGAAGGTACTTCTGAAAGCGC
AE288 EGSAPGSPAGSPTST TACTCCTGAGTCTGGTCCAGGTACCTC
EEGTSTEPSEGSAPG TACTGAACCGTCCGAAGGTAGCGCTC
TSTEPSEGSAPGTSES CAGGTAGCCCAGCAGGCTCTCCGACT
ATPESGPGSEPATSG TCCACTGAGGAAGGTACTTCTACTGA
SETPGSEPATSGSETP ACCTTCCGAAGGCAGCGCACCAGGTA
GSPAGSPTSTEEGTS CCTCTACTGAACCTTCTGAGGGCAGC
ESATPESGPGTSTEPS GCTCCAGGTACTTCTGAAAGCGCTAC
EGSAPGTSTEPSEGS CCCGGAATCTGGCCCAGGTAGCGAAC
APGSPAGSPTSTEEG CGGCTACTTCTGGTTCTGAAACCCCAG
TSTEPSEGSAPGTSTE GTAGCGAACCGGCTACCTCCGGTTCT
PSEGSAPGTSESATP GAAACTCCAGGTAGCCCGGCAGGCTC
ESGPGTSTEPSEGSA TCCGACCTCTACTGAGGAAGGTACTT
PGTSESATPESGPGS CTGAAAGCGCAACCCCGGAGTCCGGC
EPATSGSETPGTSTEP CCAGGTACCTCTACCGAACCGTCTGA
SEGSAPGTSTEPSEG GGGCAGCGCACCAGGTACTTCTACCG
SAPGTSESATPESGP AACCGTCCGAGGGTAGCGCACCAGGT
GTSESATPESGPGSP AGCCCAGCAGGTTCTCCTACCTCCACC
AGSPTSTEEGTSESA GAGGAAGGTACTTCTACCGAACCGTC
TPESGPGSEPATSGS CGAGGGTAGCGCACCAGGTACCTCTA
ETPGTSESATPESGP CTGAACCTTCTGAGGGCAGCGCTCCA
GTSTEPSEGSAPGTS GGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACC
EGSAPGTSTEPSEGS GTCCGAAGGTAGCGCACCAGGTACTT
APGTSTEPSEGSAPG CTGAAAGCGCAACCCCTGAATCCGGT
TSTEPSEGSAPGSPA CCAGGTAGCGAACCGGCTACTTCTGG
GSPTSTEEGTSTEPSE CTCTGAGACTCCAGGTACTTCTACCGA
GSAPGTSESATPESG ACCGTCCGAAGGTAGCGCACCAGGTA
PGSEPATSGSETPGT CTTCTACTGAACCGTCTGAAGGTAGC
SESATPESGPGSEPA GCACCAGGTACTTCTGAAAGCGCAAC
TSGSETPGTSESATPE CCCGGAATCCGGCCCAGGTACCTCTG
SGPGTSTEPSEGSAP AAAGCGCAACCCCGGAGTCCGGCCCA
GTSESATPESGPGSP GGTAGCCCTGCTGGCTCTCCAACCTCC
AGSPTSTEEGSPAGS ACCGAAGAAGGTACCTCTGAAAGCGC
PTSTEEGSPAGSPTST AACCCCTGAATCCGGCCCAGGTAGCG
EEGTSESATPESGPG AACCGGCAACCTCCGGTTCTGAAACC
TSTEPSEGSAPGTSES CCAGGTACCTCTGAAAGCGCTACTCC
ATPESGPGSEPATSG GGAGTCTGGCCCAGGTACCTCTACTG
SETPGTSESATPESGP AACCGTCTGAGGGTAGCGCTCCAGGT
GSEPATSGSETPGTS ACTTCTACTGAACCGTCCGAAGGTAG
ESATPESGPGTSTEPS CGCACCAGGTACTTCTACCGAACCGT
EGSAPGSPAGSPTST CCGAAGGCAGCGCTCCAGGTACCTCT
EEGTSESATPESGPG ACTGAACCTTCCGAGGGCAGCGCTCC
SEPATSGSETPGTSES AGGTACCTCTACCGAACCTTCTGAAG
ATPESGPGSPAGSPT GTAGCGCACCAGGTACTTCTACCGAA
STEEGSPAGSPTSTEE CCGTCCGAGGGTAGCGCACCAGGTAG
GTSTEPSEGSAPGTS CCCAGCAGGTTCTCCTACCTCCACCGA
ESATPESGPGTSESA GGAAGGTACTTCTACCGAACCGTCCG
TPESGPGTSESATPES AGGGTAGCGCACCAGGTACCTCTGAA
GPGSEPATSGSETPG AGCGCAACTCCTGAGTCTGGCCCAGG
SEPATSGSETPGSPA TAGCGAACCTGCTACCTCCGGCTCTG
GSPTSTEEGTSTEPSE AGACTCCAGGTACCTCTGAAAGCGCA
GSAPGTSTEPSEGSA ACCCCGGAATCTGGTCCAGGTAGCGA
PGSEPATSGSETPGT ACCTGCAACCTCTGGCTCTGAAACCC
SESATPESGPGTSTEP CAGGTACCTCTGAAAGCGCTACTCCT
SEGSAPGFPTIPLSRL GAATCTGGCCCAGGTACTTCTACTGA
FDNAMLRAHRLHQL ACCGTCCGAGGGCAGCGCACCAGGTA
AFDTYQEFEEAYIPK CTTCTGAAAGCGCTACTCCTGAGTCCG
EQKYSFLQNPQTSLC GCCCAGGTAGCCCGGCTGGCTCTCCG
FSESIPTPSNREETQQ ACTTCCACCGAGGAAGGTAGCCCGGC
KSNLELLRISLLLIQS TGGCTCTCCAACTTCTACTGAAGAAG
WLEPVQFLRSVFAN GTAGCCCGGCAGGCTCTCCGACCTCT
SLVYGASDSNVYDL ACTGAGGAAGGTACTTCTGAAAGCGC
LKDLEEGIQTLMGRL AACCCCGGAGTCCGGCCCAGGTACCT
EDGSPRTGQIFKQTY CTACCGAACCGTCTGAGGGCAGCGCA
SKFDTNSHNDDALL CCAGGTACCTCTGAAAGCGCAACTCC
KNYGLLYCFRKDMD TGAGTCTGGCCCAGGTAGCGAACCTG
KVETFLRIVQCRSVE CTACCTCCGGCTCTGAGACTCCAGGT
GSCGFGGTSESATPE ACCTCTGAAAGCGCAACCCCGGAATC
SGPGSEPATSGSETP TGGTCCAGGTAGCGAACCTGCAACCT
GTSESATPESGPGSE CTGGCTCTGAAACCCCAGGTACCTCT
PATSGSETPGTSESA GAAAGCGCTACTCCTGAATCTGGCCC
TPESGPGTSTEPSEGS AGGTACTTCTACTGAACCGTCCGAGG
APGSPAGSPTSTEEG GCAGCGCACCAGGTAGCCCTGCTGGC
TSESATPESGPGSEP TCTCCAACCTCCACCGAAGAAGGTAC
ATSGSETPGTSESAT CTCTGAAAGCGCAACCCCTGAATCCG
PESGPGSPAGSPTSTE GCCCAGGTAGCGAACCGGCAACCTCC
EGSPAGSPTSTEEGT GGTTCTGAAACCCCAGGTACTTCTGA
STEPSEGSAPGTSES AAGCGCTACTCCTGAGTCCGGCCCAG
ATPESGPGTSESATP GTAGCCCGGCTGGCTCTCCGACTTCCA
ESGPGTSESATPESG CCGAGGAAGGTAGCCCGGCTGGCTCT
PGSEPATSGSETPGS CCAACTTCTACTGAAGAAGGTACTTCT
EPATSGSETPGSPAG ACCGAACCTTCCGAGGGCAGCGCACC
SPTSTEEGTSTEPSEG AGGTACTTCTGAAAGCGCTACCCCTG
SAPGTSTEPSEGSAP AGTCCGGCCCAGGTACTTCTGAAAGC
GSEPATSGSETPGTS GCTACTCCTGAATCCGGTCCAGGTACT
ESATPESGPGTSTEPS TCTGAAAGCGCTACCCCGGAATCTGG
EGSAP CCCAGGTAGCGAACCGGCTACTTCTG
GTTCTGAAACCCCAGGTAGCGAACCG
GCTACCTCCGGTTCTGAAACTCCAGGT
AGCCCAGCAGGCTCTCCGACTTCCAC
TGAGGAAGGTACTTCTACTGAACCTT
CCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCC
AGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGC
ACCAGGTTTTCCGACTATTCCGCTGTC
TCGTCTGTTTGATAATGCTATGCTGCG
TGCGCACCGTCTGCACCAGCTGGCCTT
TGATACTTACCAGGAATTTGAAGAAG
CcTACATTCCTAAAGAGCAGAAGTACT
CTTTCCTGCAAAACCCACAGACTTCTC
TCTGCTTCAGCGAATCTATTCCGACGC
CTTCCAATCGCGAGGAAACTCAGCAA
AAGTCCAATCTGGAACTACTCCGCAT
TTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGT
CTTCGCCAATAGCCTAGTTTATGGCGC
ATCCGACAGCAACGTATACGATCTCC
TGAAAGATCTCGAGGAAGGCATTCAG
ACCCTGATGGGTCGTCTCGAGGATGG
CTCTCCGCGTACTGGTCAGATCTTCAA
GCAGACTTACTCTAAATTTGATACTAA
CAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTC
GTAAAGATATGGACAAAGTTGAAACC
TTCCTGCGTATTGTTCAGTGTCGTTCC
GTTGAGGGCAGCTGTGGTTTCTAAGG
TGGTACCTCTGAAAGCGCAACTCCTG
AGTCTGGCCCAGGTAGCGAACCTGCT
ACCTCCGGCTCTGAGACTCCAGGTAC
CTCTGAAAGCGCAACCCCGGAATCTG
GTCCAGGTAGCGAACCTGCAACCTCT
GGCTCTGAAACCCCAGGTACCTCTGA
AAGCGCTACTCCTGAATCTGGCCCAG
GTACTTCTACTGAACCGTCCGAGGGC
AGCGCACCAGGTAGCCCTGCTGGCTC
TCCAACCTCCACCGAAGAAGGTACCT
CTGAAAGCGCAACCCCTGAATCCGGC
CCAGGTAGCGAACCGGCAACCTCCGG
TTCTGAAACCCCAGGTACTTCTGAAA
GCGCTACTCCTGAGTCCGGCCCAGGT
AGCCCGGCTGGCTCTCCGACTTCCACC
GAGGAAGGTAGCCCGGCTGGCTCTCC
AACTTCTACTGAAGAAGGTACTTCTA
CCGAACCTTCCGAGGGCAGCGCACCA
GGTACTTCTGAAAGCGCTACCCCTGA
GTCCGGCCCAGGTACTTCTGAAAGCG
CTACTCCTGAATCCGGTCCAGGTACTT
CTGAAAGCGCTACCCCGGAATCTGGC
CCAGGTAGCGAACCGGCTACTTCTGG
TTCTGAAACCCCAGGTAGCGAACCGG
CTACCTCCGGTTCTGAAACTCCAGGTA
GCCCAGCAGGCTCTCCGACTTCCACT
GAGGAAGGTACTTCTACTGAACCTTC
CGAAGGCAGCGCACCAGGTACCTCTA
CTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTC
TGAAACCCCAGGTACCTCTGAAAGCG
CTACTCCTGAATCTGGCCCAGGTACTT
CTACTGAACCGTCCGAGGGCAGCGCA
CCA
AF864- GSTSESPSGTAPGTSP 785 GGTTCTACCAGCGAATCTCCTTCTGGC 786
hGH- SGESSTAPGSTSESPS ACCGCTCCAGGTACCTCTCCTAGCGG
AE288 GTAPGSTSESPSGTA CGAATCTTCTACCGCTCCAGGTTCTAC
PGTSTPESGSASPGTS TAGCGAATCTCCTTCTGGCACTGCACC
TPESGSASPGSTSESP AGGTTCTACTAGCGAATCCCCGTCTG
SGTAPGSTSESPSGT GTACTGCTCCAGGTACTTCTACTCCTG
APGTSPSGESSTAPG AAAGCGGTTCCGCTTCTCCAGGTACCT
STSESPSGTAPGTSPS CTACTCCGGAAAGCGGTTCTGCATCTC
GESSTAPGTSPSGESS CAGGTTCTACCAGCGAATCTCCTTCTG
TAPGSTSSTAESPGP GCACCGCTCCAGGTTCTACTAGCGAA
GTSPSGESSTAPGTSP TCCCCGTCTGGTACCGCACCAGGTACT
SGESSTAPGSTSSTA TCTCCTAGCGGCGAATCTTCTACCGCA
ESPGPGTSTPESGSAS CCAGGTTCTACTAGCGAATCTCCGTCT
PGTSTPESGSASPGST GGCACTGCTCCAGGTACTTCTCCTAGC
SESPSGTAPGSTSESP GGTGAATCTTCTACCGCTCCAGGTACT
SGTAPGTSTPESGSA TCCCCTAGCGGCGAATCTTCTACCGCT
SPGSTSSTAESPGPGT CCAGGTTCTACTAGCTCTACTGCAGA
STPESGSASPGSTSES ATCTCCGGGCCCAGGTACCTCTCCTAG
PSGTAPGTSPSGESST CGGTGAATCTTCTACCGCTCCAGGTAC
APGSTSSTAESPGPG TTCTCCGAGCGGTGAATCTTCTACCGC
TSPSGESSTAPGTSTP TCCAGGTTCTACTAGCTCTACTGCAGA
ESGSASPGSTSSTAES ATCTCCTGGCCCAGGTACCTCTACTCC
PGPGSTSSTAESPGP GGAAAGCGGCTCTGCATCTCCAGGTA
GSTSSTAESPGPGSTS CTTCTACCCCTGAAAGCGGTTCTGCAT
STAESPGPGTSPSGES CTCCAGGTTCTACTAGCGAATCTCCTT
STAPGSTSESPSGTAP CTGGCACTGCACCAGGTTCTACCAGC
GSTSESPSGTAPGTS GAATCTCCGTCTGGCACTGCACCAGG
TPESGPXXXGASASG TACCTCTACCCCTGAAAGCGGTTCCGC
APSTXXXXSESPSGT TTCTCCAGGTTCTACCAGCTCTACCGC
APGSTSESPSGTAPG AGAATCTCCTGGTCCAGGTACCTCTAC
STSESPSGTAPGSTSE TCCGGAAAGCGGCTCTGCATCTCCAG
SPSGTAPGSTSESPSG GTTCTACTAGCGAATCTCCTTCTGGCA
TAPGSTSESPSGTAP CTGCACCAGGTACTTCTCCGAGCGGT
GTSTPESGSASPGTSP GAATCTTCTACCGCACCAGGTTCTACT
SGESSTAPGTSPSGES AGCTCTACCGCTGAATCTCCGGGCCC
STAPGSTSSTAESPGP AGGTACTTCTCCGAGCGGTGAATCTTC
GTSPSGESSTAPGTS TACTGCTCCAGGTACCTCTACTCCTGA
TPESGSASPGSTSESP AAGCGGTTCTGCATCTCCAGGTTCCAC
SGTAPGSTSESPSGT TAGCTCTACCGCAGAATCTCCGGGCC
APGTSPSGESSTAPG CAGGTTCTACTAGCTCTACTGCTGAAT
STSESPSGTAPGTSTP CTCCTGGCCCAGGTTCTACTAGCTCTA
ESGSASPGTSTPESGS CTGCTGAATCTCCGGGTCCAGGTTCTA
ASPGSTSESPSGTAP CCAGCTCTACTGCTGAATCTCCTGGTC
GTSTPESGSASPGSTS CAGGTACCTCCCCGAGCGGTGAATCT
STAESPGPGSTSESPS TCTACTGCACCAGGTTCTACTAGCGA
GTAPGSTSESPSGTA ATCTCCTTCTGGCACTGCACCAGGTTC
PGTSPSGESSTAPGST TACCAGCGAATCTCCGTCTGGCACTG
SSTAESPGPGTSPSGE CACCAGGTACCTCTACCCCTGAAAGC
SSTAPGTSTPESGSAS GGTCCXXXXXXXXXXXXTGCAAGCG
PGTSPSGESSTAPGTS CAAGCGGCGCGCCAAGCACGGGAXX
PSGESSTAPGTSPSGE XXXXXXTAGCGAATCTCCTTCTGGTA
SSTAPGSTSSTAESPG CCGCTCCAGGTTCTACCAGCGAATCC
PGSTSSTAESPGPGTS CCGTCTGGTACTGCTCCAGGTTCTACC
PSGESSTAPGSSPSAS AGCGAATCTCCTTCTGGTACTGCACCA
TGTGPGSSTPSGATG GGTTCTACTAGCGAATCTCCTTCTGGT
SPGSSTPSGATGSPG ACCGCTCCAGGTTCTACCAGCGAATC
FPTIPLSRLFDNAML CCCGTCTGGTACTGCTCCAGGTTCTAC
RAHRLHQLAFDTYQ CAGCGAATCTCCTTCTGGTACTGCACC
EFEEAYIPKEQKYSF AGGTACTTCTACTCCGGAAAGCGGTT
LQNPQTSLCFSESIPT CCGCATCTCCAGGTACTTCTCCTAGCG
PSNREETQQKSNLEL GTGAATCTTCTACTGCTCCAGGTACCT
LRISLLLIQSWLEPVQ CTCCTAGCGGCGAATCTTCTACTGCTC
FLRSVFANSLVYGAS CAGGTTCTACCAGCTCTACTGCTGAAT
DSNVYDLLKDLEEGI CTCCGGGTCCAGGTACTTCCCCGAGC
QTLMGRLEDGSPRT GGTGAATCTTCTACTGCACCAGGTACT
GQIFKQTYSKFDTNS TCTACTCCGGAAAGCGGTTCCGCTTCT
HNDDALLKNYGLLY CCAGGTTCTACCAGCGAATCTCCTTCT
CFRKDMDKVETFLRI GGCACCGCTCCAGGTTCTACTAGCGA
VQCRSVEGSCGFGG ATCCCCGTCTGGTACCGCACCAGGTA
TSESATPESGPGSEP CTTCTCCTAGCGGCGAATCTTCTACCG
ATSGSETPGTSESAT CACCAGGTTCTACTAGCGAATCCCCG
PESGPGSEPATSGSE TCTGGTACCGCACCAGGTACTTCTACC
TPGTSESATPESGPG CCGGAAAGCGGCTCTGCTTCTCCAGG
TSTEPSEGSAPGSPA TACTTCTACCCCGGAAAGCGGCTCCG
GSPTSTEEGTSESATP CATCTCCAGGTTCTACTAGCGAATCTC
ESGPGSEPATSGSET CTTCTGGTACCGCTCCAGGTACTTCTA
PGTSESATPESGPGSP CCCCTGAAAGCGGCTCCGCTTCTCCA
AGSPTSTEEGSPAGS GGTTCCACTAGCTCTACCGCTGAATCT
PTSTEEGTSTEPSEGS CCGGGTCCAGGTTCTACCAGCGAATC
APGTSESATPESGPG TCCTTCTGGCACCGCTCCAGGTTCTAC
TSESATPESGPGTSES TAGCGAATCCCCGTCTGGTACCGCAC
ATPESGPGSEPATSG CAGGTACTTCTCCTAGCGGCGAATCTT
SETPGSEPATSGSETP CTACCGCACCAGGTTCTACCAGCTCTA
GSPAGSPTSTEEGTS CTGCTGAATCTCCGGGTCCAGGTACTT
TEPSEGSAPGTSTEPS CCCCGAGCGGTGAATCTTCTACTGCA
EGSAPGSEPATSGSE CCAGGTACTTCTACTCCGGAAAGCGG
TPGTSESATPESGPG TTCCGCTTCTCCAGGTACCTCCCCTAG
TSTEPSEGSAP CGGCGAATCTTCTACTGCTCCAGGTAC
CTCTCCTAGCGGCGAATCTTCTACCGC
TCCAGGTACCTCCCCTAGCGGTGAAT
CTTCTACCGCACCAGGTTCTACTAGCT
CTACTGCTGAATCTCCGGGTCCAGGTT
CTACCAGCTCTACTGCTGAATCTCCTG
GTCCAGGTACCTCCCCGAGCGGTGAA
TCTTCTACTGCACCAGGTTCTAGCCCT
TCTGCTTCCACCGGTACCGGCCCAGGT
AGCTCTACTCCGTCTGGTGCAACTGGC
TCTCCAGGTAGCTCTACTCCGTCTGGT
GCAACCGGCTCCCCAGGTTTTCCGACT
ATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCA
CCAGCTGGCCTTTGATACTTACCAGG
AATTTGAAGAAGCcTACATTCCTAAAG
AGCAGAAGTACTCTTTCCTGCAAAAC
CCACAGACTTCTCTCTGCTTCAGCGAA
TCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGA
ACTACTCCGCATTTCTCTGCTTCTGAT
TCAGAGCTGGCTAGAACCAGTGCAAT
TTCTGCGTTCCGTCTTCGCCAATAGCC
TAGTTTATGGCGCATCCGACAGCAAC
GTATACGATCTCCTGAAAGATCTCGA
GGAAGGCATTCAGACCCTGATGGGTC
GTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTACCTCTGA
AAGCGCAACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCCGGCTCT
GAGACTCCAGGTACCTCTGAAAGCGC
AACCCCGGAATCTGGTCCAGGTAGCG
AACCTGCAACCTCTGGCTCTGAAACC
CCAGGTACCTCTGAAAGCGCTACTCC
TGAATCTGGCCCAGGTACTTCTACTGA
ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AG864- GASPGTSSTGSPGSS 787 GGTGCTTCCCCGGGCACCAGCTCTACT 788
hGH- PSASTGTGPGSSPSA GGTTCTCCAGGTTCTAGCCCGTCTGCT
AE288 STGTGPGTPGSGTAS TCTACTGGTACTGGTCCAGGTTCTAGC
SSPGSSTPSGATGSP CCTTCTGCTTCCACTGGTACTGGTCCA
GSNPSASTGTGPGAS GGTACCCCGGGTAGCGGTACCGCTTC
PGTSSTGSPGTPGSG TTCTTCTCCAGGTAGCTCTACTCCGTC
TASSSPGSSTPSGAT TGGTGCTACCGGCTCTCCAGGTTCTAA
GSPGTPGSGTASSSP CCCTTCTGCATCCACCGGTACCGGCCC
GASPGTSSTGSPGAS AGGTGCTTCTCCGGGCACCAGCTCTA
PGTSSTGSPGTPGSG CTGGTTCTCCAGGTACCCCGGGCAGC
TASSSPGSSTPSGAT GGTACCGCATCTTCTTCTCCAGGTAGC
GSPGASPGTSSTGSP TCTACTCCTTCTGGTGCAACTGGTTCT
GTPGSGTASSSPGSS CCAGGTACTCCTGGCAGCGGTACCGC
TPSGATGSPGSNPSA TTCTTCTTCTCCAGGTGCTTCTCCTGG
STGTGPGSSPSASTG TACTAGCTCTACTGGTTCTCCAGGTGC
TGPGSSTPSGATGSP TTCTCCGGGCACTAGCTCTACTGGTTC
GSSTPSGATGSPGAS TCCAGGTACCCCGGGTAGCGGTACTG
PGTSSTGSPGASPGT CTTCTTCCTCTCCAGGTAGCTCTACCC
SSTGSPGASPGTSST CTTCTGGTGCAACCGGCTCTCCAGGTG
GSPGTPGSGTASSSP CTTCTCCGGGCACCAGCTCTACCGGTT
GASPGTSSTGSPGAS CTCCAGGTACCCCGGGTAGCGGTACC
PGTSSTGSPGASPGT GCTTCTTCTTCTCCAGGTAGCTCTACT
SSTGSPGSSPSASTGT CCGTCTGGTGCTACCGGCTCTCCAGGT
GPGTPGSGTASSSPG TCTAACCCTTCTGCATCCACCGGTACC
ASPGTSSTGSPGASP GGCCCAGGTTCTAGCCCTTCTGCTTCC
GTSSTGSPGASPGTS ACCGGTACTGGCCCAGGTAGCTCTAC
STGSPGSSTPSGATG CCCTTCTGGTGCTACCGGCTCCCCAGG
SPGSSTPSGATGSPG TAGCTCTACTCCTTCTGGTGCAACTGG
ASPGTSSTGSPGTPG CTCTCCAGGTGCATCTCCGGGCACTA
SGTASSSPGSSTPSG GCTCTACTGGTTCTCCAGGTGCATCCC
ATGSPGSSTPSGATG CTGGCACTAGCTCTACTGGTTCTCCAG
SPGSSTPSGATGSPG GTGCTTCTCCTGGTACCAGCTCTACTG
SSPSASTGTGPGASP GTTCTCCAGGTACTCCTGGCAGCGGT
GTSSTGSPGASPGTS ACCGCTTCTTCTTCTCCAGGTGCTTCT
STGSPGTPGSGTASS CCTGGTACTAGCTCTACTGGTTCTCCA
SPGASPGTSSTGSPG GGTGCTTCTCCGGGCACTAGCTCTACT
ASPGTSSTGSPGASP GGTTCTCCAGGTGCTTCCCCGGGCACT
GTSSTGSPGASPGTS AGCTCTACCGGTTCTCCAGGTTCTAGC
STGSPGTPGSGTASS CCTTCTGCATCTACTGGTACTGGCCCA
SPGSSTPSGATGSPG GGTACTCCGGGCAGCGGTACTGCTTC
TPGSGTASSSPGSSTP TTCCTCTCCAGGTGCATCTCCGGGCAC
SGATGSPGTPGSGTA TAGCTCTACTGGTTCTCCAGGTGCATC
SSSPGSSTPSGATGSP CCCTGGCACTAGCTCTACTGGTTCTCC
GSSTPSGATGSPGSS AGGTGCTTCTCCTGGTACCAGCTCTAC
PSASTGTGPGSSPSA TGGTTCTCCAGGTAGCTCTACTCCGTC
STGTGPGASPGTSST TGGTGCAACCGGTTCCCCAGGTAGCT
GSPGTPGSGTASSSP CTACTCCTTCTGGTGCTACTGGCTCCC
GSSTPSGATGSPGSS CAGGTGCATCCCCTGGCACCAGCTCT
PSASTGTGPGSSPSA ACCGGTTCTCCAGGTACCCCGGGCAG
STGTGPGASPGTSST CGGTACCGCATCTTCCTCTCCAGGTAG
GSPGASPGTSSTGSP CTCTACCCCGTCTGGTGCTACCGGTTC
GSSTPSGATGSPGSS CCCAGGTAGCTCTACCCCGTCTGGTGC
PSASTGTGPGASPGT AACCGGCTCCCCAGGTAGCTCTACTC
SSTGSPGSSPSASTGT CGTCTGGTGCAACCGGCTCCCCAGGT
GPGTPGSGTASSSPG TCTAGCCCGTCTGCTTCCACTGGTACT
SSTPSGATGSPGSSTP GGCCCAGGTGCTTCCCCGGGCACCAG
SGATGSPGASPGTSS CTCTACTGGTTCTCCAGGTGCATCCCC
TGSPGFPTIPLSRLFD GGGTACCAGCTCTACCGGTTCTCCAG
NAMLRAHRLHQLAF GTACTCCTGGCAGCGGTACTGCATCTT
DTYQEFEEAYIPKEQ CCTCTCCAGGTGCTTCTCCGGGCACCA
KYSFLQNPQTSLCFS GCTCTACTGGTTCTCCAGGTGCATCTC
ESIPTPSNREETQQKS CGGGCACTAGCTCTACTGGTTCTCCAG
NLELLRISLLLIQSWL GTGCATCCCCTGGCACTAGCTCTACTG
EPVQFLRSVFANSLV GTTCTCCAGGTGCTTCTCCTGGTACCA
YGASDSNVYDLLKD GCTCTACTGGTTCTCCAGGTACCCCTG
LEEGIQTLMGRLEDG GTAGCGGTACTGCTTCTTCCTCTCCAG
SPRTGQIFKQTYSKF GTAGCTCTACTCCGTCTGGTGCTACCG
DTNSHNDDALLKNY GTTCTCCAGGTACCCCGGGTAGCGGT
GLLYCFRKDMDKVE ACCGCATCTTCTTCTCCAGGTAGCTCT
TFLRIVQCRSVEGSC ACCCCGTCTGGTGCTACTGGTTCTCCA
GFGGTSESATPESGP GGTACTCCGGGCAGCGGTACTGCTTC
GSEPATSGSETPGTS TTCCTCTCCAGGTAGCTCTACCCCTTC
ESATPESGPGSEPAT TGGTGCTACTGGCTCTCCAGGTAGCTC
SGSETPGTSESATPES TACCCCGTCTGGTGCTACTGGCTCCCC
GPGTSTEPSEGSAPG AGGTTCTAGCCCTTCTGCATCCACCGG
SPAGSPTSTEEGTSES TACCGGTCCAGGTTCTAGCCCGTCTGC
ATPESGPGSEPATSG ATCTACTGGTACTGGTCCAGGTGCATC
SETPGTSESATPESGP CCCGGGCACTAGCTCTACCGGTTCTCC
GSPAGSPTSTEEGSP AGGTACTCCTGGTAGCGGTACTGCTTC
AGSPTSTEEGTSTEPS TTCTTCTCCAGGTAGCTCTACTCCTTC
EGSAPGTSESATPES TGGTGCTACTGGTTCTCCAGGTTCTAG
GPGTSESATPESGPG CCCTTCTGCATCCACCGGTACCGGCCC
TSESATPESGPGSEP AGGTTCTAGCCCGTCTGCTTCTACCGG
ATSGSETPGSEPATS TACTGGTCCAGGTGCTTCTCCGGGTAC
GSETPGSPAGSPTST TAGCTCTACTGGTTCTCCAGGTGCATC
EEGTSTEPSEGSAPG TCCTGGTACTAGCTCTACTGGTTCTCC
TSTEPSEGSAPGSEP AGGTAGCTCTACTCCGTCTGGTGCAA
ATSGSETPGTSESAT CCGGCTCTCCAGGTTCTAGCCCTTCTG
PESGPGTSTEPSEGS CATCTACCGGTACTGGTCCAGGTGCA
AP TCCCCTGGTACCAGCTCTACCGGTTCT
CCAGGTTCTAGCCCTTCTGCTTCTACC
GGTACCGGTCCAGGTACCCCTGGCAG
CGGTACCGCATCTTCCTCTCCAGGTAG
CTCTACTCCGTCTGGTGCAACCGGTTC
CCCAGGTAGCTCTACTCCTTCTGGTGC
TACTGGCTCCCCAGGTGCATCCCCTGG
CACCAGCTCTACCGGTTCTCCAGGTTT
TCCGACTATTCCGCTGTCTCGTCTGTT
TGATAATGCTATGCTGCGTGCGCACC
GTCTGCACCAGCTGGCCTTTGATACTT
ACCAGGAATTTGAAGAAGCcTACATT
CCTAAAGAGCAGAAGTACTCTTTCCT
GCAAAACCCACAGACTTCTCTCTGCTT
CAGCGAATCTATTCCGACGCCTTCCA
ATCGCGAGGAAACTCAGCAAAAGTCC
AATCTGGAACTACTCCGCATTTCTCTG
CTTCTGATTCAGAGCTGGCTAGAACC
AGTGCAATTTCTGCGTTCCGTCTTCGC
CAATAGCCTAGTTTATGGCGCATCCG
ACAGCAACGTATACGATCTCCTGAAA
GATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTC
CGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGC
CACAATGACGATGCGCTTCTAAAAAA
CTATGGTCTGCTGTATTGTTTTCGTAA
AGATATGGACAAAGTTGAAACCTTCC
TGCGTATTGTTCAGTGTCGTTCCGTTG
AGGGCAGCTGTGGTTTCTAAGGTGGT
ACCTCTGAAAGCGCAACTCCTGAGTC
TGGCCCAGGTAGCGAACCTGCTACCT
CCGGCTCTGAGACTCCAGGTACCTCT
GAAAGCGCAACCCCGGAATCTGGTCC
AGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGC
ACCAGGTAGCCCTGCTGGCTCTCCAA
CCTCCACCGAAGAAGGTACCTCTGAA
AGCGCAACCCCTGAATCCGGCCCAGG
TAGCGAACCGGCAACCTCCGGTTCTG
AAACCCCAGGTACTTCTGAAAGCGCT
ACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGG
AAGGTAGCCCGGCTGGCTCTCCAACT
TCTACTGAAGAAGGTACTTCTACCGA
ACCTTCCGAGGGCAGCGCACCAGGTA
CTTCTGAAAGCGCTACCCCTGAGTCC
GGCCCAGGTACTTCTGAAAGCGCTAC
TCCTGAATCCGGTCCAGGTACTTCTGA
AAGCGCTACCCCGGAATCTGGCCCAG
GTAGCGAACCGGCTACTTCTGGTTCTG
AAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCC
AGCAGGCTCTCCGACTTCCACTGAGG
AAGGTACTTCTACTGAACCTTCCGAA
GGCAGCGCACCAGGTACCTCTACTGA
ACCTTCTGAGGGCAGCGCTCCAGGTA
GCGAACCTGCAACCTCTGGCTCTGAA
ACCCCAGGTACCTCTGAAAGCGCTAC
TCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCA
AM875- GTSTEPSEGSAPGSE 789 GGTACTTCTACTGAACCGTCTGAAGG 790
hGH- PATSGSETPGSPAGS CAGCGCACCAGGTAGCGAACCGGCTA
AE288 PTSTEEGSTSSTAESP CTTCCGGTTCTGAAACCCCAGGTAGC
GPGTSTPESGSASPG CCAGCAGGTTCTCCAACTTCTACTGAA
STSESPSGTAPGSTSE GAAGGTTCTACCAGCTCTACCGCAGA
SPSGTAPGTSTPESGS ATCTCCTGGTCCAGGTACCTCTACTCC
ASPGTSTPESGSASP GGAAAGCGGCTCTGCATCTCCAGGTT
GSEPATSGSETPGTS CTACTAGCGAATCTCCTTCTGGCACTG
ESATPESGPGSPAGS CACCAGGTTCTACTAGCGAATCCCCG
PTSTEEGTSTEPSEGS TCTGGTACTGCTCCAGGTACTTCTACT
APGTSESATPESGPG CCTGAAAGCGGTTCCGCTTCTCCAGGT
TSTEPSEGSAPGTSTE ACCTCTACTCCGGAAAGCGGTTCTGC
PSEGSAPGSPAGSPT ATCTCCAGGTAGCGAACCGGCAACCT
STEEGTSTEPSEGSAP CCGGCTCTGAAACCCCAGGTACCTCT
GTSTEPSEGSAPGTS GAAAGCGCTACTCCTGAATCCGGCCC
ESATPESGPGTSESA AGGTAGCCCGGCAGGTTCTCCGACTT
TPESGPGTSTEPSEGS CCACTGAGGAAGGTACCTCTACTGAA
APGTSTEPSEGSAPG CCTTCTGAGGGCAGCGCTCCAGGTAC
TSESATPESGPGTSTE TTCTGAAAGCGCTACCCCGGAGTCCG
PSEGSAPGSEPATSG GTCCAGGTACTTCTACTGAACCGTCCG
SETPGSPAGSPTSTEE AAGGTAGCGCACCAGGTACTTCTACC
GSSTPSGATGSPGTP GAACCGTCCGAGGGTAGCGCACCAGG
GSGTASSSPGSSTPS TAGCCCAGCAGGTTCTCCTACCTCCAC
GATGSPGTSTEPSEG CGAGGAAGGTACTTCTACCGAACCGT
SAPGTSTEPSEGSAP CCGAGGGTAGCGCACCAGGTACTTCT
GSEPATSGSETPGSP ACCGAACCTTCCGAGGGCAGCGCACC
AGSPTSTEEGSPAGS AGGTACTTCTGAAAGCGCTACCCCTG
PTSTEEGTSTEPSEGS AGTCCGGCCCAGGTACTTCTGAAAGC
APGASASGAPSTGGT GCTACTCCTGAATCCGGTCCAGGTAC
SESATPESGPGSPAG CTCTACTGAACCTTCCGAAGGCAGCG
SPTSTEEGSPAGSPTS CTCCAGGTACCTCTACCGAACCGTCC
TEEGSTSSTAESPGP GAGGGCAGCGCACCAGGTACTTCTGA
GSTSESPSGTAPGTSP AAGCGCAACCCCTGAATCCGGTCCAG
SGESSTAPGTPGSGT GTACTTCTACTGAACCTTCCGAAGGTA
ASSSPGSSTPSGATG GCGCTCCAGGTAGCGAACCTGCTACT
SPGSSPSASTGTGPG TCTGGTTCTGAAACCCCAGGTAGCCC
SEPATSGSETPGTSES GGCTGGCTCTCCGACCTCCACCGAGG
ATPESGPGSEPATSG AAGGTAGCTCTACCCCGTCTGGTGCT
SETPGSTSSTAESPGP ACTGGTTCTCCAGGTACTCCGGGCAG
GSTSSTAESPGPGTSP CGGTACTGCTTCTTCCTCTCCAGGTAG
SGESSTAPGSEPATS CTCTACCCCTTCTGGTGCTACTGGCTC
GSETPGSEPATSGSE TCCAGGTACCTCTACCGAACCGTCCG
TPGTSTEPSEGSAPG AGGGTAGCGCACCAGGTACCTCTACT
STSSTAESPGPGTSTP GAACCGTCTGAGGGTAGCGCTCCAGG
ESGSASPGSTSESPSG TAGCGAACCGGCAACCTCCGGTTCTG
TAPGTSTEPSEGSAP AAACTCCAGGTAGCCCTGCTGGCTCT
GTSTEPSEGSAPGTS CCGACTTCTACTGAGGAAGGTAGCCC
TEPSEGSAPGSSTPSG GGCTGGTTCTCCGACTTCTACTGAGGA
ATGSPGSSPSASTGT AGGTACTTCTACCGAACCTTCCGAAG
GPGASPGTSSTGSPG GTAGCGCTCCAGGTGCAAGCGCAAGC
SEPATSGSETPGTSES GGCGCGCCAAGCACGGGAGGTACTTC
ATPESGPGSPAGSPT TGAAAGCGCTACTCCTGAGTCCGGCC
STEEGSSTPSGATGS CAGGTAGCCCGGCTGGCTCTCCGACT
PGSSPSASTGTGPGA TCCACCGAGGAAGGTAGCCCGGCTGG
SPGTSSTGSPGTSESA CTCTCCAACTTCTACTGAAGAAGGTTC
TPESGPGTSTEPSEGS TACCAGCTCTACCGCTGAATCTCCTGG
APGTSTEPSEGSAPG CCCAGGTTCTACTAGCGAATCTCCGTC
FPTIPLSRLFDNAML TGGCACCGCACCAGGTACTTCCCCTA
RAHRLHQLAFDTYQ GCGGTGAATCTTCTACTGCACCAGGT
EFEEAYIPKEQKYSF ACCCCTGGCAGCGGTACCGCTTCTTCC
LQNPQTSLCFSESIPT TCTCCAGGTAGCTCTACCCCGTCTGGT
PSNREETQQKSNLEL GCTACTGGCTCTCCAGGTTCTAGCCCG
LRISLLLIQSWLEPVQ TCTGCATCTACCGGTACCGGCCCAGG
FLRSVFANSLVYGAS TAGCGAACCGGCAACCTCCGGCTCTG
DSNVYDLLKDLEEGI AAACTCCAGGTACTTCTGAAAGCGCT
QTLMGRLEDGSPRT ACTCCGGAATCCGGCCCAGGTAGCGA
GQIFKQTYSKFDTNS ACCGGCTACTTCCGGCTCTGAAACCC
HNDDALLKNYGLLY CAGGTTCCACCAGCTCTACTGCAGAA
CFRKDMDKVETFLRI TCTCCGGGCCCAGGTTCTACTAGCTCT
VQCRSVEGSCGFGG ACTGCAGAATCTCCGGGTCCAGGTAC
TSESATPESGPGSEP TTCTCCTAGCGGCGAATCTTCTACCGC
ATSGSETPGTSESAT TCCAGGTAGCGAACCGGCAACCTCTG
PESGPGSEPATSGSE GCTCTGAAACTCCAGGTAGCGAACCT
TPGTSESATPESGPG GCAACCTCCGGCTCTGAAACCCCAGG
TSTEPSEGSAPGSPA TACTTCTACTGAACCTTCTGAGGGCAG
GSPTSTEEGTSESATP CGCACCAGGTTCTACCAGCTCTACCG
ESGPGSEPATSGSET CAGAATCTCCTGGTCCAGGTACCTCTA
PGTSESATPESGPGSP CTCCGGAAAGCGGCTCTGCATCTCCA
AGSPTSTEEGSPAGS GGTTCTACTAGCGAATCTCCTTCTGGC
PTSTEEGTSTEPSEGS ACTGCACCAGGTACTTCTACCGAACC
APGTSESATPESGPG GTCCGAAGGCAGCGCTCCAGGTACCT
TSESATPESGPGTSES CTACTGAACCTTCCGAGGGCAGCGCT
ATPESGPGSEPATSG CCAGGTACCTCTACCGAACCTTCTGA
SETPGSEPATSGSETP AGGTAGCGCACCAGGTAGCTCTACTC
GSPAGSPTSTEEGTS CGTCTGGTGCAACCGGCTCCCCAGGT
TEPSEGSAPGTSTEPS TCTAGCCCGTCTGCTTCCACTGGTACT
EGSAPGSEPATSGSE GGCCCAGGTGCTTCCCCGGGCACCAG
TPGTSESATPESGPG CTCTACTGGTTCTCCAGGTAGCGAACC
TSTEPSEGSAP TGCTACCTCCGGTTCTGAAACCCCAG
GTACCTCTGAAAGCGCAACTCCGGAG
TCTGGTCCAGGTAGCCCTGCAGGTTCT
CCTACCTCCACTGAGGAAGGTAGCTC
TACTCCGTCTGGTGCAACCGGCTCCCC
AGGTTCTAGCCCGTCTGCTTCCACTGG
TACTGGCCCAGGTGCTTCCCCGGGCA
CCAGCTCTACTGGTTCTCCAGGTACCT
CTGAAAGCGCTACTCCGGAGTCTGGC
CCAGGTACCTCTACTGAACCGTCTGA
GGGTAGCGCTCCAGGTACTTCTACTG
AACCGTCCGAAGGTAGCGCACCAGGT
TTTCCGACTATTCCGCTGTCTCGTCTG
TTTGATAATGCTATGCTGCGTGCGCAC
CGTCTGCACCAGCTGGCCTTTGATACT
TACCAGGAATTTGAAGAAGCcTACATT
CCTAAAGAGCAGAAGTACTCTTTCCT
GCAAAACCCACAGACTTCTCTCTGCTT
CAGCGAATCTATTCCGACGCCTTCCA
ATCGCGAGGAAACTCAGCAAAAGTCC
AATCTGGAACTACTCCGCATTTCTCTG
CTTCTGATTCAGAGCTGGCTAGAACC
AGTGCAATTTCTGCGTTCCGTCTTCGC
CAATAGCCTAGTTTATGGCGCATCCG
ACAGCAACGTATACGATCTCCTGAAA
GATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTC
CGCGTACTGGTCAGATCTTCAAGCAG
ACTTACTCTAAATTTGATACTAACAGC
CACAATGACGATGCGCTTCTAAAAAA
CTATGGTCTGCTGTATTGTTTTCGTAA
AGATATGGACAAAGTTGAAACCTTCC
TGCGTATTGTTCAGTGTCGTTCCGTTG
AGGGCAGCTGTGGTTTCTAAGGTGGT
ACCTCTGAAAGCGCAACTCCTGAGTC
TGGCCCAGGTAGCGAACCTGCTACCT
CCGGCTCTGAGACTCCAGGTACCTCT
GAAAGCGCAACCCCGGAATCTGGTCC
AGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGC
ACCAGGTAGCCCTGCTGGCTCTCCAA
CCTCCACCGAAGAAGGTACCTCTGAA
AGCGCAACCCCTGAATCCGGCCCAGG
TAGCGAACCGGCAACCTCCGGTTCTG
AAACCCCAGGTACTTCTGAAAGCGCT
ACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGG
AAGGTAGCCCGGCTGGCTCTCCAACT
TCTACTGAAGAAGGTACTTCTACCGA
ACCTTCCGAGGGCAGCGCACCAGGTA
CTTCTGAAAGCGCTACCCCTGAGTCC
GGCCCAGGTACTTCTGAAAGCGCTAC
TCCTGAATCCGGTCCAGGTACTTCTGA
AAGCGCTACCCCGGAATCTGGCCCAG
GTAGCGAACCGGCTACTTCTGGTTCTG
AAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCC
AGCAGGCTCTCCGACTTCCACTGAGG
AAGGTACTTCTACTGAACCTTCCGAA
GGCAGCGCACCAGGTACCTCTACTGA
ACCTTCTGAGGGCAGCGCTCCAGGTA
GCGAACCTGCAACCTCTGGCTCTGAA
ACCCCAGGTACCTCTGAAAGCGCTAC
TCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCA
AE912- MAEPAGSPTSTEEGT 791 ATGGCTGAACCTGCTGGCTCTCCAAC 792
hGH- PGSGTASSSPGSSTPS CTCCACTGAGGAAGGTACCCCGGGTA
AE288 GATGSPGASPGTSST GCGGTACTGCTTCTTCCTCTCCAGGTA
GSPGSPAGSPTSTEE GCTCTACCCCTTCTGGTGCAACCGGCT
GTSESATPESGPGTS CTCCAGGTGCTTCTCCGGGCACCAGCT
TEPSEGSAPGSPAGS CTACCGGTTCTCCAGGTAGCCCGGCT
PTSTEEGTSTEPSEGS GGCTCTCCTACCTCTACTGAGGAAGG
APGTSTEPSEGSAPG TACTTCTGAAAGCGCTACTCCTGAGTC
TSESATPESGPGSEP TGGTCCAGGTACCTCTACTGAACCGTC
ATSGSETPGSEPATS CGAAGGTAGCGCTCCAGGTAGCCCAG
GSETPGSPAGSPTST CAGGCTCTCCGACTTCCACTGAGGAA
EEGTSESATPESGPG GGTACTTCTACTGAACCTTCCGAAGG
TSTEPSEGSAPGTSTE CAGCGCACCAGGTACCTCTACTGAAC
PSEGSAPGSPAGSPT CTTCTGAGGGCAGCGCTCCAGGTACT
STEEGTSTEPSEGSAP TCTGAAAGCGCTACCCCGGAATCTGG
GTSTEPSEGSAPGTS CCCAGGTAGCGAACCGGCTACTTCTG
ESATPESGPGTSTEPS GTTCTGAAACCCCAGGTAGCGAACCG
EGSAPGTSESATPES GCTACCTCCGGTTCTGAAACTCCAGGT
GPGSEPATSGSETPG AGCCCGGCAGGCTCTCCGACCTCTAC
TSTEPSEGSAPGTSTE TGAGGAAGGTACTTCTGAAAGCGCAA
PSEGSAPGTSESATP CCCCGGAGTCCGGCCCAGGTACCTCT
ESGPGTSESATPESG ACCGAACCGTCTGAGGGCAGCGCACC
PGSPAGSPTSTEEGT AGGTACTTCTACCGAACCGTCCGAGG
SESATPESGPGSEPA GTAGCGCACCAGGTAGCCCAGCAGGT
TSGSETPGTSESATPE TCTCCTACCTCCACCGAGGAAGGTAC
SGPGTSTEPSEGSAP TTCTACCGAACCGTCCGAGGGTAGCG
GTSTEPSEGSAPGTS CACCAGGTACCTCTACTGAACCTTCTG
TEPSEGSAPGTSTEPS AGGGCAGCGCTCCAGGTACTTCTGAA
EGSAPGTSTEPSEGS AGCGCTACCCCGGAGTCCGGTCCAGG
APGTSTEPSEGSAPG TACTTCTACTGAACCGTCCGAAGGTA
SPAGSPTSTEEGTSTE GCGCACCAGGTACTTCTGAAAGCGCA
PSEGSAPGTSESATP ACCCCTGAATCCGGTCCAGGTAGCGA
ESGPGSEPATSGSET ACCGGCTACTTCTGGCTCTGAGACTCC
PGTSESATPESGPGS AGGTACTTCTACCGAACCGTCCGAAG
EPATSGSETPGTSES GTAGCGCACCAGGTACTTCTACTGAA
ATPESGPGTSTEPSE CCGTCTGAAGGTAGCGCACCAGGTAC
GSAPGTSESATPESG TTCTGAAAGCGCAACCCCGGAATCCG
PGSPAGSPTSTEEGSP GCCCAGGTACCTCTGAAAGCGCAACC
AGSPTSTEEGSPAGS CCGGAGTCCGGCCCAGGTAGCCCTGC
PTSTEEGTSESATPES TGGCTCTCCAACCTCCACCGAAGAAG
GPGTSTEPSEGSAPG GTACCTCTGAAAGCGCAACCCCTGAA
TSESATPESGPGSEP TCCGGCCCAGGTAGCGAACCGGCAAC
ATSGSETPGTSESAT CTCCGGTTCTGAAACCCCAGGTACCTC
PESGPGSEPATSGSE TGAAAGCGCTACTCCGGAGTCTGGCC
TPGTSESATPESGPG CAGGTACCTCTACTGAACCGTCTGAG
TSTEPSEGSAPGSPA GGTAGCGCTCCAGGTACTTCTACTGA
GSPTSTEEGTSESATP ACCGTCCGAAGGTAGCGCACCAGGTA
ESGPGSEPATSGSET CTTCTACCGAACCGTCCGAAGGCAGC
PGTSESATPESGPGSP GCTCCAGGTACCTCTACTGAACCTTCC
AGSPTSTEEGSPAGS GAGGGCAGCGCTCCAGGTACCTCTAC
PTSTEEGTSTEPSEGS CGAACCTTCTGAAGGTAGCGCACCAG
APGTSESATPESGPG GTACTTCTACCGAACCGTCCGAGGGT
TSESATPESGPGTSES AGCGCACCAGGTAGCCCAGCAGGTTC
ATPESGPGSEPATSG TCCTACCTCCACCGAGGAAGGTACTT
SETPGSEPATSGSETP CTACCGAACCGTCCGAGGGTAGCGCA
GSPAGSPTSTEEGTS CCAGGTACCTCTGAAAGCGCAACTCC
TEPSEGSAPGTSTEPS TGAGTCTGGCCCAGGTAGCGAACCTG
EGSAPGSEPATSGSE CTACCTCCGGCTCTGAGACTCCAGGT
TPGTSESATPESGPG ACCTCTGAAAGCGCAACCCCGGAATC
TSTEPSEGSAPGFPTI TGGTCCAGGTAGCGAACCTGCAACCT
PLSRLFDNAMLRAH CTGGCTCTGAAACCCCAGGTACCTCT
RLHQLAFDTYQEFEE GAAAGCGCTACTCCTGAATCTGGCCC
AYIPKEQKYSFLQNP AGGTACTTCTACTGAACCGTCCGAGG
QTSLCFSESIPTPSNR GCAGCGCACCAGGTACTTCTGAAAGC
EETQQKSNLELLRIS GCTACTCCTGAGTCCGGCCCAGGTAG
LLLIQSWLEPVQFLR CCCGGCTGGCTCTCCGACTTCCACCGA
SVFANSLVYGASDS GGAAGGTAGCCCGGCTGGCTCTCCAA
NVYDLLKDLEEGIQT CTTCTACTGAAGAAGGTAGCCCGGCA
LMGRLEDGSPRTGQI GGCTCTCCGACCTCTACTGAGGAAGG
FKQTYSKFDTNSHN TACTTCTGAAAGCGCAACCCCGGAGT
DDALLKNYGLLYCF CCGGCCCAGGTACCTCTACCGAACCG
RKDMDKVETFLRIV TCTGAGGGCAGCGCACCAGGTACCTC
QCRSVEGSCGFGGTS TGAAAGCGCAACTCCTGAGTCTGGCC
ESATPESGPGSEPAT CAGGTAGCGAACCTGCTACCTCCGGC
SGSETPGTSESATPES TCTGAGACTCCAGGTACCTCTGAAAG
GPGSEPATSGSETPG CGCAACCCCGGAATCTGGTCCAGGTA
TSESATPESGPGTSTE GCGAACCTGCAACCTCTGGCTCTGAA
PSEGSAPGSPAGSPT ACCCCAGGTACCTCTGAAAGCGCTAC
STEEGTSESATPESGP TCCTGAATCTGGCCCAGGTACTTCTAC
GSEPATSGSETPGTS TGAACCGTCCGAGGGCAGCGCACCAG
ESATPESGPGSPAGS GTAGCCCTGCTGGCTCTCCAACCTCCA
PTSTEEGSPAGSPTST CCGAAGAAGGTACCTCTGAAAGCGCA
EEGTSTEPSEGSAPG ACCCCTGAATCCGGCCCAGGTAGCGA
TSESATPESGPGTSES ACCGGCAACCTCCGGTTCTGAAACCC
ATPESGPGTSESATP CAGGTACTTCTGAAAGCGCTACTCCT
ESGPGSEPATSGSET GAGTCCGGCCCAGGTAGCCCGGCTGG
PGSEPATSGSETPGSP CTCTCCGACTTCCACCGAGGAAGGTA
AGSPTSTEEGTSTEPS GCCCGGCTGGCTCTCCAACTTCTACTG
EGSAPGTSTEPSEGS AAGAAGGTACTTCTACCGAACCTTCC
APGSEPATSGSETPG GAGGGCAGCGCACCAGGTACTTCTGA
TSESATPESGPGTSTE AAGCGCTACCCCTGAGTCCGGCCCAG
PSEGSAP GTACTTCTGAAAGCGCTACTCCTGAAT
CCGGTCCAGGTACTTCTGAAAGCGCT
ACCCCGGAATCTGGCCCAGGTAGCGA
ACCGGCTACTTCTGGTTCTGAAACCCC
AGGTAGCGAACCGGCTACCTCCGGTT
CTGAAACTCCAGGTAGCCCAGCAGGC
TCTCCGACTTCCACTGAGGAAGGTAC
TTCTACTGAACCTTCCGAAGGCAGCG
CACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATC
TGGCCCAGGTACTTCTACTGAACCGTC
CGAGGGCAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATA
ATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAG
GAATTTGAAGAAGCcTACATTCCTAAA
GAGCAGAAGTACTCTTTCCTGCAAAA
CCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGA
GGAAACTCAGCAAAAGTCCAATCTGG
AACTACTCCGCATTTCTCTGCTTCTGA
TTCAGAGCTGGCTAGAACCAGTGCAA
TTTCTGCGTTCCGTCTTCGCCAATAGC
CTAGTTTATGGCGCATCCGACAGCAA
CGTATACGATCTCCTGAAAGATCTCG
AGGAAGGCATTCAGACCCTGATGGGT
CGTCTCGAGGATGGCTCTCCGCGTACT
GGTCAGATCTTCAAGCAGACTTACTCT
AAATTTGATACTAACAGCCACAATGA
CGATGCGCTTCTAAAAAACTATGGTC
TGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATT
GTTCAGTGTCGTTCCGTTGAGGGCAG
CTGTGGTTTCTAAGGTGGTACCTCTGA
AAGCGCAACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCCGGCTCT
GAGACTCCAGGTACCTCTGAAAGCGC
AACCCCGGAATCTGGTCCAGGTAGCG
AACCTGCAACCTCTGGCTCTGAAACC
CCAGGTACCTCTGAAAGCGCTACTCC
TGAATCTGGCCCAGGTACTTCTACTGA
ACCGTCCGAGGGCAGCGCACCAGGTA
GCCCTGCTGGCTCTCCAACCTCCACCG
AAGAAGGTACCTCTGAAAGCGCAACC
CCTGAATCCGGCCCAGGTAGCGAACC
GGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCT
CCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAG
AAGGTACTTCTACCGAACCTTCCGAG
GGCAGCGCACCAGGTACTTCTGAAAG
CGCTACCCCTGAGTCCGGCCCAGGTA
CTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACC
GGCTACTTCTGGTTCTGAAACCCCAG
GTAGCGAACCGGCTACCTCCGGTTCT
GAAACTCCAGGTAGCCCAGCAGGCTC
TCCGACTTCCACTGAGGAAGGTACTT
CTACTGAACCTTCCGAAGGCAGCGCA
CCAGGTACCTCTACTGAACCTTCTGAG
GGCAGCGCTCCAGGTAGCGAACCTGC
AACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTG
GCCCAGGTACTTCTACTGAACCGTCC
GAGGGCAGCGCACCA
AM923- MAEPAGSPTSTEEGA 793 ATGGCTGAACCTGCTGGCTCTCCAAC 794
hGH- SPGTSSTGSPGSSTPS CTCCACTGAGGAAGGTGCATCCCCGG
AE288 GATGSPGSSTPSGAT GCACCAGCTCTACCGGTTCTCCAGGT
GSPGTSTEPSEGSAP AGCTCTACCCCGTCTGGTGCTACCGGC
GSEPATSGSETPGSP TCTCCAGGTAGCTCTACCCCGTCTGGT
AGSPTSTEEGSTSST GCTACTGGCTCTCCAGGTACTTCTACT
AESPGPGTSTPESGS GAACCGTCTGAAGGCAGCGCACCAGG
ASPGSTSESPSGTAP TAGCGAACCGGCTACTTCCGGTTCTG
GSTSESPSGTAPGTS AAACCCCAGGTAGCCCAGCAGGTTCT
TPESGSASPGTSTPES CCAACTTCTACTGAAGAAGGTTCTAC
GSASPGSEPATSGSE CAGCTCTACCGCAGAATCTCCTGGTCC
TPGTSESATPESGPG AGGTACCTCTACTCCGGAAAGCGGCT
SPAGSPTSTEEGTSTE CTGCATCTCCAGGTTCTACTAGCGAAT
PSEGSAPGTSESATP CTCCTTCTGGCACTGCACCAGGTTCTA
ESGPGTSTEPSEGSA CTAGCGAATCCCCGTCTGGTACTGCTC
PGTSTEPSEGSAPGSP CAGGTACTTCTACTCCTGAAAGCGGTT
AGSPTSTEEGTSTEPS CCGCTTCTCCAGGTACCTCTACTCCGG
EGSAPGTSTEPSEGS AAAGCGGTTCTGCATCTCCAGGTAGC
APGTSESATPESGPG GAACCGGCAACCTCCGGCTCTGAAAC
TSESATPESGPGTSTE CCCAGGTACCTCTGAAAGCGCTACTC
PSEGSAPGTSTEPSE CTGAATCCGGCCCAGGTAGCCCGGCA
GSAPGTSESATPESG GGTTCTCCGACTTCCACTGAGGAAGG
PGTSTEPSEGSAPGS TACCTCTACTGAACCTTCTGAGGGCA
EPATSGSETPGSPAG GCGCTCCAGGTACTTCTGAAAGCGCT
SPTSTEEGSSTPSGAT ACCCCGGAGTCCGGTCCAGGTACTTC
GSPGTPGSGTASSSP TACTGAACCGTCCGAAGGTAGCGCAC
GSSTPSGATGSPGTS CAGGTACTTCTACCGAACCGTCCGAG
TEPSEGSAPGTSTEPS GGTAGCGCACCAGGTAGCCCAGCAGG
EGSAPGSEPATSGSE TTCTCCTACCTCCACCGAGGAAGGTA
TPGSPAGSPTSTEEG CTTCTACCGAACCGTCCGAGGGTAGC
SPAGSPTSTEEGTSTE GCACCAGGTACTTCTACCGAACCTTCC
PSEGSAPGASASGAP GAGGGCAGCGCACCAGGTACTTCTGA
STGGTSESATPESGP AAGCGCTACCCCTGAGTCCGGCCCAG
GSPAGSPTSTEEGSP GTACTTCTGAAAGCGCTACTCCTGAAT
AGSPTSTEEGSTSST CCGGTCCAGGTACCTCTACTGAACCTT
AESPGPGSTSESPSGT CCGAAGGCAGCGCTCCAGGTACCTCT
APGTSPSGESSTAPG ACCGAACCGTCCGAGGGCAGCGCACC
TPGSGTASSSPGSSTP AGGTACTTCTGAAAGCGCAACCCCTG
SGATGSPGSSPSAST AATCCGGTCCAGGTACTTCTACTGAA
GTGPGSEPATSGSET CCTTCCGAAGGTAGCGCTCCAGGTAG
PGTSESATPESGPGS CGAACCTGCTACTTCTGGTTCTGAAAC
EPATSGSETPGSTSST CCCAGGTAGCCCGGCTGGCTCTCCGA
AESPGPGSTSSTAESP CCTCCACCGAGGAAGGTAGCTCTACC
GPGTSPSGESSTAPG CCGTCTGGTGCTACTGGTTCTCCAGGT
SEPATSGSETPGSEP ACTCCGGGCAGCGGTACTGCTTCTTCC
ATSGSETPGTSTEPSE TCTCCAGGTAGCTCTACCCCTTCTGGT
GSAPGSTSSTAESPG GCTACTGGCTCTCCAGGTACCTCTACC
PGTSTPESGSASPGST GAACCGTCCGAGGGTAGCGCACCAGG
SESPSGTAPGTSTEPS TACCTCTACTGAACCGTCTGAGGGTA
EGSAPGTSTEPSEGS GCGCTCCAGGTAGCGAACCGGCAACC
APGTSTEPSEGSAPG TCCGGTTCTGAAACTCCAGGTAGCCCT
SSTPSGATGSPGSSPS GCTGGCTCTCCGACTTCTACTGAGGA
ASTGTGPGASPGTSS AGGTAGCCCGGCTGGTTCTCCGACTTC
TGSPGSEPATSGSET TACTGAGGAAGGTACTTCTACCGAAC
PGTSESATPESGPGSP CTTCCGAAGGTAGCGCTCCAGGTGCA
AGSPTSTEEGSSTPS AGCGCAAGCGGCGCGCCAAGCACGG
GATGSPGSSPSASTG GAGGTACTTCTGAAAGCGCTACTCCT
TGPGASPGTSSTGSP GAGTCCGGCCCAGGTAGCCCGGCTGG
GTSESATPESGPGTS CTCTCCGACTTCCACCGAGGAAGGTA
TEPSEGSAPGTSTEPS GCCCGGCTGGCTCTCCAACTTCTACTG
EGSAPGFPTIPLSRLF AAGAAGGTTCTACCAGCTCTACCGCT
DNAMLRAHRLHQL GAATCTCCTGGCCCAGGTTCTACTAGC
AFDTYQEFEEAYIPK GAATCTCCGTCTGGCACCGCACCAGG
EQKYSFLQNPQTSLC TACTTCCCCTAGCGGTGAATCTTCTAC
FSESIPTPSNREETQQ TGCACCAGGTACCCCTGGCAGCGGTA
KSNLELLRISLLLIQS CCGCTTCTTCCTCTCCAGGTAGCTCTA
WLEPVQFLRSVFAN CCCCGTCTGGTGCTACTGGCTCTCCAG
SLVYGASDSNVYDL GTTCTAGCCCGTCTGCATCTACCGGTA
LKDLEEGIQTLMGRL CCGGCCCAGGTAGCGAACCGGCAACC
EDGSPRTGQIFKQTY TCCGGCTCTGAAACTCCAGGTACTTCT
SKFDTNSHNDDALL GAAAGCGCTACTCCGGAATCCGGCCC
KNYGLLYCFRKDMD AGGTAGCGAACCGGCTACTTCCGGCT
KVETFLRIVQCRSVE CTGAAACCCCAGGTTCCACCAGCTCT
GSCGFGGTSESATPE ACTGCAGAATCTCCGGGCCCAGGTTC
SGPGSEPATSGSETP TACTAGCTCTACTGCAGAATCTCCGG
GTSESATPESGPGSE GTCCAGGTACTTCTCCTAGCGGCGAA
PATSGSETPGTSESA TCTTCTACCGCTCCAGGTAGCGAACC
TPESGPGTSTEPSEGS GGCAACCTCTGGCTCTGAAACTCCAG
APGSPAGSPTSTEEG GTAGCGAACCTGCAACCTCCGGCTCT
TSESATPESGPGSEP GAAACCCCAGGTACTTCTACTGAACC
ATSGSETPGTSESAT TTCTGAGGGCAGCGCACCAGGTTCTA
PESGPGSPAGSPTSTE CCAGCTCTACCGCAGAATCTCCTGGTC
EGSPAGSPTSTEEGT CAGGTACCTCTACTCCGGAAAGCGGC
STEPSEGSAPGTSES TCTGCATCTCCAGGTTCTACTAGCGAA
ATPESGPGTSESATP TCTCCTTCTGGCACTGCACCAGGTACT
ESGPGTSESATPESG TCTACCGAACCGTCCGAAGGCAGCGC
PGSEPATSGSETPGS TCCAGGTACCTCTACTGAACCTTCCGA
EPATSGSETPGSPAG GGGCAGCGCTCCAGGTACCTCTACCG
SPTSTEEGTSTEPSEG AACCTTCTGAAGGTAGCGCACCAGGT
SAPGTSTEPSEGSAP AGCTCTACTCCGTCTGGTGCAACCGG
GSEPATSGSETPGTS CTCCCCAGGTTCTAGCCCGTCTGCTTC
ESATPESGPGTSTEPS CACTGGTACTGGCCCAGGTGCTTCCCC
EGSAP GGGCACCAGCTCTACTGGTTCTCCAG
GTAGCGAACCTGCTACCTCCGGTTCTG
AAACCCCAGGTACCTCTGAAAGCGCA
ACTCCGGAGTCTGGTCCAGGTAGCCC
TGCAGGTTCTCCTACCTCCACTGAGGA
AGGTAGCTCTACTCCGTCTGGTGCAA
CCGGCTCCCCAGGTTCTAGCCCGTCTG
CTTCCACTGGTACTGGCCCAGGTGCTT
CCCCGGGCACCAGCTCTACTGGTTCTC
CAGGTACCTCTGAAAGCGCTACTCCG
GAGTCTGGCCCAGGTACCTCTACTGA
ACCGTCTGAGGGTAGCGCTCCAGGTA
CTTCTACTGAACCGTCCGAAGGTAGC
GCACCAGGTTTTCCGACTATTCCGCTG
TCTCGTCTGTTTGATAATGCTATGCTG
CGTGCGCACCGTCTGCACCAGCTGGC
CTTTGATACTTACCAGGAATTTGAAG
AAGCcTACATTCCTAAAGAGCAGAAG
TACTCTTTCCTGCAAAACCCACAGACT
TCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCA
GCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCT
GGCTAGAACCAGTGCAATTTCTGCGT
TCCGTCTTCGCCAATAGCCTAGTTTAT
GGCGCATCCGACAGCAACGTATACGA
TCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAG
GATGGCTCTCCGCGTACTGGTCAGAT
CTTCAAGCAGACTTACTCTAAATTTGA
TACTAACAGCCACAATGACGATGCGC
TTCTAAAAAACTATGGTCTGCTGTATT
GTTTTCGTAAAGATATGGACAAAGTT
GAAACCTTCCTGCGTATTGTTCAGTGT
CGTTCCGTTGAGGGCAGCTGTGGTTTC
TAAGGTGGTACCTCTGAAAGCGCAAC
TCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAG
GTACCTCTGAAAGCGCAACCCCGGAA
TCTGGTCCAGGTAGCGAACCTGCAAC
CTCTGGCTCTGAAACCCCAGGTACCTC
TGAAAGCGCTACTCCTGAATCTGGCC
CAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCAGGTAGCCCTGCTGG
CTCTCCAACCTCCACCGAAGAAGGTA
CCTCTGAAAGCGCAACCCCTGAATCC
GGCCCAGGTAGCGAACCGGCAACCTC
CGGTTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCCGGCCCA
GGTAGCCCGGCTGGCTCTCCGACTTCC
ACCGAGGAAGGTAGCCCGGCTGGCTC
TCCAACTTCTACTGAAGAAGGTACTTC
TACCGAACCTTCCGAGGGCAGCGCAC
CAGGTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTA
CTTCTGAAAGCGCTACCCCGGAATCT
GGCCCAGGTAGCGAACCGGCTACTTC
TGGTTCTGAAACCCCAGGTAGCGAAC
CGGCTACCTCCGGTTCTGAAACTCCA
GGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACC
TCTACTGAACCTTCTGAGGGCAGCGC
TCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAA
AGCGCTACTCCTGAATCTGGCCCAGG
TACTTCTACTGAACCGTCCGAGGGCA
GCGCACCA
AM1318- GTSTEPSEGSAPGSE 795 GGTACTTCTACTGAACCGTCTGAAGG 796
hGH- PATSGSETPGSPAGS CAGCGCACCAGGTAGCGAACCGGCTA
AE288 PTSTEEGSTSSTAESP CTTCCGGTTCTGAAACCCCAGGTAGC
GPGTSTPESGSASPG CCAGCAGGTTCTCCAACTTCTACTGAA
STSESPSGTAPGSTSE GAAGGTTCTACCAGCTCTACCGCAGA
SPSGTAPGTSTPESGS ATCTCCTGGTCCAGGTACCTCTACTCC
ASPGTSTPESGSASP GGAAAGCGGCTCTGCATCTCCAGGTT
GSEPATSGSETPGTS CTACTAGCGAATCTCCTTCTGGCACTG
ESATPESGPGSPAGS CACCAGGTTCTACTAGCGAATCCCCG
PTSTEEGTSTEPSEGS TCTGGTACTGCTCCAGGTACTTCTACT
APGTSESATPESGPG CCTGAAAGCGGTTCCGCTTCTCCAGGT
TSTEPSEGSAPGTSTE ACCTCTACTCCGGAAAGCGGTTCTGC
PSEGSAPGSPAGSPT ATCTCCAGGTAGCGAACCGGCAACCT
STEEGTSTEPSEGSAP CCGGCTCTGAAACCCCAGGTACCTCT
GTSTEPSEGSAPGTS GAAAGCGCTACTCCTGAATCCGGCCC
ESATPESGPGTSESA AGGTAGCCCGGCAGGTTCTCCGACTT
TPESGPGTSTEPSEGS CCACTGAGGAAGGTACCTCTACTGAA
APGTSTEPSEGSAPG CCTTCTGAGGGCAGCGCTCCAGGTAC
TSESATPESGPGTSTE TTCTGAAAGCGCTACCCCGGAGTCCG
PSEGSAPGSEPATSG GTCCAGGTACTTCTACTGAACCGTCCG
SETPGSPAGSPTSTEE AAGGTAGCGCACCAGGTACTTCTACC
GSSTPSGATGSPGTP GAACCGTCCGAGGGTAGCGCACCAGG
GSGTASSSPGSSTPS TAGCCCAGCAGGTTCTCCTACCTCCAC
GATGSPGTSTEPSEG CGAGGAAGGTACTTCTACCGAACCGT
SAPGTSTEPSEGSAP CCGAGGGTAGCGCACCAGGTACTTCT
GSEPATSGSETPGSP ACCGAACCTTCCGAGGGCAGCGCACC
AGSPTSTEEGSPAGS AGGTACTTCTGAAAGCGCTACCCCTG
PTSTEEGTSTEPSEGS AGTCCGGCCCAGGTACTTCTGAAAGC
APGPEPTGPAPSGGS GCTACTCCTGAATCCGGTCCAGGTAC
EPATSGSETPGTSES CTCTACTGAACCTTCCGAAGGCAGCG
ATPESGPGSPAGSPT CTCCAGGTACCTCTACCGAACCGTCC
STEEGTSESATPESGP GAGGGCAGCGCACCAGGTACTTCTGA
GSPAGSPTSTEEGSP AAGCGCAACCCCTGAATCCGGTCCAG
AGSPTSTEEGTSESA GTACTTCTACTGAACCTTCCGAAGGTA
TPESGPGSPAGSPTST GCGCTCCAGGTAGCGAACCTGCTACT
EEGSPAGSPTSTEEG TCTGGTTCTGAAACCCCAGGTAGCCC
STSSTAESPGPGSTSE GGCTGGCTCTCCGACCTCCACCGAGG
SPSGTAPGTSPSGESS AAGGTAGCTCTACCCCGTCTGGTGCT
TAPGSTSESPSGTAP ACTGGTTCTCCAGGTACTCCGGGCAG
GSTSESPSGTAPGTSP CGGTACTGCTTCTTCCTCTCCAGGTAG
SGESSTAPGTSTEPSE CTCTACCCCTTCTGGTGCTACTGGCTC
GSAPGTSESATPESG TCCAGGTACCTCTACCGAACCGTCCG
PGTSESATPESGPGS AGGGTAGCGCACCAGGTACCTCTACT
EPATSGSETPGTSES GAACCGTCTGAGGGTAGCGCTCCAGG
ATPESGPGTSESATP TAGCGAACCGGCAACCTCCGGTTCTG
ESGPGTSTEPSEGSA AAACTCCAGGTAGCCCTGCTGGCTCT
PGTSESATPESGPGT CCGACTTCTACTGAGGAAGGTAGCCC
STEPSEGSAPGTSPSG GGCTGGTTCTCCGACTTCTACTGAGGA
ESSTAPGTSPSGESST AGGTACTTCTACCGAACCTTCCGAAG
APGTSPSGESSTAPG GTAGCGCTCCAGGTCCAGAACCAACG
TSTEPSEGSAPGSPA GGGCCGGCCCCAAGCGGAGGTAGCGA
GSPTSTEEGTSTEPSE ACCGGCAACCTCCGGCTCTGAAACCC
GSAPGSSPSASTGTG CAGGTACCTCTGAAAGCGCTACTCCT
PGSSTPSGATGSPGS GAATCCGGCCCAGGTAGCCCGGCAGG
STPSGATGSPGSSTPS TTCTCCGACTTCCACTGAGGAAGGTA
GATGSPGSSTPSGAT CTTCTGAAAGCGCTACTCCTGAGTCCG
GSPGASPGTSSTGSP GCCCAGGTAGCCCGGCTGGCTCTCCG
GASASGAPSTGGTSP ACTTCCACCGAGGAAGGTAGCCCGGC
SGESSTAPGSTSSTA TGGCTCTCCAACTTCTACTGAAGAAG
ESPGPGTSPSGESSTA GTACTTCTGAAAGCGCTACTCCTGAGT
PGTSESATPESGPGT CCGGCCCAGGTAGCCCGGCTGGCTCT
STEPSEGSAPGTSTEP CCGACTTCCACCGAGGAAGGTAGCCC
SEGSAPGSSPSASTG GGCTGGCTCTCCAACTTCTACTGAAG
TGPGSSTPSGATGSP AAGGTTCTACCAGCTCTACCGCTGAA
GASPGTSSTGSPGTS TCTCCTGGCCCAGGTTCTACTAGCGAA
TPESGSASPGTSPSGE TCTCCGTCTGGCACCGCACCAGGTACT
SSTAPGTSPSGESSTA TCCCCTAGCGGTGAATCTTCTACTGCA
PGTSESATPESGPGS CCAGGTTCTACCAGCGAATCTCCTTCT
EPATSGSETPGTSTEP GGCACCGCTCCAGGTTCTACTAGCGA
SEGSAPGSTSESPSGT ATCCCCGTCTGGTACCGCACCAGGTA
APGSTSESPSGTAPG CTTCTCCTAGCGGCGAATCTTCTACCG
TSTPESGSASPGSPA CACCAGGTACTTCTACCGAACCTTCCG
GSPTSTEEGTSESATP AGGGCAGCGCACCAGGTACTTCTGAA
ESGPGTSTEPSEGSA AGCGCTACCCCTGAGTCCGGCCCAGG
PGSPAGSPTSTEEGT TACTTCTGAAAGCGCTACTCCTGAATC
SESATPESGPGSEPA CGGTCCAGGTAGCGAACCGGCAACCT
TSGSETPGSSTPSGA CTGGCTCTGAAACCCCAGGTACCTCT
TGSPGASPGTSSTGS GAAAGCGCTACTCCGGAATCTGGTCC
PGSSTPSGATGSPGS AGGTACTTCTGAAAGCGCTACTCCGG
TSESPSGTAPGTSPSG AATCCGGTCCAGGTACCTCTACTGAA
ESSTAPGSTSSTAESP CCTTCTGAGGGCAGCGCTCCAGGTAC
GPGSSTPSGATGSPG TTCTGAAAGCGCTACCCCGGAGTCCG
ASPGTSSTGSPGTPG GTCCAGGTACTTCTACTGAACCGTCCG
SGTASSSPGSPAGSP AAGGTAGCGCACCAGGTACCTCCCCT
TSTEEGSPAGSPTSTE AGCGGCGAATCTTCTACTGCTCCAGG
EGTSTEPSEGSAPGF TACCTCTCCTAGCGGCGAATCTTCTAC
PTIPLSRLFDNAMLR CGCTCCAGGTACCTCCCCTAGCGGTG
AHRLHQLAFDTYQE AATCTTCTACCGCACCAGGTACTTCTA
FEEAYIPKEQKYSFL CCGAACCGTCCGAGGGTAGCGCACCA
QNPQTSLCFSESIPTP GGTAGCCCAGCAGGTTCTCCTACCTCC
SNREETQQKSNLELL ACCGAGGAAGGTACTTCTACCGAACC
RISLLLIQSWLEPVQF GTCCGAGGGTAGCGCACCAGGTTCTA
LRSVFANSLVYGAS GCCCTTCTGCTTCCACCGGTACCGGCC
DSNVYDLLKDLEEGI CAGGTAGCTCTACTCCGTCTGGTGCA
QTLMGRLEDGSPRT ACTGGCTCTCCAGGTAGCTCTACTCCG
GQIFKQTYSKFDTNS TCTGGTGCAACCGGCTCCCCAGGTAG
HNDDALLKNYGLLY CTCTACCCCGTCTGGTGCTACCGGCTC
CFRKDMDKVETFLRI TCCAGGTAGCTCTACCCCGTCTGGTGC
VQCRSVEGSCGFGG AACCGGCTCCCCAGGTGCATCCCCGG
TSESATPESGPGSEP GTACTAGCTCTACCGGTTCTCCAGGTG
ATSGSETPGTSESAT CAAGCGCAAGCGGCGCGCCAAGCACG
PESGPGSEPATSGSE GGAGGTACTTCTCCGAGCGGTGAATC
TPGTSESATPESGPG TTCTACCGCACCAGGTTCTACTAGCTC
TSTEPSEGSAPGSPA TACCGCTGAATCTCCGGGCCCAGGTA
GSPTSTEEGTSESATP CTTCTCCGAGCGGTGAATCTTCTACTG
ESGPGSEPATSGSET CTCCAGGTACCTCTGAAAGCGCTACT
PGTSESATPESGPGSP CCGGAGTCTGGCCCAGGTACCTCTAC
AGSPTSTEEGSPAGS TGAACCGTCTGAGGGTAGCGCTCCAG
PTSTEEGTSTEPSEGS GTACTTCTACTGAACCGTCCGAAGGT
APGTSESATPESGPG AGCGCACCAGGTTCTAGCCCTTCTGC
TSESATPESGPGTSES ATCTACTGGTACTGGCCCAGGTAGCT
ATPESGPGSEPATSG CTACTCCTTCTGGTGCTACCGGCTCTC
SETPGSEPATSGSETP CAGGTGCTTCTCCGGGTACTAGCTCTA
GSPAGSPTSTEEGTS CCGGTTCTCCAGGTACTTCTACTCCGG
TEPSEGSAPGTSTEPS AAAGCGGTTCCGCATCTCCAGGTACT
EGSAPGSEPATSGSE TCTCCTAGCGGTGAATCTTCTACTGCT
TPGTSESATPESGPG CCAGGTACCTCTCCTAGCGGCGAATC
TSTEPSEGSAP TTCTACTGCTCCAGGTACTTCTGAAAG
CGCAACCCCTGAATCCGGTCCAGGTA
GCGAACCGGCTACTTCTGGCTCTGAG
ACTCCAGGTACTTCTACCGAACCGTCC
GAAGGTAGCGCACCAGGTTCTACCAG
CGAATCCCCTTCTGGTACTGCTCCAGG
TTCTACCAGCGAATCCCCTTCTGGCAC
CGCACCAGGTACTTCTACCCCTGAAA
GCGGCTCCGCTTCTCCAGGTAGCCCG
GCAGGCTCTCCGACCTCTACTGAGGA
AGGTACTTCTGAAAGCGCAACCCCGG
AGTCCGGCCCAGGTACCTCTACCGAA
CCGTCTGAGGGCAGCGCACCAGGTAG
CCCTGCTGGCTCTCCAACCTCCACCGA
AGAAGGTACCTCTGAAAGCGCAACCC
CTGAATCCGGCCCAGGTAGCGAACCG
GCAACCTCCGGTTCTGAAACCCCAGG
TAGCTCTACCCCGTCTGGTGCTACCGG
TTCCCCAGGTGCTTCTCCTGGTACTAG
CTCTACCGGTTCTCCAGGTAGCTCTAC
CCCGTCTGGTGCTACTGGCTCTCCAGG
TTCTACTAGCGAATCCCCGTCTGGTAC
TGCTCCAGGTACTTCCCCTAGCGGTGA
ATCTTCTACTGCTCCAGGTTCTACCAG
CTCTACCGCAGAATCTCCGGGTCCAG
GTAGCTCTACCCCTTCTGGTGCAACCG
GCTCTCCAGGTGCATCCCCGGGTACC
AGCTCTACCGGTTCTCCAGGTACTCCG
GGTAGCGGTACCGCTTCTTCCTCTCCA
GGTAGCCCTGCTGGCTCTCCGACTTCT
ACTGAGGAAGGTAGCCCGGCTGGTTC
TCCGACTTCTACTGAGGAAGGTACTTC
TACCGAACCTTCCGAAGGTAGCGCTC
CAGGTTTTCCGACTATTCCGCTGTCTC
GTCTGTTTGATAATGCTATGCTGCGTG
CGCACCGTCTGCACCAGCTGGCCTTTG
ATACTTACCAGGAATTTGAAGAAGCcT
ACATTCCTAAAGAGCAGAAGTACTCT
TTCCTGCAAAACCCACAGACTTCTCTC
TGCTTCAGCGAATCTATTCCGACGCCT
TCCAATCGCGAGGAAACTCAGCAAAA
GTCCAATCTGGAACTACTCCGCATTTC
TCTGCTTCTGATTCAGAGCTGGCTAGA
ACCAGTGCAATTTCTGCGTTCCGTCTT
CGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTG
AAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCT
CTCCGCGTACTGGTCAGATCTTCAAGC
AGACTTACTCTAAATTTGATACTAACA
GCCACAATGACGATGCGCTTCTAAAA
AACTATGGTCTGCTGTATTGTTTTCGT
AAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGT
TGAGGGCAGCTGTGGTTTCTAAGGTG
GTACCTCTGAAAGCGCAACTCCTGAG
TCTGGCCCAGGTAGCGAACCTGCTAC
CTCCGGCTCTGAGACTCCAGGTACCTC
TGAAAGCGCAACCCCGGAATCTGGTC
CAGGTAGCGAACCTGCAACCTCTGGC
TCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTA
CTTCTACTGAACCGTCCGAGGGCAGC
GCACCAGGTAGCCCTGCTGGCTCTCC
AACCTCCACCGAAGAAGGTACCTCTG
AAAGCGCAACCCCTGAATCCGGCCCA
GGTAGCGAACCGGCAACCTCCGGTTC
TGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGC
CCGGCTGGCTCTCCGACTTCCACCGA
GGAAGGTAGCCCGGCTGGCTCTCCAA
CTTCTACTGAAGAAGGTACTTCTACCG
AACCTTCCGAGGGCAGCGCACCAGGT
ACTTCTGAAAGCGCTACCCCTGAGTC
CGGCCCAGGTACTTCTGAAAGCGCTA
CTCCTGAATCCGGTCCAGGTACTTCTG
AAAGCGCTACCCCGGAATCTGGCCCA
GGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCC
CAGCAGGCTCTCCGACTTCCACTGAG
GAAGGTACTTCTACTGAACCTTCCGA
AGGCAGCGCACCAGGTACCTCTACTG
AACCTTCTGAGGGCAGCGCTCCAGGT
AGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTA
CTGAACCGTCCGAGGGCAGCGCACCA
*Sequence name reflects N- to C-terminus configuration of the growth factor and XTEN components
TABLE 37
Exemplary GHXTEN comprising growth hormones, XTEN and cleavage sequences
GHXTEN SEQ ID
Name* Amino Acid Sequence NO: DNA Nucleotide Sequence SEQ ID NO:
AE912- MAEPAGSPTSTEEGT 797 ATGGCTGAACCTGCTGGCTCTCCAACCT 798
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Thrombin- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGLTP CCTGCAACCTCTGGCTCTGAAACCCCAG
RSLLVGGGGSEPATS GTACCTCTGAAAGCGCTACTCCTGAATC
GSETPGTSESATPES TGGCCCAGGTACTTCTACTGAACCGTCC
GPGSEPATSGSETPG GAGGGCAGCGCACCAGGTAGCCCTGCT
SPAGSPTSTEEGTSTE GGCTCTCCAACCTCCACCGAAGAAGGT
PSEGSAPGSEPATSG ACCTCTGAAAGCGCAACCCCTGAATCCG
SETPGSEPATSGSETP GCCCAGGTAGCGAACCGGCAACCTCCG
GSEPATSGSETPGTS GTTCTGAAACCCCAGGTACTTCTGAAAG
TEPSEGSAPGTSESA CGCTACTCCTGAGTCCGGCCCAGGTAGC
TPESGPGSEPATSGS CCGGCTGGCTCTCCGACTTCCACCGAGG
ETPGTSTEPSEGSAP AAGGTAGCCCGGCTGGCTCTCCAACTTC
TACTGAAGAAGGTACTTCTACCGAACCT
TCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAATC
CGGTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACCG
GCTACTTCTGGTTCTGAAACCCCAGGTA
GCGAACCGGCTACCTCCGGTTCTGAAAC
TCCAGGTAGCCCAGCAGGCTCTCCGACT
TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTctgacc
ccgcgcagcctgctggtgggcggcGGTGGTAGCGAA
CCGGCAACTTCCGGCTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGTC
TGGCCCAGGTAGCGAACCTGCTACCTCT
GGCTCTGAAACCCCAGGTAGCCCGGCA
GGCTCTCCGACTTCCACCGAGGAAGGTA
CCTCTACTGAACCTTCTGAGGGTAGCGC
TCCAGGTAGCGAACCGGCAACCTCTGG
CTCTGAAACCCCAGGTAGCGAACCTGCT
ACCTCCGGCTCTGAAACTCCAGGTAGCG
AACCGGCTACTTCCGGTTCTGAAACTCC
AGGTACCTCTACCGAACCTTCCGAAGGC
AGCGCACCAGGTACTTCTGAAAGCGCA
ACCCCTGAATCCGGTCCAGGTAGCGAA
CCGGCTACTTCTGGCTCTGAGACTCCAG
GTACTTCTACCGAACCGTCCGAAGGTAG
CGCACCA
AE912- MAEPAGSPTSTEEGT 799 ATGGCTGAACCTGCTGGCTCTCCAACCT 800
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
FXIa- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGGG CCTGCAACCTCTGGCTCTGAAACCCCAG
KLTRVVGGGGSEPA GTACCTCTGAAAGCGCTACTCCTGAATC
TSGSETPGTSESATPE TGGCCCAGGTACTTCTACTGAACCGTCC
SGPGSEPATSGSETP GAGGGCAGCGCACCAGGTAGCCCTGCT
GSPAGSPTSTEEGTS GGCTCTCCAACCTCCACCGAAGAAGGT
TEPSEGSAPGSEPAT ACCTCTGAAAGCGCAACCCCTGAATCCG
SGSETPGSEPATSGS GCCCAGGTAGCGAACCGGCAACCTCCG
ETPGSEPATSGSETP GTTCTGAAACCCCAGGTACTTCTGAAAG
GTSTEPSEGSAPGTS CGCTACTCCTGAGTCCGGCCCAGGTAGC
ESATPESGPGSEPAT CCGGCTGGCTCTCCGACTTCCACCGAGG
SGSETPGTSTEPSEGS AAGGTAGCCCGGCTGGCTCTCCAACTTC
AP TACTGAAGAAGGTACTTCTACCGAACCT
TCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAATC
CGGTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACCG
GCTACTTCTGGTTCTGAAACCCCAGGTA
GCGAACCGGCTACCTCCGGTTCTGAAAC
TCCAGGTAGCCCAGCAGGCTCTCCGACT
TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTggcgg
caaactgacccgcgtggtgggcggcGGTGGTAGCGA
ACCGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGT
CTGGCCCAGGTAGCGAACCTGCTACCTC
TGGCTCTGAAACCCCAGGTAGCCCGGC
AGGCTCTCCGACTTCCACCGAGGAAGGT
ACCTCTACTGAACCTTCTGAGGGTAGCG
CTCCAGGTAGCGAACCGGCAACCTCTG
GCTCTGAAACCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAAACTCCAGGTAG
CGAACCGGCTACTTCCGGTTCTGAAACT
CCAGGTACCTCTACCGAACCTTCCGAAG
GCAGCGCACCAGGTACTTCTGAAAGCG
CAACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTCC
AGGTACTTCTACCGAACCGTCCGAAGGT
AGCGCACCA
AE912- MAEPAGSPTSTEEGT 801 ATGGCTGAACCTGCTGGCTCTCCAACCT 802
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Elastase- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGGG CCTGCAACCTCTGGCTCTGAAACCCCAG
LGPVSGVPGGSEPAT GTACCTCTGAAAGCGCTACTCCTGAATC
SGSETPGTSESATPES TGGCCCAGGTACTTCTACTGAACCGTCC
GPGSEPATSGSETPG GAGGGCAGCGCACCAGGTAGCCCTGCT
SPAGSPTSTEEGTSTE GGCTCTCCAACCTCCACCGAAGAAGGT
PSEGSAPGSEPATSG ACCTCTGAAAGCGCAACCCCTGAATCCG
SETPGSEPATSGSETP GCCCAGGTAGCGAACCGGCAACCTCCG
GSEPATSGSETPGTS GTTCTGAAACCCCAGGTACTTCTGAAAG
TEPSEGSAPGTSESA CGCTACTCCTGAGTCCGGCCCAGGTAGC
TPESGPGSEPATSGS CCGGCTGGCTCTCCGACTTCCACCGAGG
ETPGTSTEPSEGSAP AAGGTAGCCCGGCTGGCTCTCCAACTTC
TACTGAAGAAGGTACTTCTACCGAACCT
TCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAATC
CGGTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACCG
GCTACTTCTGGTTCTGAAACCCCAGGTA
GCGAACCGGCTACCTCCGGTTCTGAAAC
TCCAGGTAGCCCAGCAGGCTCTCCGACT
TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTggcgg
cctgggcccggtgagcggcgtgccgGGTGGTAGCGA
ACCGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGT
CTGGCCCAGGTAGCGAACCTGCTACCTC
TGGCTCTGAAACCCCAGGTAGCCCGGC
AGGCTCTCCGACTTCCACCGAGGAAGGT
ACCTCTACTGAACCTTCTGAGGGTAGCG
CTCCAGGTAGCGAACCGGCAACCTCTG
GCTCTGAAACCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAAACTCCAGGTAG
CGAACCGGCTACTTCCGGTTCTGAAACT
CCAGGTACCTCTACCGAACCTTCCGAAG
GCAGCGCACCAGGTACTTCTGAAAGCG
CAACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTCC
AGGTACTTCTACCGAACCGTCCGAAGGT
AGCGCACCA
AE912- MAEPAGSPTSTEEGT 803 ATGGCTGAACCTGCTGGCTCTCCAACCT 804
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
MMP-17- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGAPL CCTGCAACCTCTGGCTCTGAAACCCCAG
GLRLRGGGGSEPATS GTACCTCTGAAAGCGCTACTCCTGAATC
GSETPGTSESATPES TGGCCCAGGTACTTCTACTGAACCGTCC
GPGSEPATSGSETPG GAGGGCAGCGCACCAGGTAGCCCTGCT
SPAGSPTSTEEGTSTE GGCTCTCCAACCTCCACCGAAGAAGGT
PSEGSAPGSEPATSG ACCTCTGAAAGCGCAACCCCTGAATCCG
SETPGSEPATSGSETP GCCCAGGTAGCGAACCGGCAACCTCCG
GSEPATSGSETPGTS GTTCTGAAACCCCAGGTACTTCTGAAAG
TEPSEGSAPGTSESA CGCTACTCCTGAGTCCGGCCCAGGTAGC
TPESGPGSEPATSGS CCGGCTGGCTCTCCGACTTCCACCGAGG
ETPGTSTEPSEGSAP AAGGTAGCCCGGCTGGCTCTCCAACTTC
TACTGAAGAAGGTACTTCTACCGAACCT
TCCGAGGGCAGCGCACCAGGTACTTCTG
AAAGCGCTACCCCTGAGTCCGGCCCAG
GTACTTCTGAAAGCGCTACTCCTGAATC
CGGTCCAGGTACTTCTGAAAGCGCTACC
CCGGAATCTGGCCCAGGTAGCGAACCG
GCTACTTCTGGTTCTGAAACCCCAGGTA
GCGAACCGGCTACCTCCGGTTCTGAAAC
TCCAGGTAGCCCAGCAGGCTCTCCGACT
TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTgcgcc
gctgggcctgcgcctgcgcggcggcGGTGGTAGCGA
ACCGGCAACTTCCGGCTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGT
CTGGCCCAGGTAGCGAACCTGCTACCTC
TGGCTCTGAAACCCCAGGTAGCCCGGC
AGGCTCTCCGACTTCCACCGAGGAAGGT
ACCTCTACTGAACCTTCTGAGGGTAGCG
CTCCAGGTAGCGAACCGGCAACCTCTG
GCTCTGAAACCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAAACTCCAGGTAG
CGAACCGGCTACTTCCGGTTCTGAAACT
CCAGGTACCTCTACCGAACCTTCCGAAG
GCAGCGCACCAGGTACTTCTGAAAGCG
CAACCCCTGAATCCGGTCCAGGTAGCG
AACCGGCTACTTCTGGCTCTGAGACTCC
AGGTACTTCTACCGAACCGTCCGAAGGT
AGCGCACCA
AE912- MAEPAGSPTSTEEGT 805 ATGGCTGAACCTGCTGGCTCTCCAACCT 806
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Thrombin- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGLTP CCTGCAACCTCTGGCTCTGAAACCCCAG
RSLLVGGGGTSESAT GTACCTCTGAAAGCGCTACTCCTGAATC
PESGPGSEPATSGSE TGGCCCAGGTACTTCTACTGAACCGTCC
TPGTSESATPESGPG GAGGGCAGCGCACCAGGTAGCCCTGCT
SEPATSGSETPGTSES GGCTCTCCAACCTCCACCGAAGAAGGT
ATPESGPGTSTEPSE ACCTCTGAAAGCGCAACCCCTGAATCCG
GSAPGSPAGSPTSTE GCCCAGGTAGCGAACCGGCAACCTCCG
EGTSESATPESGPGS GTTCTGAAACCCCAGGTACTTCTGAAAG
EPATSGSETPGTSES CGCTACTCCTGAGTCCGGCCCAGGTAGC
ATPESGPGSPAGSPT CCGGCTGGCTCTCCGACTTCCACCGAGG
STEEGSPAGSPTSTEE AAGGTAGCCCGGCTGGCTCTCCAACTTC
GTSTEPSEGSAPGTS TACTGAAGAAGGTACTTCTACCGAACCT
ESATPESGPGTSESA TCCGAGGGCAGCGCACCAGGTACTTCTG
TPESGPGTSESATPES AAAGCGCTACCCCTGAGTCCGGCCCAG
GPGSEPATSGSETPG GTACTTCTGAAAGCGCTACTCCTGAATC
SEPATSGSETPGSPA CGGTCCAGGTACTTCTGAAAGCGCTACC
GSPTSTEEGTSTEPSE CCGGAATCTGGCCCAGGTAGCGAACCG
GSAPGTSTEPSEGSA GCTACTTCTGGTTCTGAAACCCCAGGTA
PGSEPATSGSETPGT GCGAACCGGCTACCTCCGGTTCTGAAAC
SESATPESGPGTSTEP TCCAGGTAGCCCAGCAGGCTCTCCGACT
SEGSAP TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTctgacc
ccgcgcagcctgctggtgggcggcGGTGGTACCTCT
GAAAGCGCAACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AGACTCCAGGTACCTCTGAAAGCGCAA
CCCCGGAATCTGGTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATCT
GGCCCAGGTACTTCTACTGAACCGTCCG
AGGGCAGCGCACCAGGTAGCCCTGCTG
GCTCTCCAACCTCCACCGAAGAAGGTAC
CTCTGAAAGCGCAACCCCTGAATCCGGC
CCAGGTAGCGAACCGGCAACCTCCGGT
TCTGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTA
CTGAAGAAGGTACTTCTACCGAACCTTC
CGAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAGGT
ACTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACCCC
GGAATCTGGCCCAGGTAGCGAACCGGC
TACTTCTGGTTCTGAAACCCCAGGTAGC
GAACCGGCTACCTCCGGTTCTGAAACTC
CAGGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCCAG
GTAGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCTGGCCCAGGTACTTCTACTG
AACCGTCCGAGGGCAGCGCACCA
AE912- MAEPAGSPTSTEEGT 807 ATGGCTGAACCTGCTGGCTCTCCAACCT 808
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
FXIa- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PL SRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGGG CCTGCAACCTCTGGCTCTGAAACCCCAG
KLTRVVGGGGTSES GTACCTCTGAAAGCGCTACTCCTGAATC
ATPESGPGSEPATSG TGGCCCAGGTACTTCTACTGAACCGTCC
SETPGTSESATPESGP GAGGGCAGCGCACCAGGTAGCCCTGCT
GSEPATSGSETPGTS GGCTCTCCAACCTCCACCGAAGAAGGT
ESATPESGPGTSTEPS ACCTCTGAAAGCGCAACCCCTGAATCCG
EGSAPGSPAGSPTST GCCCAGGTAGCGAACCGGCAACCTCCG
EEGTSESATPESGPG GTTCTGAAACCCCAGGTACTTCTGAAAG
SEPATSGSETPGTSES CGCTACTCCTGAGTCCGGCCCAGGTAGC
ATPESGPGSPAGSPT CCGGCTGGCTCTCCGACTTCCACCGAGG
STEEGSPAGSPTSTEE AAGGTAGCCCGGCTGGCTCTCCAACTTC
GTSTEPSEGSAPGTS TACTGAAGAAGGTACTTCTACCGAACCT
ESATPESGPGTSESA TCCGAGGGCAGCGCACCAGGTACTTCTG
TPESGPGTSESATPES AAAGCGCTACCCCTGAGTCCGGCCCAG
GPGSEPATSGSETPG GTACTTCTGAAAGCGCTACTCCTGAATC
SEPATSGSETPGSPA CGGTCCAGGTACTTCTGAAAGCGCTACC
GSPTSTEEGTSTEPSE CCGGAATCTGGCCCAGGTAGCGAACCG
GSAPGTSTEPSEGSA GCTACTTCTGGTTCTGAAACCCCAGGTA
PGSEPATSGSETPGT GCGAACCGGCTACCTCCGGTTCTGAAAC
SESATPESGPGTSTEP TCCAGGTAGCCCAGCAGGCTCTCCGACT
SEGSAP TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTggcgg
caaactgacccgcgtggtgggcggcGGTGGTACCTC
TGAAAGCGCAACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AGACTCCAGGTACCTCTGAAAGCGCAA
CCCCGGAATCTGGTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATCT
GGCCCAGGTACTTCTACTGAACCGTCCG
AGGGCAGCGCACCAGGTAGCCCTGCTG
GCTCTCCAACCTCCACCGAAGAAGGTAC
CTCTGAAAGCGCAACCCCTGAATCCGGC
CCAGGTAGCGAACCGGCAACCTCCGGT
TCTGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTA
CTGAAGAAGGTACTTCTACCGAACCTTC
CGAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAGGT
ACTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACCCC
GGAATCTGGCCCAGGTAGCGAACCGGC
TACTTCTGGTTCTGAAACCCCAGGTAGC
GAACCGGCTACCTCCGGTTCTGAAACTC
CAGGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCCAG
GTAGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCTGGCCCAGGTACTTCTACTG
AACCGTCCGAGGGCAGCGCACCA
AE912- MAEPAGSPTSTEEGT 809 ATGGCTGAACCTGCTGGCTCTCCAACCT 810
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Elastase- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGGG CCTGCAACCTCTGGCTCTGAAACCCCAG
LGPVSGVPGGTSESA GTACCTCTGAAAGCGCTACTCCTGAATC
TPESGPGSEPATSGS TGGCCCAGGTACTTCTACTGAACCGTCC
ETPGTSESATPESGP GAGGGCAGCGCACCAGGTAGCCCTGCT
GSEPATSGSETPGTS GGCTCTCCAACCTCCACCGAAGAAGGT
ESATPESGPGTSTEPS ACCTCTGAAAGCGCAACCCCTGAATCCG
EGSAPGSPAGSPTST GCCCAGGTAGCGAACCGGCAACCTCCG
EEGTSESATPESGPG GTTCTGAAACCCCAGGTACTTCTGAAAG
SEPATSGSETPGTSES CGCTACTCCTGAGTCCGGCCCAGGTAGC
ATPESGPGSPAGSPT CCGGCTGGCTCTCCGACTTCCACCGAGG
STEEGSPAGSPTSTEE AAGGTAGCCCGGCTGGCTCTCCAACTTC
GTSTEPSEGSAPGTS TACTGAAGAAGGTACTTCTACCGAACCT
ESATPESGPGTSESA TCCGAGGGCAGCGCACCAGGTACTTCTG
TPESGPGTSESATPES AAAGCGCTACCCCTGAGTCCGGCCCAG
GPGSEPATSGSETPG GTACTTCTGAAAGCGCTACTCCTGAATC
SEPATSGSETPGSPA CGGTCCAGGTACTTCTGAAAGCGCTACC
GSPTSTEEGTSTEPSE CCGGAATCTGGCCCAGGTAGCGAACCG
GSAPGTSTEPSEGSA GCTACTTCTGGTTCTGAAACCCCAGGTA
PGSEPATSGSETPGT GCGAACCGGCTACCTCCGGTTCTGAAAC
SESATPESGPGTSTEP TCCAGGTAGCCCAGCAGGCTCTCCGACT
SEGSAP TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTggcgg
cctgggcccggtgagcggcgtgccgGGTGGTACCTC
TGAAAGCGCAACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AGACTCCAGGTACCTCTGAAAGCGCAA
CCCCGGAATCTGGTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATCT
GGCCCAGGTACTTCTACTGAACCGTCCG
AGGGCAGCGCACCAGGTAGCCCTGCTG
GCTCTCCAACCTCCACCGAAGAAGGTAC
CTCTGAAAGCGCAACCCCTGAATCCGGC
CCAGGTAGCGAACCGGCAACCTCCGGT
TCTGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTA
CTGAAGAAGGTACTTCTACCGAACCTTC
CGAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAGGT
ACTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACCCC
GGAATCTGGCCCAGGTAGCGAACCGGC
TACTTCTGGTTCTGAAACCCCAGGTAGC
GAACCGGCTACCTCCGGTTCTGAAACTC
CAGGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCCAG
GTAGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCTGGCCCAGGTACTTCTACTG
AACCGTCCGAGGGCAGCGCACCA
AE912- MAEPAGSPTSTEEGT 811 ATGGCTGAACCTGCTGGCTCTCCAACCT 812
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
MMP-17- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
TSESATPESGPGSEP CTACTCCGGAGTCTGGCCCAGGTACCTC
ATSGSETPGTSESAT TACTGAACCGTCTGAGGGTAGCGCTCCA
PESGPGSEPATSGSE GGTACTTCTACTGAACCGTCCGAAGGTA
TPGTSESATPESGPG GCGCACCAGGTACTTCTACCGAACCGTC
TSTEPSEGSAPGSPA CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPTSTEEGTSESATP GAACCTTCCGAGGGCAGCGCTCCAGGT
ESGPGSEPATSGSET ACCTCTACCGAACCTTCTGAAGGTAGCG
PGTSESATPESGPGSP CACCAGGTACTTCTACCGAACCGTCCGA
AGSPTSTEEGSPAGS GGGTAGCGCACCAGGTAGCCCAGCAGG
PTSTEEGTSTEPSEGS TTCTCCTACCTCCACCGAGGAAGGTACT
APGTSESATPESGPG TCTACCGAACCGTCCGAGGGTAGCGCA
TSESATPESGPGTSES CCAGGTACCTCTGAAAGCGCAACTCCTG
ATPESGPGSEPATSG AGTCTGGCCCAGGTAGCGAACCTGCTAC
SETPGSEPATSGSETP CTCCGGCTCTGAGACTCCAGGTACCTCT
GSPAGSPTSTEEGTS GAAAGCGCAACCCCGGAATCTGGTCCA
TEPSEGSAPGTSTEPS GGTAGCGAACCTGCAACCTCTGGCTCTG
EGSAPGSEPATSGSE AAACCCCAGGTACCTCTGAAAGCGCTA
TPGTSESATPESGPG CTCCTGAATCTGGCCCAGGTACTTCTAC
TSTEPSEGSAPGFPTI TGAACCGTCCGAGGGCAGCGCACCAGG
PLSRLFDNAMLRAH TACTTCTGAAAGCGCTACTCCTGAGTCC
RLHQLAFDTYQEFEE GGCCCAGGTAGCCCGGCTGGCTCTCCGA
AYIPKEQKYSFLQNP CTTCCACCGAGGAAGGTAGCCCGGCTG
QTSLCFSESIPTPSNR GCTCTCCAACTTCTACTGAAGAAGGTAG
EETQQKSNLELLRIS CCCGGCAGGCTCTCCGACCTCTACTGAG
LLLIQSWLEPVQFLR GAAGGTACTTCTGAAAGCGCAACCCCG
SVFANSLVYGASDS GAGTCCGGCCCAGGTACCTCTACCGAAC
NVYDLLKDLEEGIQT CGTCTGAGGGCAGCGCACCAGGTACCT
LMGRLEDGSPRTGQI CTGAAAGCGCAACTCCTGAGTCTGGCCC
FKQTYSKFDTNSHN AGGTAGCGAACCTGCTACCTCCGGCTCT
DDALLKNYGLLYCF GAGACTCCAGGTACCTCTGAAAGCGCA
RKDMDKVETFLRIV ACCCCGGAATCTGGTCCAGGTAGCGAA
QCRSVEGSCGFGAPL CCTGCAACCTCTGGCTCTGAAACCCCAG
GLRLRGGGGTSESA GTACCTCTGAAAGCGCTACTCCTGAATC
TPESGPGSEPATSGS TGGCCCAGGTACTTCTACTGAACCGTCC
ETPGTSESATPESGP GAGGGCAGCGCACCAGGTAGCCCTGCT
GSEPATSGSETPGTS GGCTCTCCAACCTCCACCGAAGAAGGT
ESATPESGPGTSTEPS ACCTCTGAAAGCGCAACCCCTGAATCCG
EGSAPGSPAGSPTST GCCCAGGTAGCGAACCGGCAACCTCCG
EEGTSESATPESGPG GTTCTGAAACCCCAGGTACTTCTGAAAG
SEPATSGSETPGTSES CGCTACTCCTGAGTCCGGCCCAGGTAGC
ATPESGPGSPAGSPT CCGGCTGGCTCTCCGACTTCCACCGAGG
STEEGSPAGSPTSTEE AAGGTAGCCCGGCTGGCTCTCCAACTTC
GTSTEPSEGSAPGTS TACTGAAGAAGGTACTTCTACCGAACCT
ESATPESGPGTSESA TCCGAGGGCAGCGCACCAGGTACTTCTG
TPESGPGTSESATPES AAAGCGCTACCCCTGAGTCCGGCCCAG
GPGSEPATSGSETPG GTACTTCTGAAAGCGCTACTCCTGAATC
SEPATSGSETPGSPA CGGTCCAGGTACTTCTGAAAGCGCTACC
GSPTSTEEGTSTEPSE CCGGAATCTGGCCCAGGTAGCGAACCG
GSAPGTSTEPSEGSA GCTACTTCTGGTTCTGAAACCCCAGGTA
PGSEPATSGSETPGT GCGAACCGGCTACCTCCGGTTCTGAAAC
SESATPESGPGTSTEP TCCAGGTAGCCCAGCAGGCTCTCCGACT
SEGSAP TCCACTGAGGAAGGTACTTCTACTGAAC
CTTCCGAAGGCAGCGCACCAGGTACCTC
TACTGAACCTTCTGAGGGCAGCGCTCCA
GGTAGCGAACCTGCAACCTCTGGCTCTG
AAACCCCAGGTACCTCTGAAAGCGCTA
CTCCTGAATCTGGCCCAGGTACTTCTAC
TGAACCGTCCGAGGGCAGCGCACCAGG
TTTTCCGACTATTCCGCTGTCTCGTCTGT
TTGATAATGCTATGCTGCGTGCGCACCG
TCTGCACCAGCTGGCCTTTGATACTTAC
CAGGAATTTGAAGAAGCcTACATTCCTA
AAGAGCAGAAGTACTCTTTCCTGCAAA
ACCCACAGACTTCTCTCTGCTTCAGCGA
ATCTATTCCGACGCCTTCCAATCGCGAG
GAAACTCAGCAAAAGTCCAATCTGGAA
CTACTCCGCATTTCTCTGCTTCTGATTCA
GAGCTGGCTAGAACCAGTGCAATTTCTG
CGTTCCGTCTTCGCCAATAGCCTAGTTT
ATGGCGCATCCGACAGCAACGTATACG
ATCTCCTGAAAGATCTCGAGGAAGGCA
TTCAGACCCTGATGGGTCGTCTCGAGGA
TGGCTCTCCGCGTACTGGTCAGATCTTC
AAGCAGACTTACTCTAAATTTGATACTA
ACAGCCACAATGACGATGCGCTTCTAA
AAAACTATGGTCTGCTGTATTGTTTTCG
TAAAGATATGGACAAAGTTGAAACCTT
CCTGCGTATTGTTCAGTGTCGTTCCGTT
GAGGGCAGCTGTGGTTTCTAAGGTgcgcc
gctgggcctgcgcctgcgcggcggcGGTGGTACCTC
TGAAAGCGCAACTCCTGAGTCTGGCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AGACTCCAGGTACCTCTGAAAGCGCAA
CCCCGGAATCTGGTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATCT
GGCCCAGGTACTTCTACTGAACCGTCCG
AGGGCAGCGCACCAGGTAGCCCTGCTG
GCTCTCCAACCTCCACCGAAGAAGGTAC
CTCTGAAAGCGCAACCCCTGAATCCGGC
CCAGGTAGCGAACCGGCAACCTCCGGT
TCTGAAACCCCAGGTACTTCTGAAAGCG
CTACTCCTGAGTCCGGCCCAGGTAGCCC
GGCTGGCTCTCCGACTTCCACCGAGGAA
GGTAGCCCGGCTGGCTCTCCAACTTCTA
CTGAAGAAGGTACTTCTACCGAACCTTC
CGAGGGCAGCGCACCAGGTACTTCTGA
AAGCGCTACCCCTGAGTCCGGCCCAGGT
ACTTCTGAAAGCGCTACTCCTGAATCCG
GTCCAGGTACTTCTGAAAGCGCTACCCC
GGAATCTGGCCCAGGTAGCGAACCGGC
TACTTCTGGTTCTGAAACCCCAGGTAGC
GAACCGGCTACCTCCGGTTCTGAAACTC
CAGGTAGCCCAGCAGGCTCTCCGACTTC
CACTGAGGAAGGTACTTCTACTGAACCT
TCCGAAGGCAGCGCACCAGGTACCTCT
ACTGAACCTTCTGAGGGCAGCGCTCCAG
GTAGCGAACCTGCAACCTCTGGCTCTGA
AACCCCAGGTACCTCTGAAAGCGCTACT
CCTGAATCTGGCCCAGGTACTTCTACTG
AACCGTCCGAGGGCAGCGCACCA
AM923- MAEPAGSPTSTEEGA 813 ATGGCTGAACCTGCTGGCTCTCCAACCT 814
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
Thrombin- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE144 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGLTPRSLLVG GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGSEPATSGSETPG GCGAACCTGCAACCTCCGGCTCTGAAAC
TSESATPESGPGSEP CCCAGGTACTTCTACTGAACCTTCTGAG
ATSGSETPGSPAGSP GGCAGCGCACCAGGTTCTACCAGCTCTA
TSTEEGTSTEPSEGS CCGCAGAATCTCCTGGTCCAGGTACCTC
APGSEPATSGSETPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SEPATSGSETPGSEP GGTTCTACTAGCGAATCTCCTTCTGGCA
ATSGSETPGTSTEPSE CTGCACCAGGTACTTCTACCGAACCGTC
GSAPGTSESATPESG CGAAGGCAGCGCTCCAGGTACCTCTACT
PGSEPATSGSETPGT GAACCTTCCGAGGGCAGCGCTCCAGGT
STEPSEGSAP ACCTCTACCGAACCTTCTGAAGGTAGCG
CACCAGGTAGCTCTACTCCGTCTGGTGC
AACCGGCTCCCCAGGTTCTAGCCCGTCT
GCTTCCACTGGTACTGGCCCAGGTGCTT
CCCCGGGCACCAGCTCTACTGGTTCTCC
AGGTAGCGAACCTGCTACCTCCGGTTCT
GAAACCCCAGGTACCTCTGAAAGCGCA
ACTCCGGAGTCTGGTCCAGGTAGCCCTG
CAGGTTCTCCTACCTCCACTGAGGAAGG
TAGCTCTACTCCGTCTGGTGCAACCGGC
TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTctgaccccgcgcagcctgctggtgg
gcggcGGTGGTAGCGAACCGGCAACTTCC
GGCTCTGAAACCCCAGGTACTTCTGAAA
GCGCTACTCCTGAGTCTGGCCCAGGTAG
CGAACCTGCTACCTCTGGCTCTGAAACC
CCAGGTAGCCCGGCAGGCTCTCCGACTT
CCACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGCGA
ACCGGCAACCTCTGGCTCTGAAACCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACTTC
CGGTTCTGAAACTCCAGGTACCTCTACC
GAACCTTCCGAAGGCAGCGCACCAGGT
ACTTCTGAAAGCGCAACCCCTGAATCCG
GTCCAGGTAGCGAACCGGCTACTTCTGG
CTCTGAGACTCCAGGTACTTCTACCGAA
CCGTCCGAAGGTAGCGCACCA
AM923- MAEPAGSPTSTEEGA 815 ATGGCTGAACCTGCTGGCTCTCCAACCT 816
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
FXIa- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE144 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGGGKLTRVV GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGGSEPATSGSETP GCGAACCTGCAACCTCCGGCTCTGAAAC
GTSESATPESGPGSE CCCAGGTACTTCTACTGAACCTTCTGAG
PATSGSETPGSPAGS GGCAGCGCACCAGGTTCTACCAGCTCTA
PTSTEEGTSTEPSEGS CCGCAGAATCTCCTGGTCCAGGTACCTC
APGSEPATSGSETPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SEPATSGSETPGSEP GGTTCTACTAGCGAATCTCCTTCTGGCA
ATSGSETPGTSTEPSE CTGCACCAGGTACTTCTACCGAACCGTC
GSAPGTSESATPESG CGAAGGCAGCGCTCCAGGTACCTCTACT
PGSEPATSGSETPGT GAACCTTCCGAGGGCAGCGCTCCAGGT
STEPSEGSAP ACCTCTACCGAACCTTCTGAAGGTAGCG
CACCAGGTAGCTCTACTCCGTCTGGTGC
AACCGGCTCCCCAGGTTCTAGCCCGTCT
GCTTCCACTGGTACTGGCCCAGGTGCTT
CCCCGGGCACCAGCTCTACTGGTTCTCC
AGGTAGCGAACCTGCTACCTCCGGTTCT
GAAACCCCAGGTACCTCTGAAAGCGCA
ACTCCGGAGTCTGGTCCAGGTAGCCCTG
CAGGTTCTCCTACCTCCACTGAGGAAGG
TAGCTCTACTCCGTCTGGTGCAACCGGC
TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTggcggcaaactgacccgcgtggtg
ggcggcGGTGGTAGCGAACCGGCAACTTC
CGGCTCTGAAACCCCAGGTACTTCTGAA
AGCGCTACTCCTGAGTCTGGCCCAGGTA
GCGAACCTGCTACCTCTGGCTCTGAAAC
CCCAGGTAGCCCGGCAGGCTCTCCGACT
TCCACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGCGA
ACCGGCAACCTCTGGCTCTGAAACCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACTTC
CGGTTCTGAAACTCCAGGTACCTCTACC
GAACCTTCCGAAGGCAGCGCACCAGGT
ACTTCTGAAAGCGCAACCCCTGAATCCG
GTCCAGGTAGCGAACCGGCTACTTCTGG
CTCTGAGACTCCAGGTACTTCTACCGAA
CCGTCCGAAGGTAGCGCACCA
AM923- MAEPAGSPTSTEEGA 817 ATGGCTGAACCTGCTGGCTCTCCAACCT 818
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
Elastase- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE144 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGGGLGPVSG GCAACCTCTGGCTCTGAAACTCCAGGTA
VPGGSEPATSGSETP GCGAACCTGCAACCTCCGGCTCTGAAAC
GTSESATPESGPGSE CCCAGGTACTTCTACTGAACCTTCTGAG
PATSGSETPGSPAGS GGCAGCGCACCAGGTTCTACCAGCTCTA
PTSTEEGTSTEPSEGS CCGCAGAATCTCCTGGTCCAGGTACCTC
APGSEPATSGSETPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SEPATSGSETPGSEP GGTTCTACTAGCGAATCTCCTTCTGGCA
ATSGSETPGTSTEPSE CTGCACCAGGTACTTCTACCGAACCGTC
GSAPGTSESATPESG CGAAGGCAGCGCTCCAGGTACCTCTACT
PGSEPATSGSETPGT GAACCTTCCGAGGGCAGCGCTCCAGGT
STEPSEGSAP ACCTCTACCGAACCTTCTGAAGGTAGCG
CACCAGGTAGCTCTACTCCGTCTGGTGC
AACCGGCTCCCCAGGTTCTAGCCCGTCT
GCTTCCACTGGTACTGGCCCAGGTGCTT
CCCCGGGCACCAGCTCTACTGGTTCTCC
AGGTAGCGAACCTGCTACCTCCGGTTCT
GAAACCCCAGGTACCTCTGAAAGCGCA
ACTCCGGAGTCTGGTCCAGGTAGCCCTG
CAGGTTCTCCTACCTCCACTGAGGAAGG
TAGCTCTACTCCGTCTGGTGCAACCGGC
TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTggcggcctgggcccggtgagcggc
gtgccgGGTGGTAGCGAACCGGCAACTTCC
GGCTCTGAAACCCCAGGTACTTCTGAAA
GCGCTACTCCTGAGTCTGGCCCAGGTAG
CGAACCTGCTACCTCTGGCTCTGAAACC
CCAGGTAGCCCGGCAGGCTCTCCGACTT
CCACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGCGA
ACCGGCAACCTCTGGCTCTGAAACCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACTTC
CGGTTCTGAAACTCCAGGTACCTCTACC
GAACCTTCCGAAGGCAGCGCACCAGGT
ACTTCTGAAAGCGCAACCCCTGAATCCG
GTCCAGGTAGCGAACCGGCTACTTCTGG
CTCTGAGACTCCAGGTACTTCTACCGAA
CCGTCCGAAGGTAGCGCACCA
AM923- MAEPAGSPTSTEEGA 819 ATGGCTGAACCTGCTGGCTCTCCAACCT 820
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
MMP-17- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE144 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGAPLGLRLR GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGGSEPATSGSETP GCGAACCTGCAACCTCCGGCTCTGAAAC
GTSESATPESGPGSE CCCAGGTACTTCTACTGAACCTTCTGAG
PATSGSETPGSPAGS GGCAGCGCACCAGGTTCTACCAGCTCTA
PTSTEEGTSTEPSEGS CCGCAGAATCTCCTGGTCCAGGTACCTC
APGSEPATSGSETPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SEPATSGSETPGSEP GGTTCTACTAGCGAATCTCCTTCTGGCA
ATSGSETPGTSTEPSE CTGCACCAGGTACTTCTACCGAACCGTC
GSAPGTSESATPESG CGAAGGCAGCGCTCCAGGTACCTCTACT
PGSEPATSGSETPGT GAACCTTCCGAGGGCAGCGCTCCAGGT
STEPSEGSAP ACCTCTACCGAACCTTCTGAAGGTAGCG
CACCAGGTAGCTCTACTCCGTCTGGTGC
AACCGGCTCCCCAGGTTCTAGCCCGTCT
GCTTCCACTGGTACTGGCCCAGGTGCTT
CCCCGGGCACCAGCTCTACTGGTTCTCC
AGGTAGCGAACCTGCTACCTCCGGTTCT
GAAACCCCAGGTACCTCTGAAAGCGCA
ACTCCGGAGTCTGGTCCAGGTAGCCCTG
CAGGTTCTCCTACCTCCACTGAGGAAGG
TAGCTCTACTCCGTCTGGTGCAACCGGC
TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTgcgccgctgggcctgcgcctgcgc
ggcggcGGTGGTAGCGAACCGGCAACTTC
CGGCTCTGAAACCCCAGGTACTTCTGAA
AGCGCTACTCCTGAGTCTGGCCCAGGTA
GCGAACCTGCTACCTCTGGCTCTGAAAC
CCCAGGTAGCCCGGCAGGCTCTCCGACT
TCCACCGAGGAAGGTACCTCTACTGAAC
CTTCTGAGGGTAGCGCTCCAGGTAGCGA
ACCGGCAACCTCTGGCTCTGAAACCCCA
GGTAGCGAACCTGCTACCTCCGGCTCTG
AAACTCCAGGTAGCGAACCGGCTACTTC
CGGTTCTGAAACTCCAGGTACCTCTACC
GAACCTTCCGAAGGCAGCGCACCAGGT
ACTTCTGAAAGCGCAACCCCTGAATCCG
GTCCAGGTAGCGAACCGGCTACTTCTGG
CTCTGAGACTCCAGGTACTTCTACCGAA
CCGTCCGAAGGTAGCGCACCA
AM923- MAEPAGSPTSTEEGA 821 ATGGCTGAACCTGCTGGCTCTCCAACCT 822
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
Thrombin- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE288 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPL SRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGLTPRSLLVG GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGTSESATPESGPG GCGAACCTGCAACCTCCGGCTCTGAAAC
SEPATSGSETPGTSES CCCAGGTACTTCTACTGAACCTTCTGAG
ATPESGPGSEPATSG GGCAGCGCACCAGGTTCTACCAGCTCTA
SETPGTSESATPESGP CCGCAGAATCTCCTGGTCCAGGTACCTC
GTSTEPSEGSAPGSP TACTCCGGAAAGCGGCTCTGCATCTCCA
AGSPTSTEEGTSESA GGTTCTACTAGCGAATCTCCTTCTGGCA
TPESGPGSEPATSGS CTGCACCAGGTACTTCTACCGAACCGTC
ETPGTSESATPESGP CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPAGSPTSTEEGSP GAACCTTCCGAGGGCAGCGCTCCAGGT
AGSPTSTEEGTSTEPS ACCTCTACCGAACCTTCTGAAGGTAGCG
EGSAPGTSESATPES CACCAGGTAGCTCTACTCCGTCTGGTGC
GPGTSESATPESGPG AACCGGCTCCCCAGGTTCTAGCCCGTCT
TSESATPESGPGSEP GCTTCCACTGGTACTGGCCCAGGTGCTT
ATSGSETPGSEPATS CCCCGGGCACCAGCTCTACTGGTTCTCC
GSETPGSPAGSPTST AGGTAGCGAACCTGCTACCTCCGGTTCT
EEGTSTEPSEGSAPG GAAACCCCAGGTACCTCTGAAAGCGCA
TSTEPSEGSAPGSEP ACTCCGGAGTCTGGTCCAGGTAGCCCTG
ATSGSETPGTSESAT CAGGTTCTCCTACCTCCACTGAGGAAGG
PESGPGTSTEPSEGS TAGCTCTACTCCGTCTGGTGCAACCGGC
AP TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTctgaccccgcgcagcctgctggtgg
gcggcGGTGGTACCTCTGAAAGCGCAACT
CCTGAGTCTGGCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAGACTCCAGGTAC
CTCTGAAAGCGCAACCCCGGAATCTGGT
CCAGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGCG
CTACTCCTGAATCTGGCCCAGGTACTTC
TACTGAACCGTCCGAGGGCAGCGCACC
AGGTAGCCCTGCTGGCTCTCCAACCTCC
ACCGAAGAAGGTACCTCTGAAAGCGCA
ACCCCTGAATCCGGCCCAGGTAGCGAA
CCGGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGTC
CGGCCCAGGTAGCCCGGCTGGCTCTCCG
ACTTCCACCGAGGAAGGTAGCCCGGCT
GGCTCTCCAACTTCTACTGAAGAAGGTA
CTTCTACCGAACCTTCCGAGGGCAGCGC
ACCAGGTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGAAAGC
GCTACTCCTGAATCCGGTCCAGGTACTT
CTGAAAGCGCTACCCCGGAATCTGGCCC
AGGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCCAG
CAGGCTCTCCGACTTCCACTGAGGAAGG
TACTTCTACTGAACCTTCCGAAGGCAGC
GCACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCTG
CAACCTCTGGCTCTGAAACCCCAGGTAC
CTCTGAAAGCGCTACTCCTGAATCTGGC
CCAGGTACTTCTACTGAACCGTCCGAGG
GCAGCGCACCA
AM923- MAEPAGSPTSTEEGA 823 ATGGCTGAACCTGCTGGCTCTCCAACCT 824
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
FXIa- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE288 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGGGKLTRVV GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGGTSESATPESGP GCGAACCTGCAACCTCCGGCTCTGAAAC
GSEPATSGSETPGTS CCCAGGTACTTCTACTGAACCTTCTGAG
ESATPESGPGSEPAT GGCAGCGCACCAGGTTCTACCAGCTCTA
SGSETPGTSESATPES CCGCAGAATCTCCTGGTCCAGGTACCTC
GPGTSTEPSEGSAPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SPAGSPTSTEEGTSES GGTTCTACTAGCGAATCTCCTTCTGGCA
ATPESGPGSEPATSG CTGCACCAGGTACTTCTACCGAACCGTC
SETPGTSESATPESGP CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPAGSPTSTEEGSP GAACCTTCCGAGGGCAGCGCTCCAGGT
AGSPTSTEEGTSTEPS ACCTCTACCGAACCTTCTGAAGGTAGCG
EGSAPGTSESATPES CACCAGGTAGCTCTACTCCGTCTGGTGC
GPGTSESATPESGPG AACCGGCTCCCCAGGTTCTAGCCCGTCT
TSESATPESGPGSEP GCTTCCACTGGTACTGGCCCAGGTGCTT
ATSGSETPGSEPATS CCCCGGGCACCAGCTCTACTGGTTCTCC
GSETPGSPAGSPTST AGGTAGCGAACCTGCTACCTCCGGTTCT
EEGTSTEPSEGSAPG GAAACCCCAGGTACCTCTGAAAGCGCA
TSTEPSEGSAPGSEP ACTCCGGAGTCTGGTCCAGGTAGCCCTG
ATSGSETPGTSESAT CAGGTTCTCCTACCTCCACTGAGGAAGG
PESGPGTSTEPSEGS TAGCTCTACTCCGTCTGGTGCAACCGGC
AP TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTggcggcaaactgacccgcgtggtg
ggcggcGGTGGTACCTCTGAAAGCGCAAC
TCCTGAGTCTGGCCCAGGTAGCGAACCT
GCTACCTCCGGCTCTGAGACTCCAGGTA
CCTCTGAAAGCGCAACCCCGGAATCTG
GTCCAGGTAGCGAACCTGCAACCTCTGG
CTCTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACTT
CTACTGAACCGTCCGAGGGCAGCGCAC
CAGGTAGCCCTGCTGGCTCTCCAACCTC
CACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCTCC
GACTTCCACCGAGGAAGGTAGCCCGGC
TGGCTCTCCAACTTCTACTGAAGAAGGT
ACTTCTACCGAACCTTCCGAGGGCAGCG
CACCAGGTACTTCTGAAAGCGCTACCCC
TGAGTCCGGCCCAGGTACTTCTGAAAGC
GCTACTCCTGAATCCGGTCCAGGTACTT
CTGAAAGCGCTACCCCGGAATCTGGCCC
AGGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCCAG
CAGGCTCTCCGACTTCCACTGAGGAAGG
TACTTCTACTGAACCTTCCGAAGGCAGC
GCACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCTG
CAACCTCTGGCTCTGAAACCCCAGGTAC
CTCTGAAAGCGCTACTCCTGAATCTGGC
CCAGGTACTTCTACTGAACCGTCCGAGG
GCAGCGCACCA
AM923- MAEPAGSPTSTEEGA 825 ATGGCTGAACCTGCTGGCTCTCCAACCT 826
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
Elastase- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE288 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGGGLGPVSG GCAACCTCTGGCTCTGAAACTCCAGGTA
VPGGTSESATPESGP GCGAACCTGCAACCTCCGGCTCTGAAAC
GSEPATSGSETPGTS CCCAGGTACTTCTACTGAACCTTCTGAG
ESATPESGPGSEPAT GGCAGCGCACCAGGTTCTACCAGCTCTA
SGSETPGTSESATPES CCGCAGAATCTCCTGGTCCAGGTACCTC
GPGTSTEPSEGSAPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SPAGSPTSTEEGTSES GGTTCTACTAGCGAATCTCCTTCTGGCA
ATPESGPGSEPATSG CTGCACCAGGTACTTCTACCGAACCGTC
SETPGTSESATPESGP CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPAGSPTSTEEGSP GAACCTTCCGAGGGCAGCGCTCCAGGT
AGSPTSTEEGTSTEPS ACCTCTACCGAACCTTCTGAAGGTAGCG
EGSAPGTSESATPES CACCAGGTAGCTCTACTCCGTCTGGTGC
GPGTSESATPESGPG AACCGGCTCCCCAGGTTCTAGCCCGTCT
TSESATPESGPGSEP GCTTCCACTGGTACTGGCCCAGGTGCTT
ATSGSETPGSEPATS CCCCGGGCACCAGCTCTACTGGTTCTCC
GSETPGSPAGSPTST AGGTAGCGAACCTGCTACCTCCGGTTCT
EEGTSTEPSEGSAPG GAAACCCCAGGTACCTCTGAAAGCGCA
TSTEPSEGSAPGSEP ACTCCGGAGTCTGGTCCAGGTAGCCCTG
ATSGSETPGTSESAT CAGGTTCTCCTACCTCCACTGAGGAAGG
PESGPGTSTEPSEGS TAGCTCTACTCCGTCTGGTGCAACCGGC
AP TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTggcggcctgggcccggtgagcggc
gtgccgGGTGGTACCTCTGAAAGCGCAACT
CCTGAGTCTGGCCCAGGTAGCGAACCTG
CTACCTCCGGCTCTGAGACTCCAGGTAC
CTCTGAAAGCGCAACCCCGGAATCTGGT
CCAGGTAGCGAACCTGCAACCTCTGGCT
CTGAAACCCCAGGTACCTCTGAAAGCG
CTACTCCTGAATCTGGCCCAGGTACTTC
TACTGAACCGTCCGAGGGCAGCGCACC
AGGTAGCCCTGCTGGCTCTCCAACCTCC
ACCGAAGAAGGTACCTCTGAAAGCGCA
ACCCCTGAATCCGGCCCAGGTAGCGAA
CCGGCAACCTCCGGTTCTGAAACCCCAG
GTACTTCTGAAAGCGCTACTCCTGAGTC
CGGCCCAGGTAGCCCGGCTGGCTCTCCG
ACTTCCACCGAGGAAGGTAGCCCGGCT
GGCTCTCCAACTTCTACTGAAGAAGGTA
CTTCTACCGAACCTTCCGAGGGCAGCGC
ACCAGGTACTTCTGAAAGCGCTACCCCT
GAGTCCGGCCCAGGTACTTCTGAAAGC
GCTACTCCTGAATCCGGTCCAGGTACTT
CTGAAAGCGCTACCCCGGAATCTGGCCC
AGGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCCAG
CAGGCTCTCCGACTTCCACTGAGGAAGG
TACTTCTACTGAACCTTCCGAAGGCAGC
GCACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCTG
CAACCTCTGGCTCTGAAACCCCAGGTAC
CTCTGAAAGCGCTACTCCTGAATCTGGC
CCAGGTACTTCTACTGAACCGTCCGAGG
GCAGCGCACCA
AM923- MAEPAGSPTSTEEGA 827 ATGGCTGAACCTGCTGGCTCTCCAACCT 828
hGH- SPGTSSTGSPGSSTPS CCACTGAGGAAGGTGCATCCCCGGGCA
MMP-17- GATGSPGSSTPSGAT CCAGCTCTACCGGTTCTCCAGGTAGCTC
AE288 GSPGTSTEPSEGSAP TACCCCGTCTGGTGCTACCGGCTCTCCA
GSEPATSGSETPGSP GGTAGCTCTACCCCGTCTGGTGCTACTG
AGSPTSTEEGSTSST GCTCTCCAGGTACTTCTACTGAACCGTC
AESPGPGTSTPESGS TGAAGGCAGCGCACCAGGTAGCGAACC
ASPGSTSESPSGTAP GGCTACTTCCGGTTCTGAAACCCCAGGT
GSTSESPSGTAPGTS AGCCCAGCAGGTTCTCCAACTTCTACTG
TPESGSASPGTSTPES AAGAAGGTTCTACCAGCTCTACCGCAG
GSASPGSEPATSGSE AATCTCCTGGTCCAGGTACCTCTACTCC
TPGTSESATPESGPG GGAAAGCGGCTCTGCATCTCCAGGTTCT
SPAGSPTSTEEGTSTE ACTAGCGAATCTCCTTCTGGCACTGCAC
PSEGSAPGTSESATP CAGGTTCTACTAGCGAATCCCCGTCTGG
ESGPGTSTEPSEGSA TACTGCTCCAGGTACTTCTACTCCTGAA
PGTSTEPSEGSAPGSP AGCGGTTCCGCTTCTCCAGGTACCTCTA
AGSPTSTEEGTSTEPS CTCCGGAAAGCGGTTCTGCATCTCCAGG
EGSAPGTSTEPSEGS TAGCGAACCGGCAACCTCCGGCTCTGA
APGTSESATPESGPG AACCCCAGGTACCTCTGAAAGCGCTACT
TSESATPESGPGTSTE CCTGAATCCGGCCCAGGTAGCCCGGCA
PSEGSAPGTSTEPSE GGTTCTCCGACTTCCACTGAGGAAGGTA
GSAPGTSESATPESG CCTCTACTGAACCTTCTGAGGGCAGCGC
PGTSTEPSEGSAPGS TCCAGGTACTTCTGAAAGCGCTACCCCG
EPATSGSETPGSPAG GAGTCCGGTCCAGGTACTTCTACTGAAC
SPTSTEEGSSTPSGAT CGTCCGAAGGTAGCGCACCAGGTACTTC
GSPGTPGSGTASSSP TACCGAACCGTCCGAGGGTAGCGCACC
GSSTPSGATGSPGTS AGGTAGCCCAGCAGGTTCTCCTACCTCC
TEPSEGSAPGTSTEPS ACCGAGGAAGGTACTTCTACCGAACCG
EGSAPGSEPATSGSE TCCGAGGGTAGCGCACCAGGTACTTCTA
TPGSPAGSPTSTEEG CCGAACCTTCCGAGGGCAGCGCACCAG
SPAGSPTSTEEGTSTE GTACTTCTGAAAGCGCTACCCCTGAGTC
PSEGSAPGASASGAP CGGCCCAGGTACTTCTGAAAGCGCTACT
STGGTSESATPESGP CCTGAATCCGGTCCAGGTACCTCTACTG
GSPAGSPTSTEEGSP AACCTTCCGAAGGCAGCGCTCCAGGTA
AGSPTSTEEGSTSST CCTCTACCGAACCGTCCGAGGGCAGCG
AESPGPGSTSESPSGT CACCAGGTACTTCTGAAAGCGCAACCCC
APGTSPSGESSTAPG TGAATCCGGTCCAGGTACTTCTACTGAA
TPGSGTASSSPGSSTP CCTTCCGAAGGTAGCGCTCCAGGTAGCG
SGATGSPGSSPSAST AACCTGCTACTTCTGGTTCTGAAACCCC
GTGPGSEPATSGSET AGGTAGCCCGGCTGGCTCTCCGACCTCC
PGTSESATPESGPGS ACCGAGGAAGGTAGCTCTACCCCGTCTG
EPATSGSETPGSTSST GTGCTACTGGTTCTCCAGGTACTCCGGG
AESPGPGSTSSTAESP CAGCGGTACTGCTTCTTCCTCTCCAGGT
GPGTSPSGESSTAPG AGCTCTACCCCTTCTGGTGCTACTGGCT
SEPATSGSETPGSEP CTCCAGGTACCTCTACCGAACCGTCCGA
ATSGSETPGTSTEPSE GGGTAGCGCACCAGGTACCTCTACTGA
GSAPGSTSSTAESPG ACCGTCTGAGGGTAGCGCTCCAGGTAG
PGTSTPESGSASPGST CGAACCGGCAACCTCCGGTTCTGAAACT
SESPSGTAPGTSTEPS CCAGGTAGCCCTGCTGGCTCTCCGACTT
EGSAPGTSTEPSEGS CTACTGAGGAAGGTAGCCCGGCTGGTTC
APGTSTEPSEGSAPG TCCGACTTCTACTGAGGAAGGTACTTCT
SSTPSGATGSPGSSPS ACCGAACCTTCCGAAGGTAGCGCTCCA
ASTGTGPGASPGTSS GGTGCAAGCGCAAGCGGCGCGCCAAGC
TGSPGSEPATSGSET ACGGGAGGTACTTCTGAAAGCGCTACTC
PGTSESATPESGPGSP CTGAGTCCGGCCCAGGTAGCCCGGCTG
AGSPTSTEEGSSTPS GCTCTCCGACTTCCACCGAGGAAGGTAG
GATGSPGSSPSASTG CCCGGCTGGCTCTCCAACTTCTACTGAA
TGPGASPGTSSTGSP GAAGGTTCTACCAGCTCTACCGCTGAAT
GTSESATPESGPGTS CTCCTGGCCCAGGTTCTACTAGCGAATC
TEPSEGSAPGTSTEPS TCCGTCTGGCACCGCACCAGGTACTTCC
EGSAPGFPTIPLSRLF CCTAGCGGTGAATCTTCTACTGCACCAG
DNAMLRAHRLHQL GTACCCCTGGCAGCGGTACCGCTTCTTC
AFDTYQEFEEAYIPK CTCTCCAGGTAGCTCTACCCCGTCTGGT
EQKYSFLQNPQTSLC GCTACTGGCTCTCCAGGTTCTAGCCCGT
FSESIPTPSNREETQQ CTGCATCTACCGGTACCGGCCCAGGTAG
KSNLELLRISLLLIQS CGAACCGGCAACCTCCGGCTCTGAAACT
WLEPVQFLRSVFAN CCAGGTACTTCTGAAAGCGCTACTCCGG
SLVYGASDSNVYDL AATCCGGCCCAGGTAGCGAACCGGCTA
LKDLEEGIQTLMGRL CTTCCGGCTCTGAAACCCCAGGTTCCAC
EDGSPRTGQIFKQTY CAGCTCTACTGCAGAATCTCCGGGCCCA
SKFDTNSHNDDALL GGTTCTACTAGCTCTACTGCAGAATCTC
KNYGLLYCFRKDMD CGGGTCCAGGTACTTCTCCTAGCGGCGA
KVETFLRIVQCRSVE ATCTTCTACCGCTCCAGGTAGCGAACCG
GSCGFGAPLGLRLR GCAACCTCTGGCTCTGAAACTCCAGGTA
GGGGTSESATPESGP GCGAACCTGCAACCTCCGGCTCTGAAAC
GSEPATSGSETPGTS CCCAGGTACTTCTACTGAACCTTCTGAG
ESATPESGPGSEPAT GGCAGCGCACCAGGTTCTACCAGCTCTA
SGSETPGTSESATPES CCGCAGAATCTCCTGGTCCAGGTACCTC
GPGTSTEPSEGSAPG TACTCCGGAAAGCGGCTCTGCATCTCCA
SPAGSPTSTEEGTSES GGTTCTACTAGCGAATCTCCTTCTGGCA
ATPESGPGSEPATSG CTGCACCAGGTACTTCTACCGAACCGTC
SETPGTSESATPESGP CGAAGGCAGCGCTCCAGGTACCTCTACT
GSPAGSPTSTEEGSP GAACCTTCCGAGGGCAGCGCTCCAGGT
AGSPTSTEEGTSTEPS ACCTCTACCGAACCTTCTGAAGGTAGCG
EGSAPGTSESATPES CACCAGGTAGCTCTACTCCGTCTGGTGC
GPGTSESATPESGPG AACCGGCTCCCCAGGTTCTAGCCCGTCT
TSESATPESGPGSEP GCTTCCACTGGTACTGGCCCAGGTGCTT
ATSGSETPGSEPATS CCCCGGGCACCAGCTCTACTGGTTCTCC
GSETPGSPAGSPTST AGGTAGCGAACCTGCTACCTCCGGTTCT
EEGTSTEPSEGSAPG GAAACCCCAGGTACCTCTGAAAGCGCA
TSTEPSEGSAPGSEP ACTCCGGAGTCTGGTCCAGGTAGCCCTG
ATSGSETPGTSESAT CAGGTTCTCCTACCTCCACTGAGGAAGG
PESGPGTSTEPSEGS TAGCTCTACTCCGTCTGGTGCAACCGGC
AP TCCCCAGGTTCTAGCCCGTCTGCTTCCA
CTGGTACTGGCCCAGGTGCTTCCCCGGG
CACCAGCTCTACTGGTTCTCCAGGTACC
TCTGAAAGCGCTACTCCGGAGTCTGGCC
CAGGTACCTCTACTGAACCGTCTGAGGG
TAGCGCTCCAGGTACTTCTACTGAACCG
TCCGAAGGTAGCGCACCAGGTTTTCCGA
CTATTCCGCTGTCTCGTCTGTTTGATAAT
GCTATGCTGCGTGCGCACCGTCTGCACC
AGCTGGCCTTTGATACTTACCAGGAATT
TGAAGAAGCcTACATTCCTAAAGAGCAG
AAGTACTCTTTCCTGCAAAACCCACAGA
CTTCTCTCTGCTTCAGCGAATCTATTCCG
ACGCCTTCCAATCGCGAGGAAACTCAG
CAAAAGTCCAATCTGGAACTACTCCGCA
TTTCTCTGCTTCTGATTCAGAGCTGGCT
AGAACCAGTGCAATTTCTGCGTTCCGTC
TTCGCCAATAGCCTAGTTTATGGCGCAT
CCGACAGCAACGTATACGATCTCCTGAA
AGATCTCGAGGAAGGCATTCAGACCCT
GATGGGTCGTCTCGAGGATGGCTCTCCG
CGTACTGGTCAGATCTTCAAGCAGACTT
ACTCTAAATTTGATACTAACAGCCACAA
TGACGATGCGCTTCTAAAAAACTATGGT
CTGCTGTATTGTTTTCGTAAAGATATGG
ACAAAGTTGAAACCTTCCTGCGTATTGT
TCAGTGTCGTTCCGTTGAGGGCAGCTGT
GGTTTCTAAGGTgcgccgctgggcctgcgcctgcgc
ggcggcGGTGGTACCTCTGAAAGCGCAAC
TCCTGAGTCTGGCCCAGGTAGCGAACCT
GCTACCTCCGGCTCTGAGACTCCAGGTA
CCTCTGAAAGCGCAACCCCGGAATCTG
GTCCAGGTAGCGAACCTGCAACCTCTGG
CTCTGAAACCCCAGGTACCTCTGAAAGC
GCTACTCCTGAATCTGGCCCAGGTACTT
CTACTGAACCGTCCGAGGGCAGCGCAC
CAGGTAGCCCTGCTGGCTCTCCAACCTC
CACCGAAGAAGGTACCTCTGAAAGCGC
AACCCCTGAATCCGGCCCAGGTAGCGA
ACCGGCAACCTCCGGTTCTGAAACCCCA
GGTACTTCTGAAAGCGCTACTCCTGAGT
CCGGCCCAGGTAGCCCGGCTGGCTCTCC
GACTTCCACCGAGGAAGGTAGCCCGGC
TGGCTCTCCAACTTCTACTGAAGAAGGT
ACTTCTACCGAACCTTCCGAGGGCAGCG
CACCAGGTACTTCTGAAAGCGCTACCCC
TGAGTCCGGCCCAGGTACTTCTGAAAGC
GCTACTCCTGAATCCGGTCCAGGTACTT
CTGAAAGCGCTACCCCGGAATCTGGCCC
AGGTAGCGAACCGGCTACTTCTGGTTCT
GAAACCCCAGGTAGCGAACCGGCTACC
TCCGGTTCTGAAACTCCAGGTAGCCCAG
CAGGCTCTCCGACTTCCACTGAGGAAGG
TACTTCTACTGAACCTTCCGAAGGCAGC
GCACCAGGTACCTCTACTGAACCTTCTG
AGGGCAGCGCTCCAGGTAGCGAACCTG
CAACCTCTGGCTCTGAAACCCCAGGTAC
CTCTGAAAGCGCTACTCCTGAATCTGGC
CCAGGTACTTCTACTGAACCGTCCGAGG
GCAGCGCACCA
AE624- MAEPAGSPTSTEEGT 829 ATGGCTGAACCTGCTGGCTCTCCAACCT 830
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Thrombin- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGL AGTCTGGCCCAGGTAGCGAACCTGCTAC
TPRSLLVGGGGSEPA CTCCGGCTCTGAGACTCCAGGTACCTCT
TSGSETPGTSESATPE GAAAGCGCAACCCCGGAATCTGGTCCA
SGPGSEPATSGSETP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSPAGSPTSTEEGTS AAACCCCAGGTACCTCTGAAAGCGCTA
TEPSEGSAPGSEPAT CTCCTGAATCTGGCCCAGGTACTTCTAC
SGSETPGSEPATSGS TGAACCGTCCGAGGGCAGCGCACCAGG
ETPGSEPATSGSETP TACTTCTGAAAGCGCTACTCCTGAGTCC
GTSTEPSEGSAPGTS GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ESATPESGPGSEPAT CTTCCACCGAGGAAGGTAGCCCGGCTG
SGSETPGTSTEPSEGS GCTCTCCAACTTCTACTGAAGAAGGTAG
AP CCCGGCAGGCTCTCCGACCTCTACTGAG
GAAGGTACTTCTGAAAGCGCAACCCCG
GAGTCCGGCCCAGGTACCTCTACCGAAC
CGTCTGAGGGCAGCGCACCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGAT
AATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAGGA
ATTTGAAGAAGCcTACATTCCTAAAGAG
CAGAAGTACTCTTTCCTGCAAAACCCAC
AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTctgaccccgcgcagcctgctg
gtgggcggcGGTGGTAGCGAACCGGCAACT
TCCGGCTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCTGGCCCAGG
TAGCGAACCTGCTACCTCTGGCTCTGAA
ACCCCAGGTAGCCCGGCAGGCTCTCCG
ACTTCCACCGAGGAAGGTACCTCTACTG
AACCTTCTGAGGGTAGCGCTCCAGGTAG
CGAACCGGCAACCTCTGGCTCTGAAACC
CCAGGTAGCGAACCTGCTACCTCCGGCT
CTGAAACTCCAGGTAGCGAACCGGCTA
CTTCCGGTTCTGAAACTCCAGGTACCTC
TACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTGA
ATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTA
CCGAACCGTCCGAAGGTAGCGCACCA
AE624- MAEPAGSPTSTEEGT 831 ATGGCTGAACCTGCTGGCTCTCCAACCT 832
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
FXIa- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGG AGTCTGGCCCAGGTAGCGAACCTGCTAC
GKLTRVVGGGGSEP CTCCGGCTCTGAGACTCCAGGTACCTCT
ATSGSETPGTSESAT GAAAGCGCAACCCCGGAATCTGGTCCA
PESGPGSEPATSGSE GGTAGCGAACCTGCAACCTCTGGCTCTG
TPGSPAGSPTSTEEG AAACCCCAGGTACCTCTGAAAGCGCTA
TSTEPSEGSAPGSEP CTCCTGAATCTGGCCCAGGTACTTCTAC
ATSGSETPGSEPATS TGAACCGTCCGAGGGCAGCGCACCAGG
GSETPGSEPATSGSE TACTTCTGAAAGCGCTACTCCTGAGTCC
TPGTSTEPSEGSAPG GGCCCAGGTAGCCCGGCTGGCTCTCCGA
TSESATPESGPGSEP CTTCCACCGAGGAAGGTAGCCCGGCTG
ATSGSETPGTSTEPSE GCTCTCCAACTTCTACTGAAGAAGGTAG
GSAP CCCGGCAGGCTCTCCGACCTCTACTGAG
GAAGGTACTTCTGAAAGCGCAACCCCG
GAGTCCGGCCCAGGTACCTCTACCGAAC
CGTCTGAGGGCAGCGCACCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGAT
AATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAGGA
ATTTGAAGAAGCcTACATTCCTAAAGAG
CAGAAGTACTCTTTCCTGCAAAACCCAC
AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTggcggcaaactgacccgcgt
ggtgggcggcGGTGGTAGCGAACCGGCAAC
TTCCGGCTCTGAAACCCCAGGTACTTCT
GAAAGCGCTACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCTGGCTCTGA
AACCCCAGGTAGCCCGGCAGGCTCTCC
GACTTCCACCGAGGAAGGTACCTCTACT
GAACCTTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCTGGCTCTGAAA
CCCCAGGTAGCGAACCTGCTACCTCCGG
CTCTGAAACTCCAGGTAGCGAACCGGCT
ACTTCCGGTTCTGAAACTCCAGGTACCT
CTACCGAACCTTCCGAAGGCAGCGCAC
CAGGTACTTCTGAAAGCGCAACCCCTGA
ATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTA
CCGAACCGTCCGAAGGTAGCGCACCA
AE624- MAEPAGSPTSTEEGT 833 ATGGCTGAACCTGCTGGCTCTCCAACCT 834
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Elastase- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGG AGTCTGGCCCAGGTAGCGAACCTGCTAC
GLGPVSGVPGGSEPA CTCCGGCTCTGAGACTCCAGGTACCTCT
TSGSETPGTSESATPE GAAAGCGCAACCCCGGAATCTGGTCCA
SGPGSEPATSGSETP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSPAGSPTSTEEGTS AAACCCCAGGTACCTCTGAAAGCGCTA
TEPSEGSAPGSEPAT CTCCTGAATCTGGCCCAGGTACTTCTAC
SGSETPGSEPATSGS TGAACCGTCCGAGGGCAGCGCACCAGG
ETPGSEPATSGSETP TACTTCTGAAAGCGCTACTCCTGAGTCC
GTSTEPSEGSAPGTS GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ESATPESGPGSEPAT CTTCCACCGAGGAAGGTAGCCCGGCTG
SGSETPGTSTEPSEGS GCTCTCCAACTTCTACTGAAGAAGGTAG
AP CCCGGCAGGCTCTCCGACCTCTACTGAG
GAAGGTACTTCTGAAAGCGCAACCCCG
GAGTCCGGCCCAGGTACCTCTACCGAAC
CGTCTGAGGGCAGCGCACCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGAT
AATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAGGA
ATTTGAAGAAGCcTACATTCCTAAAGAG
CAGAAGTACTCTTTCCTGCAAAACCCAC
AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTggcggcctgggcccggtgag
cggcgtgccgGGTGGTAGCGAACCGGCAACT
TCCGGCTCTGAAACCCCAGGTACTTCTG
AAAGCGCTACTCCTGAGTCTGGCCCAGG
TAGCGAACCTGCTACCTCTGGCTCTGAA
ACCCCAGGTAGCCCGGCAGGCTCTCCG
ACTTCCACCGAGGAAGGTACCTCTACTG
AACCTTCTGAGGGTAGCGCTCCAGGTAG
CGAACCGGCAACCTCTGGCTCTGAAACC
CCAGGTAGCGAACCTGCTACCTCCGGCT
CTGAAACTCCAGGTAGCGAACCGGCTA
CTTCCGGTTCTGAAACTCCAGGTACCTC
TACCGAACCTTCCGAAGGCAGCGCACC
AGGTACTTCTGAAAGCGCAACCCCTGA
ATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTA
CCGAACCGTCCGAAGGTAGCGCACCA
AE624- MAEPAGSPTSTEEGT 835 ATGGCTGAACCTGCTGGCTCTCCAACCT 836
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
MMP-17- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE144 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGA AGTCTGGCCCAGGTAGCGAACCTGCTAC
PLGLRLRGGGGSEPA CTCCGGCTCTGAGACTCCAGGTACCTCT
TSGSETPGTSESATPE GAAAGCGCAACCCCGGAATCTGGTCCA
SGPGSEPATSGSETP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSPAGSPTSTEEGTS AAACCCCAGGTACCTCTGAAAGCGCTA
TEPSEGSAPGSEPAT CTCCTGAATCTGGCCCAGGTACTTCTAC
SGSETPGSEPATSGS TGAACCGTCCGAGGGCAGCGCACCAGG
ETPGSEPATSGSETP TACTTCTGAAAGCGCTACTCCTGAGTCC
GTSTEPSEGSAPGTS GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ESATPESGPGSEPAT CTTCCACCGAGGAAGGTAGCCCGGCTG
SGSETPGTSTEPSEGS GCTCTCCAACTTCTACTGAAGAAGGTAG
AP CCCGGCAGGCTCTCCGACCTCTACTGAG
GAAGGTACTTCTGAAAGCGCAACCCCG
GAGTCCGGCCCAGGTACCTCTACCGAAC
CGTCTGAGGGCAGCGCACCAGGTTTTCC
GACTATTCCGCTGTCTCGTCTGTTTGAT
AATGCTATGCTGCGTGCGCACCGTCTGC
ACCAGCTGGCCTTTGATACTTACCAGGA
ATTTGAAGAAGCcTACATTCCTAAAGAG
CAGAAGTACTCTTTCCTGCAAAACCCAC
AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTgcgccgctgggcctgcgcct
gcgcggcggcGGTGGTAGCGAACCGGCAAC
TTCCGGCTCTGAAACCCCAGGTACTTCT
GAAAGCGCTACTCCTGAGTCTGGCCCAG
GTAGCGAACCTGCTACCTCTGGCTCTGA
AACCCCAGGTAGCCCGGCAGGCTCTCC
GACTTCCACCGAGGAAGGTACCTCTACT
GAACCTTCTGAGGGTAGCGCTCCAGGTA
GCGAACCGGCAACCTCTGGCTCTGAAA
CCCCAGGTAGCGAACCTGCTACCTCCGG
CTCTGAAACTCCAGGTAGCGAACCGGCT
ACTTCCGGTTCTGAAACTCCAGGTACCT
CTACCGAACCTTCCGAAGGCAGCGCAC
CAGGTACTTCTGAAAGCGCAACCCCTGA
ATCCGGTCCAGGTAGCGAACCGGCTACT
TCTGGCTCTGAGACTCCAGGTACTTCTA
CCGAACCGTCCGAAGGTAGCGCACCA
AE624- MAEPAGSPTSTEEGT 837 ATGGCTGAACCTGCTGGCTCTCCAACCT 838
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Thrombin- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGL AGTCTGGCCCAGGTAGCGAACCTGCTAC
TPRSLLVGGGGTSES CTCCGGCTCTGAGACTCCAGGTACCTCT
ATPESGPGSEPATSG GAAAGCGCAACCCCGGAATCTGGTCCA
SETPGTSESATPESGP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSEPATSGSETPGTS AAACCCCAGGTACCTCTGAAAGCGCTA
ESATPESGPGTSTEPS CTCCTGAATCTGGCCCAGGTACTTCTAC
EGSAPGSPAGSPTST TGAACCGTCCGAGGGCAGCGCACCAGG
EEGTSESATPESGPG TACTTCTGAAAGCGCTACTCCTGAGTCC
SEPATSGSETPGTSES GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ATPESGPGSPAGSPT CTTCCACCGAGGAAGGTAGCCCGGCTG
STEEGSPAGSPTSTEE GCTCTCCAACTTCTACTGAAGAAGGTAG
GTSTEPSEGSAPGTS CCCGGCAGGCTCTCCGACCTCTACTGAG
ESATPESGPGTSESA GAAGGTACTTCTGAAAGCGCAACCCCG
TPESGPGTSESATPES GAGTCCGGCCCAGGTACCTCTACCGAAC
GPGSEPATSGSETPG CGTCTGAGGGCAGCGCACCAGGTTTTCC
SEPATSGSETPGSPA GACTATTCCGCTGTCTCGTCTGTTTGAT
GSPTSTEEGTSTEPSE AATGCTATGCTGCGTGCGCACCGTCTGC
GSAPGTSTEPSEGSA ACCAGCTGGCCTTTGATACTTACCAGGA
PGSEPATSGSETPGT ATTTGAAGAAGCcTACATTCCTAAAGAG
SESATPESGPGTSTEP CAGAAGTACTCTTTCCTGCAAAACCCAC
SEGSAP AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTctgaccccgcgcagcctgctg
gtgggcggcGGTGGTACCTCTGAAAGCGCA
ACTCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAGG
TACCTCTGAAAGCGCAACCCCGGAATCT
GGTCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGCA
CCAGGTAGCCCTGCTGGCTCTCCAACCT
CCACCGAAGAAGGTACCTCTGAAAGCG
CAACCCCTGAATCCGGCCCAGGTAGCG
AACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACTTCTGAAAGCGCTACTCCTGAG
TCCGGCCCAGGTAGCCCGGCTGGCTCTC
CGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGG
TACTTCTACCGAACCTTCCGAGGGCAGC
GCACCAGGTACTTCTGAAAGCGCTACCC
CTGAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTACT
TCTGAAAGCGCTACCCCGGAATCTGGCC
CAGGTAGCGAACCGGCTACTTCTGGTTC
TGAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCCCA
GCAGGCTCTCCGACTTCCACTGAGGAAG
GTACTTCTACTGAACCTTCCGAAGGCAG
CGCACCAGGTACCTCTACTGAACCTTCT
GAGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTGG
CCCAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCA
AE624- MAEPAGSPTSTEEGT 839 ATGGCTGAACCTGCTGGCTCTCCAACCT 840
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
FXIa- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGG AGTCTGGCCCAGGTAGCGAACCTGCTAC
GKLTRVVGGGGTSE CTCCGGCTCTGAGACTCCAGGTACCTCT
SATPESGPGSEPATS GAAAGCGCAACCCCGGAATCTGGTCCA
GSETPGTSESATPES GGTAGCGAACCTGCAACCTCTGGCTCTG
GPGSEPATSGSETPG AAACCCCAGGTACCTCTGAAAGCGCTA
TSESATPESGPGTSTE CTCCTGAATCTGGCCCAGGTACTTCTAC
PSEGSAPGSPAGSPT TGAACCGTCCGAGGGCAGCGCACCAGG
STEEGTSESATPESGP TACTTCTGAAAGCGCTACTCCTGAGTCC
GSEPATSGSETPGTS GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ESATPESGPGSPAGS CTTCCACCGAGGAAGGTAGCCCGGCTG
PTSTEEGSPAGSPTST GCTCTCCAACTTCTACTGAAGAAGGTAG
EEGTSTEPSEGSAPG CCCGGCAGGCTCTCCGACCTCTACTGAG
TSESATPESGPGTSES GAAGGTACTTCTGAAAGCGCAACCCCG
ATPESGPGTSESATP GAGTCCGGCCCAGGTACCTCTACCGAAC
ESGPGSEPATSGSET CGTCTGAGGGCAGCGCACCAGGTTTTCC
PGSEPATSGSETPGSP GACTATTCCGCTGTCTCGTCTGTTTGAT
AGSPTSTEEGTSTEPS AATGCTATGCTGCGTGCGCACCGTCTGC
EGSAPGTSTEPSEGS ACCAGCTGGCCTTTGATACTTACCAGGA
APGSEPATSGSETPG ATTTGAAGAAGCcTACATTCCTAAAGAG
TSESATPESGPGTSTE CAGAAGTACTCTTTCCTGCAAAACCCAC
PSEGSAP AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTggcggcaaactgacccgcgt
ggtgggcggcGGTGGTACCTCTGAAAGCGCA
ACTCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAGG
TACCTCTGAAAGCGCAACCCCGGAATCT
GGTCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGCA
CCAGGTAGCCCTGCTGGCTCTCCAACCT
CCACCGAAGAAGGTACCTCTGAAAGCG
CAACCCCTGAATCCGGCCCAGGTAGCG
AACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACTTCTGAAAGCGCTACTCCTGAG
TCCGGCCCAGGTAGCCCGGCTGGCTCTC
CGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGG
TACTTCTACCGAACCTTCCGAGGGCAGC
GCACCAGGTACTTCTGAAAGCGCTACCC
CTGAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTACT
TCTGAAAGCGCTACCCCGGAATCTGGCC
CAGGTAGCGAACCGGCTACTTCTGGTTC
TGAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCCCA
GCAGGCTCTCCGACTTCCACTGAGGAAG
GTACTTCTACTGAACCTTCCGAAGGCAG
CGCACCAGGTACCTCTACTGAACCTTCT
GAGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTGG
CCCAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCA
AE624- MAEPAGSPTSTEEGT 841 ATGGCTGAACCTGCTGGCTCTCCAACCT 842
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
Elastase- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGG AGTCTGGCCCAGGTAGCGAACCTGCTAC
GLGPVSGVPGGTSES CTCCGGCTCTGAGACTCCAGGTACCTCT
ATPESGPGSEPATSG GAAAGCGCAACCCCGGAATCTGGTCCA
SETPGTSESATPESGP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSEPATSGSETPGTS AAACCCCAGGTACCTCTGAAAGCGCTA
ESATPESGPGTSTEPS CTCCTGAATCTGGCCCAGGTACTTCTAC
EGSAPGSPAGSPTST TGAACCGTCCGAGGGCAGCGCACCAGG
EEGTSESATPESGPG TACTTCTGAAAGCGCTACTCCTGAGTCC
SEPATSGSETPGTSES GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ATPESGPGSPAGSPT CTTCCACCGAGGAAGGTAGCCCGGCTG
STEEGSPAGSPTSTEE GCTCTCCAACTTCTACTGAAGAAGGTAG
GTSTEPSEGSAPGTS CCCGGCAGGCTCTCCGACCTCTACTGAG
ESATPESGPGTSESA GAAGGTACTTCTGAAAGCGCAACCCCG
TPESGPGTSESATPES GAGTCCGGCCCAGGTACCTCTACCGAAC
GPGSEPATSGSETPG CGTCTGAGGGCAGCGCACCAGGTTTTCC
SEPATSGSETPGSPA GACTATTCCGCTGTCTCGTCTGTTTGAT
GSPTSTEEGTSTEPSE AATGCTATGCTGCGTGCGCACCGTCTGC
GSAPGTSTEPSEGSA ACCAGCTGGCCTTTGATACTTACCAGGA
PGSEPATSGSETPGT ATTTGAAGAAGCcTACATTCCTAAAGAG
SESATPESGPGTSTEP CAGAAGTACTCTTTCCTGCAAAACCCAC
SEGSAP AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTggcggcctgggcccggtgag
cggcgtgccgGGTGGTACCTCTGAAAGCGCA
ACTCCTGAGTCTGGCCCAGGTAGCGAAC
CTGCTACCTCCGGCTCTGAGACTCCAGG
TACCTCTGAAAGCGCAACCCCGGAATCT
GGTCCAGGTAGCGAACCTGCAACCTCTG
GCTCTGAAACCCCAGGTACCTCTGAAAG
CGCTACTCCTGAATCTGGCCCAGGTACT
TCTACTGAACCGTCCGAGGGCAGCGCA
CCAGGTAGCCCTGCTGGCTCTCCAACCT
CCACCGAAGAAGGTACCTCTGAAAGCG
CAACCCCTGAATCCGGCCCAGGTAGCG
AACCGGCAACCTCCGGTTCTGAAACCCC
AGGTACTTCTGAAAGCGCTACTCCTGAG
TCCGGCCCAGGTAGCCCGGCTGGCTCTC
CGACTTCCACCGAGGAAGGTAGCCCGG
CTGGCTCTCCAACTTCTACTGAAGAAGG
TACTTCTACCGAACCTTCCGAGGGCAGC
GCACCAGGTACTTCTGAAAGCGCTACCC
CTGAGTCCGGCCCAGGTACTTCTGAAAG
CGCTACTCCTGAATCCGGTCCAGGTACT
TCTGAAAGCGCTACCCCGGAATCTGGCC
CAGGTAGCGAACCGGCTACTTCTGGTTC
TGAAACCCCAGGTAGCGAACCGGCTAC
CTCCGGTTCTGAAACTCCAGGTAGCCCA
GCAGGCTCTCCGACTTCCACTGAGGAAG
GTACTTCTACTGAACCTTCCGAAGGCAG
CGCACCAGGTACCTCTACTGAACCTTCT
GAGGGCAGCGCTCCAGGTAGCGAACCT
GCAACCTCTGGCTCTGAAACCCCAGGTA
CCTCTGAAAGCGCTACTCCTGAATCTGG
CCCAGGTACTTCTACTGAACCGTCCGAG
GGCAGCGCACCA
AE624- MAEPAGSPTSTEEGT 843 ATGGCTGAACCTGCTGGCTCTCCAACCT 844
hGH- PGSGTASSSPGSSTPS CCACTGAGGAAGGTACCCCGGGTAGCG
MMP-17- GATGSPGASPGTSST GTACTGCTTCTTCCTCTCCAGGTAGCTCT
AE288 GSPGSPAGSPTSTEE ACCCCTTCTGGTGCAACCGGCTCTCCAG
GTSESATPESGPGTS GTGCTTCTCCGGGCACCAGCTCTACCGG
TEPSEGSAPGSPAGS TTCTCCAGGTAGCCCGGCTGGCTCTCCT
PTSTEEGTSTEPSEGS ACCTCTACTGAGGAAGGTACTTCTGAAA
APGTSTEPSEGSAPG GCGCTACTCCTGAGTCTGGTCCAGGTAC
TSESATPESGPGSEP CTCTACTGAACCGTCCGAAGGTAGCGCT
ATSGSETPGSEPATS CCAGGTAGCCCAGCAGGCTCTCCGACTT
GSETPGSPAGSPTST CCACTGAGGAAGGTACTTCTACTGAACC
EEGTSESATPESGPG TTCCGAAGGCAGCGCACCAGGTACCTCT
TSTEPSEGSAPGTSTE ACTGAACCTTCTGAGGGCAGCGCTCCAG
PSEGSAPGSPAGSPT GTACTTCTGAAAGCGCTACCCCGGAATC
STEEGTSTEPSEGSAP TGGCCCAGGTAGCGAACCGGCTACTTCT
GTSTEPSEGSAPGTS GGTTCTGAAACCCCAGGTAGCGAACCG
ESATPESGPGTSTEPS GCTACCTCCGGTTCTGAAACTCCAGGTA
EGSAPGTSESATPES GCCCGGCAGGCTCTCCGACCTCTACTGA
GPGSEPATSGSETPG GGAAGGTACTTCTGAAAGCGCAACCCC
TSTEPSEGSAPGTSTE GGAGTCCGGCCCAGGTACCTCTACCGA
PSEGSAPGTSESATP ACCGTCTGAGGGCAGCGCACCAGGTAC
ESGPGTSESATPESG TTCTACCGAACCGTCCGAGGGTAGCGCA
PGSPAGSPTSTEEGT CCAGGTAGCCCAGCAGGTTCTCCTACCT
SESATPESGPGSEPA CCACCGAGGAAGGTACTTCTACCGAAC
TSGSETPGTSESATPE CGTCCGAGGGTAGCGCACCAGGTACCT
SGPGTSTEPSEGSAP CTACTGAACCTTCTGAGGGCAGCGCTCC
GTSTEPSEGSAPGTS AGGTACTTCTGAAAGCGCTACCCCGGA
TEPSEGSAPGTSTEPS GTCCGGTCCAGGTACTTCTACTGAACCG
EGSAPGTSTEPSEGS TCCGAAGGTAGCGCACCAGGTACTTCTG
APGTSTEPSEGSAPG AAAGCGCAACCCCTGAATCCGGTCCAG
SPAGSPTSTEEGTSTE GTAGCGAACCGGCTACTTCTGGCTCTGA
PSEGSAPGTSESATP GACTCCAGGTACTTCTACCGAACCGTCC
ESGPGSEPATSGSET GAAGGTAGCGCACCAGGTACTTCTACTG
PGTSESATPESGPGS AACCGTCTGAAGGTAGCGCACCAGGTA
EPATSGSETPGTSES CTTCTGAAAGCGCAACCCCGGAATCCG
ATPESGPGTSTEPSE GCCCAGGTACCTCTGAAAGCGCAACCC
GSAPGTSESATPESG CGGAGTCCGGCCCAGGTAGCCCTGCTG
PGSPAGSPTSTEEGSP GCTCTCCAACCTCCACCGAAGAAGGTAC
AGSPTSTEEGSPAGS CTCTGAAAGCGCAACCCCTGAATCCGGC
PTSTEEGTSESATPES CCAGGTAGCGAACCGGCAACCTCCGGT
GPGTSTEPSEGSAPG TCTGAAACCCCAGGTACCTCTGAAAGCG
FPTIPLSRLFDNAML CTACTCCGGAGTCTGGCCCAGGTACCTC
RAHRLHQLAFDTYQ TACTGAACCGTCTGAGGGTAGCGCTCCA
EFEEAYIPKEQKYSF GGTACTTCTACTGAACCGTCCGAAGGTA
LQNPQTSLCFSESIPT GCGCACCAGGTACTTCTACCGAACCGTC
PSNREETQQKSNLEL CGAAGGCAGCGCTCCAGGTACCTCTACT
LRISLLLIQSWLEPVQ GAACCTTCCGAGGGCAGCGCTCCAGGT
FLRSVFANSLVYGAS ACCTCTACCGAACCTTCTGAAGGTAGCG
DSNVYDLLKDLEEGI CACCAGGTACTTCTACCGAACCGTCCGA
QTLMGRLEDGSPRT GGGTAGCGCACCAGGTAGCCCAGCAGG
GQIFKQTYSKFDTNS TTCTCCTACCTCCACCGAGGAAGGTACT
HNDDALLKNYGLLY TCTACCGAACCGTCCGAGGGTAGCGCA
CFRKDMDKVETFLRI CCAGGTACCTCTGAAAGCGCAACTCCTG
VQCRSVEGSCGFGA AGTCTGGCCCAGGTAGCGAACCTGCTAC
PLGLRLRGGGGTSES CTCCGGCTCTGAGACTCCAGGTACCTCT
ATPESGPGSEPATSG GAAAGCGCAACCCCGGAATCTGGTCCA
SETPGTSESATPESGP GGTAGCGAACCTGCAACCTCTGGCTCTG
GSEPATSGSETPGTS AAACCCCAGGTACCTCTGAAAGCGCTA
ESATPESGPGTSTEPS CTCCTGAATCTGGCCCAGGTACTTCTAC
EGSAPGSPAGSPTST TGAACCGTCCGAGGGCAGCGCACCAGG
EEGTSESATPESGPG TACTTCTGAAAGCGCTACTCCTGAGTCC
SEPATSGSETPGTSES GGCCCAGGTAGCCCGGCTGGCTCTCCGA
ATPESGPGSPAGSPT CTTCCACCGAGGAAGGTAGCCCGGCTG
STEEGSPAGSPTSTEE GCTCTCCAACTTCTACTGAAGAAGGTAG
GTSTEPSEGSAPGTS CCCGGCAGGCTCTCCGACCTCTACTGAG
ESATPESGPGTSESA GAAGGTACTTCTGAAAGCGCAACCCCG
TPESGPGTSESATPES GAGTCCGGCCCAGGTACCTCTACCGAAC
GPGSEPATSGSETPG CGTCTGAGGGCAGCGCACCAGGTTTTCC
SEPATSGSETPGSPA GACTATTCCGCTGTCTCGTCTGTTTGAT
GSPTSTEEGTSTEPSE AATGCTATGCTGCGTGCGCACCGTCTGC
GSAPGTSTEPSEGSA ACCAGCTGGCCTTTGATACTTACCAGGA
PGSEPATSGSETPGT ATTTGAAGAAGCcTACATTCCTAAAGAG
SESATPESGPGTSTEP CAGAAGTACTCTTTCCTGCAAAACCCAC
SEGSAP AGACTTCTCTCTGCTTCAGCGAATCTAT
TCCGACGCCTTCCAATCGCGAGGAAACT
CAGCAAAAGTCCAATCTGGAACTACTCC
GCATTTCTCTGCTTCTGATTCAGAGCTG
GCTAGAACCAGTGCAATTTCTGCGTTCC
GTCTTCGCCAATAGCCTAGTTTATGGCG
CATCCGACAGCAACGTATACGATCTCCT
GAAAGATCTCGAGGAAGGCATTCAGAC
CCTGATGGGTCGTCTCGAGGATGGCTCT
CCGCGTACTGGTCAGATCTTCAAGCAGA
CTTACTCTAAATTTGATACTAACAGCCA
CAATGACGATGCGCTTCTAAAAAACTAT
GGTCTGCTGTATTGTTTTCGTAAAGATA
TGGACAAAGTTGAAACCTTCCTGCGTAT
TGTTCAGTGTCGTTCCGTTGAGGGCAGC
TGTGGTTTCTAAGGTgcgccgctgggcctgcgcct
gcgcggcggcGGTGGTACCTCTGAAAGCGC
AACTCCTGAGTCTGGCCCAGGTAGCGA
ACCTGCTACCTCCGGCTCTGAGACTCCA
GGTACCTCTGAAAGCGCAACCCCGGAA
TCTGGTCCAGGTAGCGAACCTGCAACCT
CTGGCTCTGAAACCCCAGGTACCTCTGA
AAGCGCTACTCCTGAATCTGGCCCAGGT
ACTTCTACTGAACCGTCCGAGGGCAGCG
CACCAGGTAGCCCTGCTGGCTCTCCAAC
CTCCACCGAAGAAGGTACCTCTGAAAG
CGCAACCCCTGAATCCGGCCCAGGTAG
CGAACCGGCAACCTCCGGTTCTGAAACC
CCAGGTACTTCTGAAAGCGCTACTCCTG
AGTCCGGCCCAGGTAGCCCGGCTGGCTC
TCCGACTTCCACCGAGGAAGGTAGCCC
GGCTGGCTCTCCAACTTCTACTGAAGAA
GGTACTTCTACCGAACCTTCCGAGGGCA
GCGCACCAGGTACTTCTGAAAGCGCTAC
CCCTGAGTCCGGCCCAGGTACTTCTGAA
AGCGCTACTCCTGAATCCGGTCCAGGTA
CTTCTGAAAGCGCTACCCCGGAATCTGG
CCCAGGTAGCGAACCGGCTACTTCTGGT
TCTGAAACCCCAGGTAGCGAACCGGCT
ACCTCCGGTTCTGAAACTCCAGGTAGCC
CAGCAGGCTCTCCGACTTCCACTGAGGA
AGGTACTTCTACTGAACCTTCCGAAGGC
AGCGCACCAGGTACCTCTACTGAACCTT
CTGAGGGCAGCGCTCCAGGTAGCGAAC
CTGCAACCTCTGGCTCTGAAACCCCAGG
TACCTCTGAAAGCGCTACTCCTGAATCT
GGCCCAGGTACTTCTACTGAACCGTCCG
AGGGCAGCGCACCA
*Sequence name reflects N- to C-terminus configuration of the growth factor, cleavage sequence and XTEN components
