CROSS REFERENCE TO RELATED APPLICATIONS The present application is a divisional of U.S. application Ser. No. 16/343,311, filed Apr. 18, 2019, which is a 371(c) U.S. Nat'l Phase application of Int'l Appl. No. PCT/US2017/057737, filed Oct. 20, 2017, which claims the benefit of U.S. Provisional Patent Application No. 62/411,508, filed Oct. 21, 2016, the entire contents of which are incorporated herein by reference.
SEQUENCE LISTING The contents of the electronic sequence listing (1160430o004202.xml; Size: 3,081,456 bytes; and Date of Creation: Oct. 31, 2022) is herein incorporated by reference in its entirety.
FIELD OF THE INVENTION The invention relates, inter alia, to anti-Respiratory Syncytial Virus (RSV) antibodies and functional fragments thereof, and methods and reagents for their preparation and use.
BACKGROUND OF THE INVENTION All references cited herein, including without limitation patents, patent applications, and non-patent references and publications referenced throughout are hereby expressly incorporated by reference in their entireties for all purposes.
Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly, is the leading cause of infant hospitalization in the United States and accounts for an estimated 64 million infections and 160,000 deaths world-wide each year. However, despite decades of research, the development of a safe and effective vaccines or therapeutic and/or prophylactic antibodies against RSV has remained elusive, highlighting the need for novel strategies that induce or provide protective immune responses. (1-3). Indeed, to date there are currently no approved RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab (marketed as Synagis®) is restricted to high-risk infants in part due to its modest efficacy.
Certain populations of children are at risk for developing an RSV infection and these include preterm infants (Hall et al., 1979, New Engl. J. Med. 300:393-396), children with congenital malformations of the airway, children with bronchopulmonary dysplasia (Groothuis et al., 1988, Pediatrics 82:199-203), children with congenital heart disease (MacDonald et al., New Engl. J. Med. 307:397-400), and children with congenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr. Infect. Dis. J. 7:246-249; and Pohl et al., 1992, J. Infect. Dis. 165:166-169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 1 13:826-830).
RSV can infect the adult population as well. In this population, RSV causes primarily an upper respiratory tract disease, although elderly patients may be at greater risk for a serious infection and pneumonia (Evans, A. S., eds., 1989, Viral Infections of Humans. Epidemiology and Control, 3rd ed., Plenum Medical Book, New York at pages 525-544), as well as adults who are immunosuppressed, particularly bone marrow transplant patients (Hertz et al., 1989, Medicine 68:269-281). Other at risk patients include those suffering from congestive heart failure and those suffering from chronic obstructive pulmonary disease (ie. COPD). There have also been reports of epidemics among nursing home patients and institutionalized young adults (Falsey, A. R., 1991, Infect. Control Hosp. Epidemiol. 12:602-608; and Garvie et al., 1980, Br. Med. J. 281:1253-1254).
While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2nd ed., Vol. 1, Raven Press, New York at pages 1045-1072).
Similar to other pneumoviruses, RSV expresses two major surface glycoproteins: the fusion protein (F) and the attachment protein (G). Although both have been shown to induce protective neutralizing antibody responses, F is less genetically variable than G, is absolutely required for infection, and is the target for the majority of neutralizing activity in human serum (4-8). RSV F is also the target of the monoclonal antibody palivizumab, which is used to passively protect high-risk infants from severe disease (9). Consequently, the RSV F protein is considered to be a highly attractive target for vaccines and antibody-based therapies.
The mature RSV F glycoprotein initially exists in a metastable prefusion conformation (10), before undergoing a conformational change that leads to insertion of the hydrophobic fusion peptide into the host-cell membrane. Subsequent refolding of F into a stable, elongated postfusion conformation (postF) (11, 12) results in fusion of the viral and host-cell membranes. Due to its inherent instability, the preF protein has the propensity to prematurely trigger into postF, both in solution and on the viral surface (13). Recently, stabilization of preF has been achieved by protein engineering (14, 15), and stabilized preF has been shown to induce higher titers of neutralizing antibodies than postF in animal models (15).
Despite the importance of neutralizing antibodies in protection against severe RSV disease, our understanding of the human antibody response to RSV has been limited to studies of human sera and a small number of RSV-specific human monoclonal antibodies (16-19). The epitopes recognized by these human antibodies, as well as several murine antibodies, have defined at least four ‘antigenic sites’ on RSV F (1, 10, 16, 18-20) (see also, e.g, Table 1). Three of these sites—I, II, and IV—are present on both pre- and postF, whereas antigenic site Ø exists exclusively on preF. Additional preF-specific epitopes have been defined by antibodies MPE8 (17) and AM14 (21). Although serum mapping studies have shown that site 0-directed antibodies are responsible for a large proportion of the neutralizing antibody response in most individuals (8), there are additional antibody specificities that contribute to serum neutralizing activity that remain to be defined. In addition, it was heretofore unknown whether certain antibody sequence features are required for recognition of certain neutralizing sites, as observed for other viral targets (22-25). Accordingly, understanding the relationship between neutralization potency and epitope specificity would be advantageous in the selection and/or design of vaccine antigens, as well as therapeutic and/or prophylactic antibodies, which induce potent neutralizing responses to RSV.
While treatment options for established RSV disease are limited, more severe forms of the disease of the lower respiratory tract often require considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds, 1990, Fields Virology, 2nd ed., Vol. 1, Raven Press, New York at pages 1045-1072).
Ribavirin, which is the only drug approved for treatment of infection, has been shown to be effective in the treatment of pneumonia and bronchiolitis associated with RSV infection, and has been shown to modify the course of severe RSV disease in immunocompetent children (Smith et ai., 1991, New Engl. J. Med. 325:24-29). The use of ribavirin is limited due to concerns surrounding its potential risk to pregnant women who may be exposed to the aerosolized drug while it is being administered in a hospital environment.
Similarly, while a vaccine may be useful, no commercially available vaccine has been developed to date. Several vaccine candidates have been abandoned and others are under development (Murphy et al., 1994, Virus Res. 32: 13-36). The development of a vaccine has proven to be problematic. In particular, immunization would be required in the immediate neonatal period since the peak incidence of lower respiratory tract disease occurs at 2-5 months of age. However, it is known that the neonatal immune response is immature at that time. Plus, the infant at that point in time still has high titers of maternally acquired RSV antibody, which might reduce vaccine immunogenicity (Murphy et al., 1988, J. Virol. 62:3907-3910; and Murphy et ai, 1991, Vaccine 9:185-189).
Currently, the only approved approach to prophylaxis of RSV disease is passive immunization. For example, the humanized antibody, palivizumab (SYNAGIS®), which is specific for an epitope on the F protein, is approved for intramuscular administration to pediatric patients for prevention of serious lower respiratory tract disease caused by RSV at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is a composite of human (95%) and murine (5%) antibody sequences. (Johnson et ai, (1997), J. Infect. Diseases 176:1215-1224 and U.S. Pat. No. 5,824,307).
Although SYNAGIS® has been successfully used for the prevention of RSV infection in pediatric patients, multiple intramuscular doses of 15 mg/kg of SYNAGIS® are required to achieve a prophylactic effect. The necessity for the administration of multiple intramuscular doses of antibody requires repeated visits to the doctor's office, which is not only inconvenient for the patient but can also result in missed doses.
Efforts were made to improve on the therapeutic profile of an anti-RSV-F antibody, and this lead to the identification and development of motavizumab, also referred to as NUMAX™ However, clinical testing revealed that certain of the patients being administered motavizumab were having severe hypersensitivity reactions. Further development of this humanized anti-RSV-F antibody was then discontinued.
Other antibodies to RSV-F protein have been described and can be found in U.S. Pat. Nos. 6,656,467; 5,824,307, 7,786,273; 7,670,600; 7,083,784; 6,818,216; 7,700,735; 7,553,489; 7,323,172; 7,229,619; 7,425,618; 7,740,851; 7,658,921; 7,704,505; 7,635,568; 6,855,493; 6,565,849; 7,582,297; 7,208,162; 7,700,720; 6,413,771; 5,811,524; 6,537,809; 5,762,905; 7,070,786; 7,364,742; 7,879,329; 7,488,477; 7,867,497; 5,534,411; 6,835,372; 7,482,024; 7,691,603; 8,562,996; 8,568,726; US20100015596; WO2009088159A1; and WO2014159822. To date, none other than SYNAGIS® has been approved by a regulatory agency for use in preventing an RSV infection.
There remains a need for the provision of highly specific, high affinity, and highly potent neutralizing anti-RSV antibodies and antigen-binding fragments thereof with neutralize at least one, but preferably both, of subtype A and subtype B RSV viral strains, and which preferentially recognize PreF relative to Post F conformations of the F protein. There also remains a need for the provision of anti-RSV and anti-HMPV cross-neutralizing antibodies and antigen-binding fragments thereof.
SUMMARY OF THE INVENTION Applicants have now discovered, isolated, and characterized, inter alia, an extensive panel of RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult human donor and used these antibodies to comprehensively map the antigenic topology of RSV F. A large proportion of the RSV F-specific human antibody repertoire was advantageously comprised of antibodies with greatly enhanced specificity for the PreF conformation of the F protein (relative to the PostF form), many if not most of which exhibited remarkable potency in neutralization assays against one or both of RSV subtype A and RSV subtype B strains. Indeed, a large number of these antibodies display neutralization potencies that are multiple-fold greater—some 5- to 100-fold greater or more—to previous anti-RSV therapeutic antibodies, such as D25 and pavlizumamab thus serve as attractive therapeutic and/or prophylactic candidates for treating and/or preventing RSV infection and disease.
The most potent antibodies were found to target two distinct antigenic sites that are located near the apex of the preF trimer, providing strong support for the development of therapeutic and/or prophylactic antibodies targeting these antigenic sites, as well as preF-based vaccine candidates that preserve these antigenic sites. Furthermore, the neutralizing antibodies described and disclosed herein represent new opportunities for the prevention of severe RSV disease using passive immunoprophylaxis.
Given the role that the F protein plays in fusion of the virus with the cell and in cell to cell transmission of the virus, the antibodies described herein provide a method of inhibiting that process and as such, may be used for preventing infection of a patient exposed to, or at risk for acquiring an infection with RSV, or for treating and/or ameliorating one or more symptoms associated with RSV infection in a patient exposed to, or at risk for acquiring an infection with RSV, or suffering from infection with RSV. The antibodies described herein may also be used to prevent or to treat an RSV infection in a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition. A patient who may benefit from treatment with an antibody of the invention may be a pre-term infant, a full-term infant born during RSV season (approximately late fall (November) through early spring (April)) that is at risk because of other pre-existing or underlying medical conditions including congenital heart disease or chronic lung disease, a child greater than one year of age with or without an underlying medical condition, an institutionalized or hospitalized patient, or an elderly adult (>65 years of age) with or without an underlying medical condition, such as congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). A patient who may benefit from such therapy may suffer from a medical condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system. For example, the patient may suffer from an abnormality of the airway, or an airway malfunction, a chronic lung disease, a chronic or congenital heart disease, a neuromuscular disease that compromises the handling of respiratory secretions, or the patient may be immunosuppressed due to severe combined immunodeficiency disease or severe acquired immunodeficiency disease, or from any other underlying infectious disease or cancerous condition that results in immunosuppression, or the patient may be immunosuppressed due to treatment with an immunosuppressive drug (e.g. any drug used for treating a transplant patient) or radiation therapy. A patient who may benefit from the antibodies of the invention may be a patient that suffers from chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchopulmonary dysplasia, congestive heart failure (CHF), or congenital heart disease.
Because the inventive antibodies and antigen-binding fragments thereof are more effective at neutralization of RSV compared to known antibodies, lower doses of the antibodies or antibody fragments could be used to achieve a greater level of protection against infection with RSV, and more effective treatment and/or amelioration of symptoms associated with an RSV infection. Accordingly, the use of lower doses of antibodies or fragments thereof which immunospecifically bind to RSV-F antigen may result in fewer or less severe adverse events. Likewise, the use of more effective neutralizing antibodies may result in a diminished need for frequent administration of the antibodies or antibody fragments than previously envisioned as necessary for the prevention of infection, or for virus neutralization, or for treatment or amelioration of one or more symptoms associated with an RSV infection. Symptoms of RSV infection may include a bluish skin color due to lack of oxygen (hypoxia), breathing difficulty (rapid breathing or shortness of breath), cough, croupy cough (“seal bark” cough), fever, nasal flaring, nasal congestion (stuffy nose), apnea, decreased appetite, dehydration, poor feeding, altered mental status, or wheezing.
Such antibodies may be useful when administered prophylactically (prior to exposure to the virus and infection with the virus) to lessen the severity, or duration of a primary infection with RSV, or ameliorate at least one symptom associated with the infection. The antibodies may be used alone or in conjunction with a second agent useful for treating an RSV infection. In certain embodiments, the antibodies may be given therapeutically (after exposure to and infection with the virus) either alone, or in conjunction with a second agent to lessen the severity or duration of the primary infection, or to ameliorate at least one symptom associated with the infection. In certain embodiments, the antibodies may be used prophylactically as stand-alone therapy to protect patients who are at risk for acquiring an infection with RSV, such as those described above. Any of these patient populations may benefit from treatment with the antibodies of the invention, when given alone or in conjunction with a second agent, including for example, an anti-viral therapy, such as ribavirin, or other anti-viral vaccines.
The antibodies of the invention can be full-length (for example, an lgG1 or lgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab′)2 or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., (2000), J. Immunol. 164:1925-1933).
Accordingly, in certain embodiments are provided isolated antibodies or antigen-binding fragments thereof that specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence such antibodies or the antigen-binding fragments thereof are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics: a) the antibodies or antigen-binding fragments thereof cross-compete with said antibodies or antigen-binding fragments thereof for binding to RSV-F; b) the antibodies or antigen-binding fragments thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form; c) the antibodies or antigen-binding fragments thereof display a clean or low polyreactivity profile; d) the antibodies or antigen-binding fragments thereof display neutralization activity toward RSV subtype A and RSV subtype B in vitro; e) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V f) the antibodies or antigen-binding fragments thereof display antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV; g) at least a portion of the epitope with which the antibodies or antigen-binding fragments thereof interact comprises the α3 helix and β3/β4 hairpin of PreF; h) the antibodies or antigen-binding fragments thereof display an in vitro neutralization potency (IC50) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml; i) the binding affinities and/or epitopic specificities of the antibodies or antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinities and/or epitopic specificities of said antibodies or antigen-binding fragments thereof for the RSV-F or RSV-F DS-Cav1; j) the antibodies or antigen-binding fragments thereof display a cross-neutralization potency (IC50) against human metapneumovirus (HMPV); k) the antibodies or antigen-binding fragments thereof do not complete with D25, MPE8, palivizumab, or motavizumab; or 1) the antibodies or antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.
In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1) above.
In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372a s disclosed in Table 6; f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; or g) any combination of two or more of a), b), c), d), e), and f).
In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof comprise: a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and/or b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain other embodiments, the isolated antibodies or antigen-binding fragments thereof are selected from the group consisting of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In other embodiments are provided isolated nucleic acid sequences encoding antibodies or antigen-binding fragments thereof according to any of the other embodiments disclosed herein.
In other embodiments are provided expression vectors comprising isolated nucleic acid sequences according to other embodiments disclosed herein.
In other embodiments are provided host cells transfected, transformed, or transduced with nucleic acid sequences or expression vectors according to other embodiments disclosed herein.
In other embodiments are provided pharmaceutical compositions comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.
In other embodiments are provided pharmaceutical compositions: one or more nucleic acid sequences according other embodiments disclosed herein; or one or more the expression vectors according to other embodiments disclosed herein; and a pharmaceutically acceptable carrier and/or excipient.
In other embodiments are provided transgenic organisms comprising nucleic acid sequences according to other embodiments disclosed herein; or expression vectors according to other embodiments disclosed herein.
In other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need there of or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) nucleic acid sequences according to other embodiments disclosed herein; an expression vector according to other embodiments disclosed herein; a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
In other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof: a) one or more antibodies or antigen-binding fragments thereof according to other embodiments disclosed herein; b) a nucleic acid sequences according to other embodiments disclosed herein; c) an expression vector according to other embodiments disclosed herein; d) a host cell according to other embodiments disclosed herein; or e) a pharmaceutical composition according to other embodiments disclosed herein; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In other embodiments are provided methods according to other embodiments wherein the one or more antibodies or antigen-binding fragments thereof of a) is selected from the group consisting of the antibodies designated as Antibody Number 340 as disclosed in Table 6.
In other embodiments are provided methods according to other embodiments wherein the method further comprises administering to the patient a second therapeutic agent.
In other embodiments are provided methods according to other embodiments, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.
In certain embodiments are provided pharmaceutical compositions comprising any one or more of the isolated antibodies or antigen-binding fragments thereof and a pharmaceutically acceptable carrier and/or excipient.
In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
In certain embodiments are provided pharmaceutical compositions according to other embodiments for use in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.
In certain other embodiments are provided uses of the pharmaceutical compositions according to other embodiments in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1A through FIG. 1F illustrates the anti-RSV repertoire cloning and sequence analysis of the identified and isolated antibodies. FIG. 1A: RSV F-specific B cell sorting. FACS plots show RSV F reactivity of IgG+ and IgA+ B cells from the healthy adult donor. B cells in quadrant 2 (Q2) were single cell sorted. FIG. 1B: Isotype analysis. Index sort plots show the percentage of RSV F-specific B cells that express IgG or IgA. FIG. 1C: Clonal lineage analysis. Each slice represents one clonal lineage; the size of the slice is proportional to the number of clones in the lineage. The total number of clones is shown in the center of the pie. Clonal lineages were assigned based on the following criteria: 1) matching of variable and joining gene segments; 2) identical CDR3 loop lengths; and 3) >80% homology in CDR3 nucleotide sequences. FIG. 1D: VH repertoire analysis. VH germline genes were considered to be enriched in the RSV repertoire if the a given gene was found to be enriched by greater than 3-fold over non-RSV-specific repertoires (33). FIG. 1E: CDRH3 length distribution. FIG. 1F: Somatic hypermutation in VH (excluding CDRH3). Red bars indicate the average number of nucleotide substitutions. Each clonal lineage is only represented once in (D) and (E). Data for non-RSV reactive IgGs were derived from published sequences obtained by high-throughput sequencing of re-arranged antibody variable gene repertoires from healthy individuals (33).
FIG. 2A through 2D illustrates the similar antibody preferences observed for conformational state and subtype of RSV F in the repertoire. FIG. 2A: IgG affinities for preF and postF are plotted as shown. FIG. 2B: Percentage of antibodies within the donor repertoire that recognized both conformations of F (green) or bind only to preF (blue) or postF (orange). FIG. 2C: Percentage of antibodies within the donor repertoire that bind specifically to subtype A (green), subtype B (blue), or both subtypes A and B (red). N.B., non-binder. IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. FIG. 2D: Polyreactivity analysis of anti-RSV antibodies. The polyreactivity of the isolated anti-RSV F antibodies was measured using a previously described assay (42, 43). Three panels of control antibodies were included for comparison: a group of 138 antibodies currently in clinical trials, 39 antibodies that have been approved for clinical use and 14 broadly neutralizing HIV antibodies.
FIG. 3A through FIG. 3G illustrate mapping and specificities of anti-RSV antibodies for antigenic sites spanning the surface of PreF and PostF. FIG. 3A: The previously determined structure of preF with one protomer shown as ribbons and with six antigenic sites rainbow colored from red to purple. FIG. 3B: The percentage of antibodies targeting each antigenic site is shown. FIG. 3C: Percentage of preF-specific antibodies targeting each antigenic site. FIG. 3D: Apparent antibody binding affinities for subtype A PreF antigenic sites. FIG. 3E: Apparent binding affinities for subtype A postF antigenic sites. FIG. 3F: Apparent antibody binding affinities for subtype B PreF antigenic sites. FIG. 3G. Apparent binding affinities for subtype B postF. Only antibodies with apparent binding affinities greater than 2 nM were included in this analysis, since antibodies with lower affinity could not be reliably mapped. Red bars show the median and the dotted grey line is at 2 nM. N.B., non-binder.
FIG. 4A through FIG. 4G illustrate neutralizing potencies of anti-RSV antibodies and correlation between potency and Pref vs. PostF specifity for each of RSV subtypes A and B. FIG. 4A: Neutralization IC50s for the antibodies isolated from the donor repertoire. Data points are colored based on neutralization potency, according to the legend on the right. Red and blue dotted lines depict motavizumab and D25 IC50s, respectively. FIG. 4B: Percentage of neutralizing antibodies in the donor repertoire against RSV subtype A or subtype B, stratified by potency as indicated in the legend in the right portion of the figure. FIG. 4C: Percentage of antibodies within the donor repertoire that neutralized both RSV subtypes A and B (red) or neutralized only RSV subtype A (green) or subtype B (blue). FIG. 4D: Apparent binding affinities for subtype A, preF and postF, plotted for each antibody (IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B.) FIG. 4E: Neutralization IC50s plotted for RSV subtype A preF-specific, postF-specific, and cross-reactive antibodies. (Red and blue dotted lines depict motavizumab and D25 IC50s, respectively. Red bars depict median. N.B., non-binder; N.N., non-neutralizing). FIG. 4F: Apparent antibody binding affinities for subtype B, preF and postF. FIG. 4G: IC50s plotted for RSV subtype B preF-specific, postF-specific and cross-reactive antibodies. (Black bar depicts median. N.B., non-binder; N.N., non-neutralizing.)
FIG. 5A through FIG. 5C illustrate that the most potent neutralizing antibodies bind with high affinity to preF and recognize antigenic sites Ø and V. FIG. 5A: apparent preF KD plotted against neutralization IC50 and colored according to antigenic site, as shown in the legend at right of FIG. 5C. FIG. 5B: apparent postF KD plotted against neutralization IC50 and colored as in FIG. 5A. FIG. 5C: antibodies grouped according to neutralization potency and colored by antigenic site as in legend at right. N.B., non-binder; N.N., non-neutralizing. IgG KDs were calculated for antibodies with BLI responses >0.1 nm. Antibodies with BLI responses <0.05 nm were designated as N.B. Statistical significance was determined using an unpaired two-tailed t test. The Pearson's correlation coefficient, r, was calculated using Prism software version 7.0. Antibodies that failed to bind or neutralize were excluded from the statistical analysis due to the inability to accurately calculate midpoint concentrations.
FIG. 6A through FIG. 6C illustrate the nature and purification of pre- and postF sorting probes. FIG. 6A: Schematic of fluorescent prefusion RSV F probe shows one PE-conjugated streptavidin molecule bound by four avi-tagged trimeric prefusion F molecules. FIG. 6B: Coomassie-stained SDS-PAGE gel demonstrating the isolation of RSV F with a single AviTag per trimer using sequential Ni-NTA and Strep-Tactin purifications, as described in the Methods. FIG. 6C: Fluorescence size-exclusion chromatography (FSEC) trace of the tetrameric probes on a Superose 6 column. Positions of molecular weight standards are indicated with arrows.
FIG. 7A through FIG. 7C illustrates the generation and validation of preF patch panel mutants. FIG. 7A: Panel of RSV F variants used for epitope mapping. FIG. 7B: Prefusion RSV F shown as molecular surface with one protomer colored in white. The nine variants, each containing a patch of mutations, are uniquely colored according to the table in FIG. 7A. FIG. 7C: Binding of each IgG to fluorescently labeled beads coupled to each of the variants listed in FIG. 7A was measured using PE-conjugated anti-human Fc antibody on a FLEXMAP 3D flow cytometer (Luminex). Reduced binding of D25 and motavizumab to patches 1 and 5, respectively, is consistent with their structurally defined epitopes (10, 11). AM14 binding was reduced for both patch 3 and patch 9, due to its unique protomer-spanning epitope (21). This characteristic binding profile was used to assist in the classification of other possible quaternary-specific antibodies in the panel.
FIG. 8 illustrates the antigenic site V resides between the epitopes recognized by D25, MPE8 and motavizumab. Prefusion F is shown with one promoter as a cartoon colored according to antigenic site location and the other two protomers colored grey. D25 and motavizumab Fabs are shown in blue and pink, respectively. The MPE8 binding site is circled in black. Antigenic site V is located between the binding sites of D25 and MPE8 within one protomer, explaining the competition between site-V directed antibodies and these controls. Competition with motavizumab may occur across two adjacent protomers (left) or within one protomer (right), depending on the angle-of-approach of these site-V directed antibodies.
FIG. 9 illustrates percentage of anti-RSV antibodies demonstrating the indicated neutralizing activities of preF-specific, postF-specific, and cross-reactive antibodies. Antibodies were stratified according to neutralization potency and the percentage of antibodies in each group that were preF-specific (pink), postF-specific (white) or cross-reactive (orange) were plotted for subtype A (left panel) and subtype B (right panel).
FIG. 10A through FIG. 10C illustrates the relationship between subtype B neutralization and antigenic site specificity for anti-RSV antibodies. FIG. 10A: Subtype B preF affinity plotted against neutralization IC50 for all antibodies and colored by antigenic site according to the colore scheme depicted in FIG. 10C, right portion. FIG. 10B: PostF affinity plotted against IC50 and colored as in FIG. 10A. FIG. 10C: Antibodies with preF affinities higher than 2 nM grouped according to neutralization potency and colored by antigenic site (right portion).
FIG. 11 illustrates in vitro neutralization of RSV A2 for specific anti-RSV antibodies. Inhibition of RSV-replication was measured in an ELISA based neutralization Assay using Hep-2 cells. Cells, mAbs and viruses were co-incubated for 4 days at 37° C., followed by quantification of viral proteins in infected cells using a polyclonal anti-RSV antibody. % inhibition was calculated relative to control cells infected with virus in absence of neutralizing antibody. Data are expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC50) and represent the mean+/−SEM of two independent experiments. An isotype matched control mAb (*) was included in every experiment and did not exhibit virus neutralization.
DETAILED DESCRIPTION OF THE INVENTION Unless defined otherwise, 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. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Definitions “Respiratory Syncytial Virus-F protein”, also referred to as “RSV-F” is a type I transmembrane surface protein, which has an N terminal cleaved signal peptide and a membrane anchor near the C terminus (Collins, P. L. et al., (1984), PNAS (USA) 81:7683-7687). The RSV-F protein is synthesized as an inactive 67 KDa precursor denoted as F0 (Calder, L. J.; et al., Virology (2000), 277,122-131. The F0 protein is activated proteolytically in the Golgi complex by a furin-like protease at two sites, yielding two disulfide linked polypeptides, F2 and F1, from the N and C terminal, respectively. There is a 27 amino acid peptide released called “pep27”. There are furin cleavage sites (FCS) on either side of the pep27 (Collins, P. L.; Mottet, G. (1991), J. Gen. Virol., 72: 3095-3101; Sugrue, R. J, et al. (2001), J. Gen. Virol., 82,1375-1386). The F2 subunit consists of the Heptad repeat C (HRC), while the F1 contains the fusion polypeptide (FP), heptad repeat A (HRA), domain I, domain II, heptad repeat B (HRB), transmembrane (TM) and cytoplasmic domain (CP) (See Sun, Z. et al. Viruses (2013), 5:21 1-225). The RSV-F protein plays a role in fusion of the virus particle to the cell membrane, and is expressed on the surface of infected cells, thus playing a role in cell to cell transmission of the virus and syncytia formation. The amino acid sequence of the RSV-F protein is provided in GenBank as accession number AAX23994.
A stabilized variant of the PreF trimeric conformation of RSV-F, termed “RSV-DS-Cav1”, or “DS-Cav1” disclosed in, inter alia, Stewart-Jones et al., PLos One, Vol. 10(6)):e0128779. doi: 10.1371/journal.pone.0128779 and WO 2011/050168. was used in the identification, isolation, and characterization of the antibodies disclosed herein.
The term “laboratory strain” as used herein refers to a strain of RSV (subtype A or B) that has been passaged extensively in in vitro cell culture. A “laboratory strain” can acquire adaptive mutations that may affect their biological properties. A “clinical strain” as used herein refers to an RSV isolate (subtype A or B), which is obtained from an infected individual and which has been isolated and grown in tissue culture at low passage.
The term “effective dose 99” or “ED99” refers to the dosage of an agent that produces a desired effect of 99% reduction of viral forming plaques relative to the isotype (negative) control. In the present invention, the ED99 refers to the dosage of the anti-RSV-F antibodies that will neutralize the virus infection (e.g. reduce 99% of viral load) in vivo, as described in Example 5.
The term “IC50” refers to the “half maximal inhibitory concentration”, which value measures the effectiveness of compound (e.g. anti-RSV-F antibody) inhibition towards a biological or biochemical utility. This quantitative measure indicates the quantity required for a particular inhibitor to inhibit a given biological process by half. In certain embodiments, RSV virus neutralization potencies for anti-RSV and/or anti-RSV/anti-HMPV cross-neutralizing antibodies disclosed herein are expressed as neutralization IC50 values.
“Palivizumab”, also referred to as “SYNAGIS®”, is a humanized anti-RSV-F antibody with heavy and light chain variable domains having the amino acid sequences as set forth in U.S. Pat. Nos. 7,635,568 and 5,824,307. This antibody, which immunospecifically binds to the RSV-F protein, is currently FDA-approved for the passive immunoprophylaxis of serious RSV disease in high-risk children and is administered intramuscularly at recommended monthly doses of 15 mg/kg of body weight throughout the RSV season (November through April in the northern hemisphere). SYNAGIS® is composed of 95% human and 5% murine antibody sequences. See also Johnson et al., (1997), J. Infect. Diseases 176:1215-1224.
“Motavizumab”, also referred to as “NUMAX™”, is an enhanced potency RSV-F-specific humanized monoclonal antibody derived by in vitro affinity maturation of the complementarity-determining regions of the heavy and light chains of palivizumab. For reference purposes, the amino acid sequence of the NUMAX™ antibody is disclosed in U.S. Patent Publication 2003/0091584 and in U.S. Pat. No. 6,818,216 and in Wu et al., (2005) J. Mol. Bio. 350(1):126-144 and in Wu, et al. (2007) J. Mol. Biol. 368:652-665. It is also shown herein as SEQ ID NO: 359 for the heavy chain and as SEQ ID NO: 360 for the light chain of the antibody.
As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of an upper and/or lower respiratory tract RSV infection and/or human metapneumovirus (HMPV), otitis media, or a symptom or respiratory condition related thereto (such as asthma, wheezing, or a combination thereof) resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents). In certain embodiments, such terms refer to the reduction or inhibition of the replication of RSV and/or HMPV, the inhibition or reduction in the spread of RSV and/or HMPV to other tissues or subjects (e.g., the spread to the lower respiratory tract), the inhibition or reduction of infection of a cell with a RSV and/or HMPV, or the amelioration of one or more symptoms associated with an upper and/or lower respiratory tract RSV infection or otitis media.
As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the prevention or inhibition of the development or onset of an upper and/or lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto in a subject, the prevention or inhibition of the progression of an upper respiratory tract RSV and/or HMPV infection to a lower respiratory tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto resulting from the administration of a therapy (e.g., a prophylactic or therapeutic agent), the prevention of a symptom of an upper and/or lower tract RSV and/or HMPV infection, otitis media or a respiratory condition related thereto, or the administration of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents). As used herein, the terms “ameleliorate” and “alleviate” refer to a reduction or diminishment in the severity a condition or any symptoms thereof.
The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds (i.e., “full antibody molecules”), as well as multimers thereof (e.g. IgM) or antigen-binding fragments thereof. Each heavy chain is comprised of a heavy chain variable region (“HCVR” or “VH”) and a heavy chain constant region (comprised of domains CH1, CH2 and CH3). Each light chain is comprised of a light chain variable region (“LCVR or “VL”) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen binding fragment thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. Accordingly, the CDRs in a heavy chain are designated “CHRH1”, “CDRH2”, and “CDRH3”, respectively, and the CDRs in a light chain are designated “CDRL1”, “CDRL2”, and “CDRL3”.
Substitution of one or more CDR residues or omission of one or more CDRs is also possible. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9:133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vajdos et al. 2002 J Mol Biol 320:415-428).
CDR residues not contacting antigen can be identified based on previous studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and/or empirically. If a CDR or residue(s) thereof is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.
The fully human monoclonal antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.
The present invention also includes fully monoclonal antibodies comprising variants of any of the CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes antibodies having CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the CDR amino acid sequences disclosed herein.
The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences {e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
However, the term “human antibody”, as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse), have been grafted onto human FR sequences.
The term “humanized antibody” refers to human antibody in which one or more CDRs of such antibody have been replaced with one or more corresponding CDRs obtained a non-human derived (e.g., mouse, rat, rabbit, primate) antibody. Humanized antibodies may also include certain non-CDR sequences or residues derived from such non-human antibodies as well as the one or more non-human CDR sequence. Such antibodies may also be referred to as “chimeric” antibodies.
The term “recombinant” generally refers to any protein, polypeptide, or cell expressing a gene of interest that is produced by genetic engineering methods. The term “recombinant” as used with respect to a protein or polypeptide, means a polypeptide produced by expression of a recombinant polynucleotide. The proteins used in the immunogenic compositions of the invention may be isolated from a natural source or produced by genetic engineering methods.
The antibodies of the invention may, in some embodiments, be recombinant human antibodies. The term “recombinant human antibody”, as used herein, is intended to include all antibodies, including human or humanized antibodies, that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
The term “specifically binds,” or “binds specifically to”, or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1×10−6 M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. As described herein, antibodies have been identified by surface plasmon resonance, e.g., BIACORE™, biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), which bind specifically to RSV-F. Moreover, multi-specific antibodies that bind to RSV-F protein and one or more additional antigens, such as an antigen expressed by HMPV, or a bi-specific that binds to two different regions of RSV-F are nonetheless considered antibodies that “specifically bind”, as used herein. In certain embodiments, the antibodies disclosed herein display equilibrium dissociation constants (and hence specificities) of about 1×10-6 M; about 1×10-7 M; about 1×10-8 M; about 1×10-9 M; about 1×10-10 M; between about 1×10−6 M and about 1×10-7 M; between about 1×10-7M and about 1×10-8 M; between about 1×10-8 M and about 1×10-9 M; or between about 1×10-9 M and about 1×10-10 M.
The term “high affinity” antibody refers to those mAbs having a binding affinity to RSV-F and/or HMPV, expressed as KD, of at least 10-9 M; more preferably 10-10M, more preferably 10−11M, more preferably 10−12M as measured by surface plasmon resonance, e.g., BIACORE™ biolayer interferometry measurements using, e.g., a ForteBio Octet HTX instrument (Pall Life Sciences), or solution-affinity ELISA.
By the term “slow off rate”, “Koff” or “kd” is meant an antibody that dissociates from RSV-F, with a rate constant of 1×10−3 s″1 or less, preferably 1×10−4 s″1 or less, as determined by surface plasmon resonance, e.g., BIACORE™ or a ForteBio Octet HTX instrument (Pall Life Sciences).
The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. In certain embodiments, the terms “antigen-binding portion” of an antibody, or “antibody fragment”, as used herein, refers to one or more fragments of an antibody that retains the ability to bind to RSV-F and/or HMPV.
An antibody fragment may include a Fab fragment, a F(ab′)2 fragment, a Fv fragment, a dAb fragment, a fragment containing a CDR, or an isolated CDR. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and (optionally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.
An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR, which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and V|_ domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.
In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-Ch1-Ch2; (V) VH-Ch1-Ch2-Ch3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (Xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).
As with full antibody molecules, antigen-binding fragments may be mono-specific or multi-specific (e.g., bi-specific). A multi-specific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multi-specific antibody format, including the exemplary bi-specific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.
The specific embodiments, antibody or antibody fragments of the invention may be conjugated to a therapeutic moiety (“immunoconjugate”), such as an antibiotic, a second anti-RSV-F antibody, an anti-HMPV antibody, a vaccine, or a toxoid, or any other therapeutic moiety useful for treating an RSV infection and/or an HMPV infection.
An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies (Abs) having different antigenic specificities (e.g., an isolated antibody that specifically binds RSV-F and/or HMPV, or a fragment thereof, is substantially free of Abs that specifically bind antigens other than RSV-F and/or HMPV.
A “blocking antibody” or a “neutralizing antibody”, as used herein (or an “antibody that neutralizes RSV-F and/or HMPVactivity”), is intended to refer to an antibody whose binding to RSV-F or to an HMPV antigen, as the case may be as disclosed herein, results in inhibition of at least one biological activity of RSV-F and/or HMPV. For example, an antibody of the invention may aid in blocking the fusion of RSV and/or HMPV to a host cell, or prevent syncytia formation, or prevent the primary disease caused by RSV and/or HMPV. Alternatively, an antibody of the invention may demonstrate the ability to ameliorate at least one symptom of the RSV infection and or HMPV infection. This inhibition of the biological activity of RSV-F and/or HMPV can be assessed by measuring one or more indicators of RSV-F and/or HMPV biological activity by one or more of several standard in vitro assays (such as a neutralization assay, as described herein) or in vivo assays known in the art (for example, animal models to look at protection from challenge with RSV and/or HMPV following administration of one or more of the antibodies described herein).
The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biomolecular interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE™ system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).
The term “KD”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.
The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. The term “epitope” also refers to a site on an antigen to which B and/or T cells respond. It also refers to a region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics.
The term “substantial identity”, or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as discussed below. Accordingly, nucleic acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.
In certain embodiments, the disclosed antibody nucleic acid sequences are, e.g.: at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).
As applied to polypeptides, the term “substantial identity” or “substantially identical” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 90% sequence identity, even more preferably at least 95%, 98% or 99% sequence identity. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another. Accordingly, amino acid sequences that display a certain percentage “identity” share that percentage identity, and/or are that percentage “identical” to one another.
In certain embodiments, the disclosed antibody amino acid sequences are, e.g.: at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to other sequences and/or share such percentage identities with one another (or with certain subsets of the herein-disclosed antibody sequences).
Preferably, residue positions, which are not identical, differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331). Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA with default or recommended parameters; a program in GCG Version 6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and (1997) Nucleic Acids Res. 25:3389 402).
In certain embodiments, the antibody or antibody fragment for use in the method of the invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of lgG1 mAbs; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of lgG2 mAbs; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of lgG4 mAbs. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.
By the phrase “therapeutically effective amount” is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
An “immunogenic composition” relates to a composition containing an antigen/immunogen, e.g. a microorganism, such as a virus or a bacterium, or a component thereof, a protein, a polypeptide, a fragment of a protein or polypeptide, a whole cell inactivated, subunit or attenuated virus, or a polysaccharide, or combination thereof, administered to stimulate the recipient's humoral and/or cellular immune systems to one or more of the antigens/immunogens present in the immunogenic composition. The immunogenic compositions of the present invention can be used to treat a human susceptible to RSV and/or HMPV infection or suspected of having or being susceptible to RSV and/or HMPV infection, by means of administering the immunogenic compositions via a systemic route. These administrations can include injection via the intramuscular (i.m.), intradermal (i.d.), intranasal or inhalation route, or subcutaneous (s.c.) routes; application by a patch or other transdermal delivery device. In one embodiment, the immunogenic composition may be used in the manufacture of a vaccine or in the elicitation of polyclonal or monoclonal antibodies that could be used to passively protect or treat a mammal.
The terms “vaccine” or “vaccine composition”, which are used interchangeably, refer to a composition comprising at least one immunogenic composition that induces an immune response in an animal.
In certain embodiments, a protein of interest comprises an antigen. The terms “antigen,” “immunogen,” “antigenic,” “immunogenic,” “antigenically active,” and “immunologically active” when made in reference to a molecule, refer to any substance that is capable of inducing a specific humoral and/or cell-mediated immune response. In one embodiment, the antigen comprises an epitope, as defined above.
“Immunologically protective amount”, as used herein, is an amount of an antigen effective to induce an immunogenic response in the recipient that is adequate to prevent or ameliorate signs or symptoms of disease, including adverse health effects or complications thereof. Either humoral immunity or cell-mediated immunity or both can be induced. The immunogenic response of an animal to a composition can be evaluated, e.g., indirectly through measurement of antibody titers, lymphocyte proliferation assays, or directly through monitoring signs and symptoms after challenge with the microorganism. The protective immunity conferred by an immunogenic composition or vaccine can be evaluated by measuring, e.g., reduction of shed of challenge organisms, reduction in clinical signs such as mortality, morbidity, temperature, and overall physical condition, health and performance of the subject. The immune response can comprise, without limitation, induction of cellular and/or humoral immunity. The amount of a composition or vaccine that is therapeutically effective can vary, depending on the particular organism used, or the condition of the animal being treated or vaccinated.
An “immune response”, or “immunological response” as used herein, in a subject refers to the development of a humoral immune response, a cellular-immune response, or a humoral and a cellular immune response to an antigen/immunogen. A “humoral immune response” refers to one that is at least in part mediated by antibodies. A “cellular immune response” is one mediated by T-lymphocytes or other white blood ceils or both, and includes the production of cytokines, chemokines and similar molecules produced by activated T-cells, white blood ceils, or both. Immune responses can be determined using standard immunoassays and neutralization assays, which are known in the art.
“Immunogenicity”, as used herein, refers to the capability of a protein or polypeptide to elicit an immune response directed specifically against a bacteria or virus that causes the identified disease.
Unless specifically indicated otherwise, the term “antibody,” as used herein, shall be understood to encompass antibody molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., “full antibody molecules”) as well as antigen-binding fragments thereof. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
Preparation of Human Antibodies As disclosed herein, anti-RSV and or anti-RSV/anti-HMPF cross neutralizing antibodies by be obtained through B cell sorting techniques available to the artisan, and, for example, as described in the EXAMPLES below. Methods for generating human antibodies in transgenic mice are also known in the art and may be employed in order to derive antibodies in accordance with the present disclosure. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to RSV-F (see, for example, U.S. Pat. No. 6,596,541).
In certain embodiments, the antibodies of the instant invention possess affinities (KD) ranging from about 1.0×10-7M to about 1.0×10−12M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (KD) ranging from about 1×10−7 M to about 6×10−10M, when measured by binding to antigen either immobilized on solid phase or in solution phase. In certain embodiments, the antibodies of the invention possess affinities (KD) ranging from about 1×10−7 M to about 9×10−10M, when measured by binding to antigen either immobilized on solid phase or in solution phase.
The anti-RSV-F and/or anti-HMPV antibodies and antibody fragments disclosed herein encompass proteins having amino acid sequences that vary from those of the described antibodies, but that retain the ability to bind RSV-F. Such variant antibodies and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an antibody or antibody fragment that is essentially bioequivalent to an antibody or antibody fragment of the invention.
Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.
In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.
In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.
In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.
Bioequivalence may be demonstrated by in vivo and/or in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.
Bioequivalent variants of the antibodies of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include antibody variants comprising amino acid changes, which modify the glycosylation characteristics of the antibodies, e.g., mutations that eliminate or remove glycosylation.
Biological and Biophysical Characteristics of the Antibodies In certain embodiments, the inventive antibodies and antigen-binding fragments thereof specifically bind to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such antibodies also possess at least one, two, three, four, five, six, seven, eight, nine, ten, or more characteristics disclosed in the immediately following eleven paragraphs.
Without wishing to be bound by any theory, it is believed that the inventive antibodies and antigen-binding fragments thereof may function by binding to RSV-F, preferably in the PreF conformation, and in so doing act to block the fusion of the viral membrane with the host cell membrane. The antibodies of the present invention may also function by binding to RSV-F and in so doing block the cell to cell spread of the virus and block syncytia formation associated with RSV infection of cells. Advantageously, both RSV subtype A and RSV subtype B are effectively blocked, or neutralized, by the majority of the anti-RSV antibodies disclosed herein.
In certain embodiments, the inventive antibodies and antigen-binding fragment thereof display better binding affinity for the PreF form of RSV-F relative to the PostF form of RSV-F.
In certain other embodiments, the inventive antibodies and antigen-binding fragments thereof advantageously display a clean or low polyreactivity profile (see, e.g., WO 2014/179363 and Xu et al., Protein Eng Des Sel, October; 26(10):663-70. doi: 10.1093/protein/gzt047), and are thus particularly amenable to development as safe, efficacious, and developable therapeutic and/or prophylactic anti-RSV and/or HMPV treatments.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof, without wishing to be bound by any theory, may function by blocking or inhibiting RSV fusion to the cell membrane by binding to any one or more of, e.g., antigenic Sites Ø, I, II, III, IV, or Site V of the PreF conformation of the F protein. In certain embodiments, the inventive antibodies display antigenic site specificity for Site Ø, Site V, or Site III of PreF relative to RSV-F Site I, Site II, or Site IV.
In certain embodiments, at least a portion of the epitope with which the inventive antibodies and antigen-binding fragments thereof interacts comprises a portion of the α3 helix and β3/β4 hairpin of PreF. In certain embodiments, substantially all of the epitope of such antibodies comprises the α3 helix and β3/β4 hairpin of PreF. In still further embodiments, the inventive antibodies corss-copmpete with antibodies that recognize a portion or substantially all of the α3 helix and β3/β4 hairpin of PreF.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display an in vitro neutralization potency (IC50) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml.
In certain embodiments, the binding affinity and/or epitopic specificity of the inventive antibodies and antigen-binding fragments thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display a cross-neutralization potency (IC50) against human metapneumovirus (HMPV) as well as RSV. In certain such embodiments, the inventive antibodies and antigen-binding fragments thereof comprise at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of such antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of Antibody Number 340 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, motavizumab, or AM-14. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25, palivisumab, or motavizumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with D25. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with MPE8. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with palivisumab. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof do not complete with motavizumab.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof complete with one or more of D25, MPE8, palivisumab, motavizumab, and/or AM-14.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof display at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise any combination of two, three, four, five, or six characteristics disclosed in the immediately preceeding six paragraphs.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise a heavy chain (HC) amino acid sequence and a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof are each selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, the inventive antibodies and antigen-binding fragments thereof comprise are each selected from the group consisting of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
In certain embodiments, isolated nucleic acid sequences are provided that encode antibodies that specifically bind to Respiratory Syncytial Virus (RSV) F protein and antigen-binding fragments thereof, wherein at least one of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences of the antibody or the antigen-binding fragment thereof is at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to at least one the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH3 amino acid sequence of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH2 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRH1 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL3 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL2 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the CDRL1 amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (HC) amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences that encode the heavy chain (LC) amino acid sequences of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6. In certain embodiments, such nucleic acid sequences are selected from those nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, isolated nucleic acid sequences are provided that encode the inventive antibodies and antigen-binding fragments thereof, wherein such nucleic acid sequences comprise sequences are each selected from the group consisting of sequences that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the nucleic acid sequences that are disclosed in Table 6, and compliments thereof.
In certain embodiments, expression vectors are provided comprising the isolated nucleic acid sequences disclose herein and throughout, and in particular in the immediately preceeding ten paragraphs.
In certain embodiments, host cells transfected, transformed, or transduced with the nucleic acid sequences and/or the expression vectors disclosed immediately above are provided.
Epitope Mapping and Related Technologies As described above and as demonstrated in the EXAMPLES, Applicants have characterized the epitopic specificities, bin assignments, and antigenic site assignments of the inventive antibodies and antigen-binding fragments thereof. In addition to the methods for conducting such characterization, various other techniques are available to the artisan that can be used to carry out such characterization or to otherwise ascertain whether an antibody “interacts with one or more amino acids” within a polypeptide or protein. Exemplary techniques include, for example, a routine cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY) can be performed. Other methods include alanine scanning mutational analysis, peptide blot analysis (Reineke (2004) Methods Mol Biol 248:443-63), peptide cleavage analysis crystallographic studies and NMR analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein/antibody complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to-hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface. As a result, amino acids that form part of the protein/antibody interface may retain deuterium and therefore exhibit relatively higher mass compared to amino acids not included in the interface. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues that correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267 {2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.
As the artisan will understand, an epitope can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.
Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (US 2004/0101920). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the antibodies of the invention into groups of antibodies binding different epitopes.
In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in one or more of the F protein patch variants disclosed, e.g., in the EXAMPLES and which are depicted in, e.g., FIG. 7A and which are designated as RSV F Variants 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG. In certain embodiments, such inventive antibodies and antigen-binding fragments thereof interact with an amino acid sequence comprising the amino acid residues that are altered in RSV F Variant 2. In certain embodiments, the inventive antibodies and/or antigen-binding fragments thereof interact with amino acid residues that extend beyond the region(s) identified above by about 5 to 10 amino acid residues, or by about 10 to 15 amino acid residues, or by about 15 to 20 amino acid residues towards either the amino terminal or the carboxy terminal of the RSV-F protein.
In certain embodiments, the antibodies of the present invention do not bind to the same epitope on RSV-F protein as palivizumab, motavizumab, MPE8, or AM-14.
As the artisan understands, one can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-RSV-F antibody by using routine methods available in the art. For example, to determine if a test antibody binds to the same epitope as a reference RSV-F antibody of the invention, the reference antibody is allowed to bind to a RSV-F protein or peptide under saturating conditions. Next, the ability of a test antibody to bind to the RSV-F molecule is assessed. If the test antibody is able to bind to RSV-F following saturation binding with the reference anti-RSV-F antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-RSV-F antibody. On the other hand, if the test antibody is not able to bind to the RSV-F molecule following saturation binding with the reference anti-RSV-F antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-RSV-F antibody of the invention.
To determine if an antibody competes for binding with a reference anti-RSV-F antibody, the above-described binding methodology is performed in two orientations: In a first orientation, the reference antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the test antibody to the RSV-F molecule. In a second orientation, the test antibody is allowed to bind to a RSV-F molecule under saturating conditions followed by assessment of binding of the reference antibody to the RSV-F molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to the RSV-F molecule, then it is concluded that the test antibody and the reference antibody compete for binding to RSV-F. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the reference antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.
Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. (1990) 50:1495-1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art.
Immunoconjugates The invention encompasses a human RSV-F monoclonal antibody conjugated to a therapeutic moiety (“immunoconjugate”), such as an agent that is capable of reducing the severity of primary infection with RSV and/or HMPV, or to ameliorate at least one symptom associated with RSV infection and/or HMPV infection, including coughing, fever, pneumonia, or the severity thereof. Such an agent may be a second different antibody to RSV-F and/or HMPV, or a vaccine. The type of therapeutic moiety that may be conjugated to the anti-RSV-F antibody and/or anti-HMPV antibody and will take into account the condition to be treated and the desired therapeutic effect to be achieved. Alternatively, if the desired therapeutic effect is to treat the sequelae or symptoms associated with RSV and/or HMPV infection, or any other condition resulting from such infection, such as, but not limited to, pneumonia, it may be advantageous to conjugate an agent appropriate to treat the sequelae or symptoms of the condition, or to alleviate any side effects of the antibodies of the invention. Examples of suitable agents for forming immunoconjugates are known in the art, see for example, WO 05/103081.
Multi-Specific Antibodies The antibodies of the present invention may be mono-specific, bi-specific, or multi-specific. Multi-specific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The antibodies of the present invention can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked {e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multi-specific antibody with a second binding specificity.
An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi-specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of lgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of lgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention.
Therapeutic Administration and Formulations The invention provides therapeutic compositions comprising the inventive anti-RSV-F antibodies or antigen-binding fragments thereof. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-31 1.
The dose of each of the antibodies of the invention may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the antibodies of the present invention are used for treating a RSV infection and/or HMPV infection in a patient, or for treating one or more symptoms associated with a RSV infection and/or HMPV infection, such as the cough or pneumonia associated with a RSV infection and/or HMPV in a patient, or for lessening the severity of the disease, it is advantageous to administer each of the antibodies of the present invention intravenously or subcutaneously normally at a single dose of about 0.01 to about 30 mg/kg body weight, more preferably about 0.1 to about 20 mg/kg body weight, or about 0.1 to about 15 mg/kg body weight, or about 0.02 to about 7 mg/kg body weight, about 0.03 to about 5 mg/kg body weight, or about 0.05 to about 3 mg/kg body weight, or about 1 mg/kg body weight, or about 3.0 mg/kg body weight, or about 10 mg/kg body weight, or about 20 mg/kg body weight. Multiple doses may be administered as necessary. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the antibodies or antigen-binding fragments thereof of the invention can be administered as an initial dose of at least about 0.1 mg to about 800 mg, about 1 to about 600 mg, about 5 to about 300 mg, or about 10 to about 150 mg, to about 100 mg, or to about 50 mg. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the antibodies or antigen-binding fragments thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.
Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral mucosa, nasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. It may be delivered as an aerosolized formulation (See US2011/0311515 and US2012/0128669). The delivery of agents useful for treating respiratory diseases by inhalation is becoming more widely accepted (See A. J. Bitonti and J. A. Dumont, (2006), Adv. Drug Deliv. Rev, 58:1 106-1 1 18). In addition to being effective at treating local pulmonary disease, such a delivery mechanism may also be useful for systemic delivery of antibodies (See Maillet et al. (2008), Pharmaceutical Research, Vol. 25, No. 6, 2008).
The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see, for example, Langer (1990) Science 249:1527-1533).
In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose.
The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.
A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™ OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousands Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.) and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.), to name only a few.
Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.
Administration Regimens According to certain embodiments, multiple doses of an antibody to RSV-F and/or HMPV may be administered to a subject over a defined time course. The methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of an antibody to RSV-F and/or HMPV. As used herein, “sequentially administering” means that each dose of antibody to RSV-F and/or HMPV is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an antibody to RSV-F and/or HMPV, followed by one or more secondary doses of the antibody to RSV-F and/or HMPV and optionally followed by one or more tertiary doses of the antibody to RSV-F and/or HMPV.
The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the antibody to RSV-F and/or HMPV. Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of antibody to RSV-F and/or HMPV, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of antibody to RSV-F and/or HMPV contained in the initial, secondary and/or tertiary doses vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”).
In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antibody to RSV-F and/or HMPV which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and/or tertiary doses of an antibody to RSV-F and/or HIMPV. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
Accordingly, in certain embodiments are provided pharmaceutical compositions comprising: one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout and a pharmaceutically acceptable carrier and/or one or more excipients. In certain other embodiments are provided pharmaceutical compositions comprising: one or more nucleic acid sequences encoding one or more inventive antibodies or antigen-binding fragments thereof, or one or more the expression vectors harbouring such nucleic acid sequences; and a pharmaceutically acceptable carrier and/or one or more excipients.
Therapeutic Uses of the Antibodies Due to their binding to and interaction with the RSV fusion protein (RSV-F), it is believe that the inventive antibodies and antigen-binding fragments thereof are useful—without wishing to be bound to any theory—for preventing fusion of the virus with the host cell membrane, for preventing cell to cell virus spread, and for inhibition of syncytia formation. Additionally, as Applicants have demonstrated herein that, surprisingly, a subset of the inventive anti-RSV antibodies and antigen-binding fragment thereof display crass-neutralizing potency against HMPV, the inventive antibodies and antigen-binding fragments thereof are advantageous for preventing an infection of a subject with RSV and/or HMPV when administered prophylactically. Alternatively, the antibodies of the present invention may be useful for ameliorating at least one symptom associated with the infection, such as coughing, fever, pneumonia, or for lessening the severity, duration, and/or frequency of the infection. The antibodies of the invention are also contemplated for prophylactic use in patients at risk for developing or acquiring an RSV infection and/or HMPV infection. These patients include pre-term infants, full term infants born during RSV season (late fall to early spring), the elderly (for example, in anyone 65 years of age or older) and/or HMPV season, or patients immunocompromised due to illness or treatment with immunosuppressive therapeutics, or patients who may have an underlying medical condition that predisposes them to an RSV infection (for example, cystic fibrosis patients, patients with congestive heart failure or other cardiac conditions, patients with airway impairment, patients with COPD) and/or HMPV infection. It is contemplated that the antibodies of the invention may be used alone, or in conjunction with a second agent, or third agent for treating RSV infection and/or HMPV infection, or for alleviating at least one symptom or complication associated with the RSV infection and/or HMPV infection, such as the fever, coughing, bronchiolitis, or pneumonia associated with, or resulting from such an infection. The second or third agents may be delivered concurrently with the antibodies of the invention, or they may be administered separately, either before or after the antibodies of the invention. The second or third agent may be an anti-viral such as ribavirin, an NSAID or other agents to reduce fever or pain, another second but different antibody that specifically binds RSV-F, an agent (e.g. an antibody) that binds to another RSV antigen, such as RSV-G, a vaccine against RSV, an siRNA specific for an RSV antigen.
In yet a further embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for treating patients suffering from a RSV infection and/or HMPV infection. In yet another embodiment of the invention the present antibodies are used for the preparation of a pharmaceutical composition for reducing the severity of a primary infection with RSV and/or HMPV, or for reducing the duration of the infection, or for reducing at least one symptom associated with the RSV infection and/or the HMPV infection. In a further embodiment of the invention the present antibodies are used as adjunct therapy with any other agent useful for treating an RSV infection and/or and HMPV infectin, including an antiviral, a toxoid, a vaccine, a second RSV-F antibody, or any other antibody specific for an RSV antigen, including an RSV-G antibody, or any other palliative therapy known to those skilled in the art.
Accordingly, in certain embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
In certain other embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such nucleic acid sequenced disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
In additional embodiments are provided methods of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
In certain embodiments as provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof one or more of the inventive antibodies or antigen-binding fragments thereof disclosed herein and throughout, such as, e.g., one or more of the anti-RSV antibodies disclosed in Table 6, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.
In certain other embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a nucleic acid sequence encoding one or more of the inventive antibodies or antigen-binding fragments thereof, such nucleic acid sequenced disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.
In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a host cell harboring a nucleic acid sequence or an expression vector comprising such a nucleic acid sequence, wherein such nucleic acid sequences is selected from the group consisting of sequences disclosed in Table 6 and compliments thereof, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.
In additional embodiments are provided methods of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof a pharmaceutical composition comprising either: one or more of the inventive antibodies or antigen-binding fragments thereof as disclosed in Table 6; one or more nucleic acid sequences or an expression vectors comprising such a nucleic acid sequence, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; one or more host cells harboring one or more nucleic acid sequences or an expression vectors comprising such one or more nucleic acid sequences, wherein such nucleic acid sequences are selected from the group consisting of sequences disclosed in Table 6 and compliments thereof; and a pharmaceutically acceptable carrier and/or one or more excipients, such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity. In certain embodiments, the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340 as disclosed in Table 6.
Combination Therapies As noted above, according to certain embodiments, the disclosed methods comprise administering to the subject one or more additional therapeutic agents in combination with an antibody to RSV-F and or HMPV. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising the anti-RSV-F antibody. The term “in combination with” also includes sequential or concomitant administration of the anti-RSV-F antibody and a second therapeutic agent.
For example, when administered “before” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising the anti-RSV-F antibody. When administered “after” the pharmaceutical composition comprising the anti-RSV-F antibody, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising the anti-RSV-F antibodies. Administration “concurrent” or with the pharmaceutical composition comprising the anti-RSV-F antibody means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the anti-RSV-F antibody, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the anti-RSV-F antibody.
Combination therapies may include an anti-RSV-F antibody of the invention and any additional therapeutic agent that may be advantageously combined with an antibody of the invention, or with a biologically active fragment of an antibody of the invention.
For example, a second or third therapeutic agent may be employed to aid in reducing the viral load in the lungs, such as an antiviral, for example, ribavirin. The antibodies may also be used in conjunction with other therapies, as noted above, including a toxoid, a vaccine specific for RSV, a second antibody specific for RSV-F, or an antibody specific for another RSV antigen, such as RSV-G.
Diagnostic Uses of the Antibodies The inventive anti-RSV antibodies and antigen-binding fragments thereof may also be used to detect and/or measure RSV and/or HMPV in a sample, e.g., for diagnostic purposes. It is envisioned that confirmation of an infection thought to be caused by RSV and/or HMPV may be made by measuring the presence of the virus through use of any one or more of the antibodies of the invention. Exemplary diagnostic assays for RSV and/or HMPV may comprise, e.g., contacting a sample, obtained from a patient, with an anti-RSV-F and/or HMPV antibody of the invention, wherein the anti-RSV-F and/or HMPV antibody is labeled with a detectable label or reporter molecule or used as a capture ligand to selectively isolate the virus containing the F protein from patient samples. Alternatively, an unlabeled anti-RSV-F and/or HMPV antibody can be used in diagnostic applications in combination with a secondary antibody which is itself detectably labeled. The detectable label or reporter molecule can be a radioisotope, such as 3H, 14C, 32P, 35S, or 125I; a fluorescent or chemiluminescent moiety such as fluorescein isothiocyanate, or rhodamine; or an enzyme such as alkaline phosphatase, β-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure RSV containing the F protein and/or HMPV in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).
Samples that can be used in RSV and/or HMPV diagnostic assays according to the present invention include any tissue or fluid sample obtainable from a patient, which contains detectable quantities of RSV-F protein and/or HMPV, or fragments thereof, under normal or pathological conditions. Generally, levels of RSV-F and/or HMPV in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with the presence of RSV-F and/or HMPV) will be measured to initially establish a baseline, or standard, level of the F protein from RSV and/or HMPV. This baseline level of RSV-F and/or HMPV can then be compared against the levels of RSV-F and/or HMPV measured in samples obtained from individuals suspected of having an RSV and/or HMPV infection, or symptoms associated with such infection.
EXAMPLES Applicants have comprehensively profiled the human antibody response to RSV fusion protein (F) by isolating and characterizing 133 RSV F-specific monoclonal antibodies from the memory B cells of a healthy adult donor, and used these antibodies to comprehensively map the antigenic topology of RSV F. The antibody response to RSV F was determined to be comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV antibodies that target this region, as well as vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, this class of antibodies displayed convergent sequence features, thus providing a future means to rapidly detect these types of antibodies in human samples. Many of the antibodies that bound preF-specific surfaces from this donor were over 100 times more potent than palivizumab, and one antibody cross-neutralized human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine and antibody-based therapeutic candidates, and offer new options for passive prophylaxis.
Large-Scale Isolation of RSV F-Specific Monoclonal Antibodies from Healthy Adult Human Donors
In order to comprehensively profile the human antibody response to RSV F, Applicants isolated and characterized 133 monoclonal antibodies from the memory B cells of a healthy adult donor (“donor 006”). Although this donors did not have a documented history of RSV infection, healthy adults are expected to have had multiple RSV infections throughout life (26).
The magnitude of the memory B cell response in this donor to RSV F was assessed by staining peripheral B cells with a mixture of fluorescently labeled pre- and postfusion RSV F sorting probes (FIG. 6A through 6B) (11, 15). Both proteins were dual-labeled in order to eliminate background due to non-specific fluorochrome binding (27). Flow cytometric analysis revealed that 0.04-0.18% of class-switched (IgG+ and IgA+) peripheral B cells were specific for RSV F (FIG. 1A and Figure B), which is significantly lower than the percentage of RSV F-specific cells observed after experimental RSV infection and suggests that this donor was probably not recently exposed to RSV (28). Notably, index sorting showed that 17-38% of circulating RSV F-specific B cells express IgA, indicating that IgA memory B cells to RSV F are present in peripheral blood (FIG. 1B).
Approximately 200 RSV F-specific B cells were single-cell sorted from the donor sample, and antibody variable heavy (VH) and variable light (VL) chain genes were rescued by single-cell PCR (29). One hundred thirty-three (133) cognate heavy and light chain pairs were subsequently cloned and expressed as full-length IgGs in an engineered strain of Saccharomyces cerevisiae for further characterization (30). Preliminary binding studies showed that approximately 80% of antibodies cloned from RSV F glycoprotein (F)-specific B cells bound to recombinant RSV F proteins.
Sequence Analysis of RSV F-Specific Antibody Repertoires Sequence analysis of the isolated monoclonal antibodies revealed that the RSV-F specific repertoire was highly diverse, containing over 70 unique lineages (FIG. 1C and Table 2). This result is in stark contrast to the relatively restricted repertoires observed in HIV-infected patients (31), or in healthy donors after influenza vaccination (32). Compared to non-RSV-reactive antibodies (33), the RSV F-specific repertoires were skewed, generally, toward certain VH germline genes (VH1-18, VH1-2, VH1-69, VH2-70, VH4-304, and VH5-51) (FIG. 1D and Table 2) and longer heavy chain third complementarity-determining region (CDRH3) lengths (generally, approximately 14-18 amino acids in length; FIG. 1E and Table 2). Interestingly, a bias toward VH1-69 has also been observed in anti-HIV-1, anti-influenza, and anti-HCV repertoires (34-36), and recent studies have shown that there is a significant increase in the relative usage of VH1-18, VH1-2, and VH1-69 during acute dengue infection (37). Hence, it appears that these particular germline gene segments may have inherent properties that facilitate recognition of viral envelope proteins.
The average level of somatic hypermutation (SHM) ranged generally between 16 and 30 nucleotide substitutions per VH gene (excluding CDRH3) (FIG. 1F and Table 2), which is comparable to the average level of SHM observed in anti-influenza antibody repertoires (32, 38) and consistent with the recurrent nature of RSV infection (26). Interestingly, several antibodies contained 40 or greater VH gene nucleotide substitutions, suggesting that multiple rounds of RSV infection can result in antibodies with very high levels of somatic hypermutation (SHM).
A Large Proportion of Antibodies Bind Exclusively to preF
We next measured the apparent binding affinities of the IgGs to furin-cleaved RSV F ectodomains stabilized in the prefusion (DS-Cav1) or postfusion (F ΔFP) conformation using biolayer interferometry (11, 15). A relatively large proportion of the antibodies (36-67%) bound exclusively to preF (FIG. 2A and Figure B; Table 3). The vast majority of remaining antibodies bound to both pre- and postF, with only 5-7% of antibodies showing exclusive postF specificity (FIG. 2A and Figure B; Table 3). The low prevalence of postF-specific antibodies in these donor repertoires is consistent with the observation that less than 10% of anti-RSV F serum-binding activity specifically targets postF (8). Interestingly, however, the majority of cross-reactive antibodies bound with higher apparent affinity to postF (FIG. 2A; Table 3), suggesting that these antibodies were probably elicited by and/or affinity matured against postF in vivo. Hence, the significantly higher proportion of preF- versus postF-specific antibodies is likely due to the higher immunogenicity of the unique surfaces on preF compared to postF, rather than an increased abundance of preF in vivo. Finally, as expected based on the relatively high degree of sequence conservation between RSV subtypes, most of the antibodies showed binding reactivity to F proteins derived from both subtypes A and B (FIG. 2C; Table 3).
Since certain antiviral antibody specificities have been associated with poly- and autoreactivity (39-41), we also tested the RSV antibodies for polyreactivity using a previously described high-throughput assay that correlates with down-stream behaviors such as serum clearance (42, 43). One hundred and seventy-seven clinical antibodies, as well as several broadly neutralizing HIV antibodies, were also included for comparison. Interestingly, in contrast to many previously described HIV broadly neutralizing antibodies, the vast majority of RSV F-specific antibodies lacked significant polyreactivity in this assay (FIG. 2D).
RSV F-Specific Antibodies Target Six Major Antigenic Sites To map the antigenic specificities of the RSV F-specific antibodies, Applicants first performed competitive binding experiments using a previously described yeast-based assay (44). Antibodies were initially tested for competition with D25, AM14 and MPE8-three previously described preF-specific antibodies (10, 17, 21)—and motavizumab, an affinity-matured variant of palivizumab that binds to both pre- and postF (10, 11, 45). Non-competing antibodies were then tested for competition with a site IV-directed mAb (101F) (46), a site I-directed antibody (Site I Ab), and two high affinity antibodies (High Affinity Ab I and High Affinity Ab 2, respectively) that did not strongly compete with each other or any of the control antibodies. Each antibody was assigned a bin based on the results of this competition assay (see, e.g., Table 4).
In order to confirm and increase the resolution of our epitope assignments, the binding of each antibody to a panel of preF variants was measured using a luminex-based assay. Each variant contained 2-4 mutations clustered together to form a patch on the surface of preF. A total of nine patches that uniformly covered the surface of preF were generated (FIG. 7A through FIG. 7C). Deglycosylated preF was also included to identify antibodies targeting glycan-dependent epitopes. Binding of each antibody to the 10 preF variants was compared to that of wild-type preF and used to assign a patch (see, e.g., Table 4). Previously characterized antibodies D25, AM14 and motavizumab were used to validate the assay (se, e.g., FIG. 7C and Table 4). The combined bin and patch data were then used to assign each antibody to a single antigenic site (FIG. 3A through FIG. 3G), which were defined based on previously determined structures, resistance mutations, and secondary structure elements of the F protein. Overall, these data show that the large majority of isolated antibodies target six dominant antigenic sites on prefusion RSV F (0, I, II, III, IV, and V). Interestingly, only a small proportion of the isolated antibodies had binding profiles similar to that of AM14, suggesting that antibodies targeting this quaternary epitope are not commonly elicited during natural infection. None of the antibodies were sensitive to deglycosylation of F, demonstrating that glycan-dependent antibodies are also rarely elicited by natural RSV infection.
Analysis of the preF- and postF-binding activities of the antibodies targeting each antigenic site (see, e.g., FIG. 3C through FIG. 3G; Table 4) revealed that three sites are primarily found on preF (0, III, and V). Antibodies targeting site Ø and site III have been previously described (10, 17), and these sites are located on the top and side of the preF spike, respectively. Approximately 18% of the antibodies from this donor recognized site Ø and approximately 20% recognized site III. A relatively large proportion of antibodies from this donor (approximately 26%) recognized the third preF-specific site, which has not been previously described and therefore has been designated herein as region site V (See, e.g., FIG. 3C through FIG. 3G; Table 4). The majority of site V antibodies competed with D25, MPE8 and motavizumab, which was unexpected given the distance between the epitopes recognized by these three antibodies. The patch mutant analysis revealed that these antibodies interact with the α3 helix and β3/β4 hairpin of preF. This region is located between the epitopes recognized by D25, MPE8, and motavizumab, explaining the unusual competition profile observed for this class of antibodies (See, e.g., FIG. 8). In addition to the three primarily preF-specific sites, a large number of the antibodies that recognized antigenic site IV were preF-specific, likely due to contacts with β22, which dramatically rearranges during the transition from pre- to postF. In summary, the epitope mapping data show that the large majority of isolated antibodies target six dominant antigenic sites, approximately half of which are exclusively expressed on preF.
Highly Potent Neutralizing Antibodies Target preF-Specific Epitopes
The antibodies were next tested for neutralizing activity against RSV subtypes A and B using a previously described high-throughput neutralization assay (15). Greater than 70% of the isolated antibodies showed neutralizing activity, and approximately 35%-40% neutralized with high potency (IC50≤0.05 μg/ml) (see, e.g., FIG. 4A and FIG. 4B; Table 3). Notably, several clonally unrelated antibodies were ≥5.0-fold more potent than D25 and ≥100-fold more potent than palivizumab (see, e.g., FIG. 4A; Table 3). Interestingly, there was no correlation between neutralization potency and level of SHM, suggesting that extensive SHM is not required for potent neutralization of RSV. Consistent with the binding cross-reactivity data, the majority of neutralizing antibodies showed activity against both subtype A and B (FIG. 4A through FIG. 4C; Table 3).
The relationship between preF- and postF-binding affinity and neutralization potency was next investigated, which clearly demonstrated that the majority of highly potent antibodies bound preferentially or exclusively to preF (see, e.g., FIG. 4D through FIG. 4G; Table 3). Quantifying this difference revealed that more than 80% of highly potent antibodies (IC50<0.05 μg/ml) were specific for preF (See, e.g., FIG. 9; Table 3) and that the median IC50 for preF-specific antibodies was more than 8-fold lower than for pre- and postF cross-reactive antibodies and 80-fold lower than antibodies that specifically recognized postF (see, e.g., FIG. 4E; Table 3). Importantly, there was a positive correlation between preF binding and neutralization (P<0.001, r=0.24), and the apparent preF KDs generally corresponded well with the neutralization IC50s (see, e.g., FIG. 5A; Table 3). In contrast, there was no correlation between neutralization potency and postF affinity (P=0.44, r=−0.07) (see, e.g., FIG. 5B; Table 3). This result is compatible with the occupancy model of antibody-mediated neutralization (47), and suggests that DS-Cav1 is a faithful antigenic mimic of the native preF trimer. Notably, very few antibodies neutralized with IC50s lower than 100 pM, which is consistent with the previously proposed ceiling to affinity maturation (48, 49).
The relationship between neutralization potency and antigenic site was next analyzed. The results, provided in, e.g., FIG. 5C, Table 3, and Table 4, collectively, indicated that over 60% of the highly potent neutralizing antibodies targeted antigenic sites Ø and V, which are two of the three prefusion-F specific sites. In contrast, antibodies targeting sites III and IV showed a wide range of neutralization potencies, and antibodies targeting sites I and II were generally moderate to non-neutralizing. Similar results were obtained using binding affinities and neutralization potencies measured for subtype B (See, e.g., FIG. 10A through FIG. 10C; Table 3 and Table 4). Interestingly, a subset of site IV-directed antibodies neutralized with substantially lower potency than would be expected based on preF binding affinity (see, e.g., FIG. 5A; Table 3). This result may suggest that certain epitopes within site IV are less exposed in the context of the native envelope spike expressed on the crowded surface of the virion than on recombinant preF.
Several Antibodies Cross-Neutralize RSV and HMPV Given that the RSV and human metapneumovirus (HMPV) F proteins share 33% amino acid identity, and certain RSV F-specific antibodies cross-neutralize HMPV (17, 50), the antibodies from this donor were tested for neutralizing activity against HMPV. Of the 133 antibodies tested, one neutralized HMPV (see, e.g., Table 5). Sequence analysis revealed that this antibody represents the VH1-46 germline gene and contains a significant degree of somatic hypermutation (See, e.g., Table 2 and sequence listing). This cross-neutralizing antibody bound to both the preF and PostF and competed with MPE8 (See, e.g., Table 5), in agreement with previous studies indicating that MPE8 cross-neutralizes four pneumoviruses, including RSV and HMPV (17). This result suggests, inter alia, that highly conserved epitopes are relatively immunogenic in the context of natural RSV and/or HMPV infection.
Affinity Maturation of RSV F-Specific Antibodies: Some embodiments refer to affinity matured antibodies of any of the antibodies listed in Table 6 (each understood as a “parent” antibody” for producing an affinity matured variant). Affinity matured antibodies may be produced by mutagenesis of any one or more of the CDRs of the parent antibody. According to a specific embodiment, the invention provides for affinity matured variants comprising one or more point mutations e.g., 0, 1, 2, or 3 point mutations in each of the CDR sequences, of any of the antibodies listed in Table 6, or of an antibody comprising the six CDR sequences of any of the antibodies listed in Table 6. Affinity matured variants can be produced by any affinity maturation method employing standard mutagenesis techniques, e.g., for optimizing the binding characteristics, such as increasing affinity of binding, or increasing Kon, or decreasing Koff, and can be characterized by a KD difference of at least 2 fold, 5 fold, 1 log, or 2 logs, or 3 logs, as compared to the parent antibody. Such affinity matured antibodies still have the same binding specificity as the parent antibody and e.g., an optimized affinity of binding the target epitope.
Selected anti RSV antibodies were identified for affinity maturation. Oligos were ordered which comprised CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences that were variegated via NNK diversity. The NNK oligos were incorporated into the parent HC or LC via DNA shuffling, as described previously (Stemmer W P et al., DNA shuffling by random fragmentation and reassembly: In vitro recombination for molecular evolution. Proc Natl Acad Sci USA. 1994 Oct. 25; 91(22):10747-51). The library was then created by transforming the VH and VL PCR products into yeast already containing either the light chain or heavy chain plasmid of the parent. The diversified libraries were then selected using flow cytometry. For each FACS round, the libraries were affinity pressured using decreasing amounts of antigen and clones with improved binding affinities were sorted and propagated. Once improved binding populations were observed by flow cytometry (typically two rounds of selection), single yeast clones were be picked for sequencing and characterization (Table 6).
A specific embodiment refers to affinity matured variants of the antibody 267 in Table 6. Notably, each of the antibodies numbered 365-372 is an affinity matured variant of the antibody numbered 267 in Table 6.
Antibody Production and Purification of Affinity Matured Antibodies Yeast clones were grown to saturation and then induced for 48 h at 30° C. with shaking. After induction, yeast cells were pelleted and the supernatants were harvested for purification. IgGs were purified using a Protein A column and eluted with acetic acid, pH 2.0. Fab fragments were generated by papain digestion and purified over KappaSelect (GE Healthcare LifeSciences).
RSV In Vitro Neutralization in ELISA Based Microneutralization Assays In vitro RSV neutralization was tested in ELISA based Microneutralization Assays using RSV-A strain A2 (ATCC, VR1540P). Virus (at a final multiplicity of infection of approximately 0.25) was added to 96-well plates containing serially diluted mAbs in serum-free MEM and pre-incubated for 30 min at 4° C. Freshly trypsinized Hep-2 cells (1.5×10E4 cells/well) were then added to each well in MEM supplemented with 5% FCS. Following incubation for 4 days at 37° C. and 5% CO2, medium was aspirated and cells were washed twice with 200 μl PBS/well, air-dried and fixed with 100 μl Acetone (80%). RSV replication was measured by quantification of expressed viral proteins by ELISA. For this purpose, fixed cells were washed 2×times with PBS-0.1% Tween-20, blocked with 1% skimmed milk in PBS for 1 hour at RT and then stained with a polyclonal goat-anti RSV antibody preparation (BioRad, #7950-0004) for 1 hour at RT in blocking buffer. A donkey anti-goat IgG HRP conjugate was used as detection reagent and 1 step-Ultra TMB (Thermo Fisher Scientific, #34209) as substrate. % inhibition of virus replication was calculated relative to control cells infected with virus in absence of neutralizing antibodies. An isotype matched control mAb was included in all experiments. mAb potency is expressed as half-maximal inhibitory concentration that resulted in 50% reduction in virus replication (IC50). Results are provided in FIG. 11 and demonstrate that all mAbs were able to neutralize RSV-A2 in this setting, with a broad range of IC50 values.
DISCUSSION An in-depth understanding of the human antibody response to RSV infection will aid the development and evaluation of RSV vaccine and therapeutic and/or prophylactic antibody candidates for the treatment and/or prevention of RSV infection. Although previous studies have coarsely mapped the epitopes targeted by RSV-specific neutralizing antibodies in human sera (4, 8), the specificities and functional properties of antibodies induced by natural RSV infection have remained largely undefined. As disclosed herein, preF- and postF-stabilized proteins (11, 15), a high-throughput antibody isolation platform, and a structure-guided collection of prefusion F mutants, were used to clonally dissect the human memory B cell response to RSV F in a naturally infected adult donor, and highly potent and selective RSV-neutralizing—as well as highly potent anti-RSV/anti-HMPV cross-selective and cross-neutralizing—were isolated and characterized.
In the repertoire analyzed, the ratio of preF-specific antibodies to those that recognize both pre- and postF was slightly greater than 1:1 (See, e.g., FIG. 2B). These values are somewhat lower than those reported for human sera, which showed approximately 70% of anti-F serum binding is specific for preF (8). This discrepancy may be the result of differences between the levels of individual antibodies in serum, differences in the B cell phenotypes achieved for a particular specificity, or variation between donors. Despite these minor differences, the results of both studies suggest that preF-specific epitopes and epitopes shared by pre- and postF are immunogenic during natural RSV infection, whereas the unique surfaces on postF are significantly less immunogenic.
The repertoire analysis disclosed herein revealed that the large majority of RSV F-specific antibodies target six dominant antigenic sites on prefusion RSV F: Ø, I, II, III, IV, and V. These sites were defined based on previously determined structures, epitope binning/competition assays, resistance mutations, and secondary structure elements of the preF protein. It is important to note that the nomenclature for describing RSV F antigenic sites has evolved over time (6, 51-57), and previous mapping efforts were based on the postfusion conformation of F and did not include surfaces present exclusively on preF. The crystal structure of preF has provided critical information about F structure and function as well as new reagents to map antibody binding sites on the unique surfaces of preF and surfaces shared with postF. To a first approximation, each antibody can be assigned primarily to one of these sites. However, it is likely that antibody epitopes cover the entire surface of F and that there are antibodies that bind two or more adjacent antigenic sites within a protomer and quaternary antibodies that bind across protomers.
Importantly, the results disclosed herein show that the most potently neutralizing antibodies target antigenic sites Ø and V, both of which are located near the apex of the preF trimer. These findings are consistent with results obtained from human sera mapping, which determined that the majority of neutralizing activity can be removed by pre-incubation with preF (4, 8) and that preF-specific sites other than site Ø make up a considerable fraction of preF-specific neutralizing antibodies (8). Although antigenic site Ø has been shown to be a target of potently neutralizing antibodies (8, 10), the interaction of antibodies with site V is less well understood. Interestingly, it was found that the majority of site V-directed antibodies share several convergent sequence features, suggesting that it may be possible to rapidly detect these types of antibodies in human samples using high-throughput sequencing technology (58). Applicants anticipate this finding to be particularly advantageous in profiling antibody responses to RSV vaccine candidates that aim to preserve the apex of the preF trimer.
The extensive panel of antibodies described here provides new opportunities for passive prophylaxis, as well as for treatment of RSV infection. A large number of these antibodies neutralize RSV more potently than D25, which serves as the basis for MEDI8897—a monoclonal antibody that is currently in clinical trials for the prevention of RSV in young, at risk children (59). Additionally, a subset of these antibodies were demonstrated to cross-neutralize HMPV.
The development of an effective RSV vaccine has presented a number of unique challenges, and selection of the optimal vaccination strategy will be of the utmost importance. The in-depth analysis of the human antibody response to natural RSV infection presented here provides insights for the development of such a vaccine. Importantly, the results suggest that immunization of pre-immune donors with preF immunogens would be expected to boost neutralizing responses, whereas the use of postF immunogens would likely expand B cell clones with moderate or weak neutralizing activity. Similarly, immunization of RSV naïve infants with preF immunogens would be expected to activate naïve B cells targeting epitopes associated with substantially more potent neutralizing activity compared to postF immunogens. In addition, the ideal RSV vaccine should preserve antigenic sites Ø and V, since these sites are targeted by the most highly potent antibodies elicited in response to natural RSV infection.
Accordingly, disclosed herein are highly selective and potent anti-RSV antibodies, as well as highly potent cross-neutralizing anti-RSV and anti-HMPV antibodies, as well as vaccine candidates, for the treatment and or prophylaxis of RSV and/or HMPV infection. Additionally, the reagents disclosed here provide a useful set of tools for the evaluation of clinical trials, which will be critical for selecting the optimal RSV vaccination or antibody-based therapeutic strategy from the many currently under investigation (60).
TABLE 1
Antigenic sites targeted by prototypic RSV antibodies
Antigenic site Prototypic antibodies
Ø D25, 5C4, AM22 (10, 16)
I 131-2a, 2F
II 1129, palivizumab, motavisumab (6)
III MPE8 (17)
IV 101F (57), mAb 19 (19)
TABLE 2
Germline usage and sequence information of anti-RSV antibodies
VH LC Number of Number of
Antibody germline germline nucleotide nucleotide
number gene gene CDR H3 CDR L3 Lineage substitutions substitutions
Name (Ab #) usage usage Sequence Sequence number in VH in VL
ADI- 232 VH4- VK1- AGTNY QQSYSTPL 4 10 8
18875 34 39 GEVNT T
SNQYFF
GMDV
ADI- 233 VH4- VK3- ARDVG QQYGSSP 44 12 4
18876 304 20 TLVLPT LVT
VAYYY
GMDV
ADI- 234 VH1- VK2- ARESG MQAIHWP 52 9 8
18877 18 30 ATAAA RT
MFDY
ADI- 235 VH4- VK3- ARDGG QQYGASP 23 12 6
18878 304 20 YDHVW WT
GTHRY
FDK
ADI- 236 VH1- VK2- ARD VP MQGTHW 46 9 12
18879 18 30 GHGAA PPA
FMDV
ADI- 237 VH1- VK2- ARDPP MQGTHW 36 8 7
18880 18 30 AYAAT PPT
LMDV
ADI- 238 VH1- VK3- ARDAY QQYGSSF 21 19 9
18882 69 20 EVWTG LT
SYLPPF
DY
ADI- 239 VH1- VK1- ARVPES QQGTSFPF 79 30 6
18883 69 12 LVASN T
AYAV
ADI- 240 VH1-3 VK2- ARGQIV MQTLQTPI 57 8 1
18884 28 VIPRAN T
FWFDP
ADI- 241 VH4- VK3- ARDGG QQYGTSP 22 13 8
18885 304 20 YDHIW WT
GTHRY
FAL
ADI- 242 VH1- VK1-9 ARVFF QQLHSDF 76 20 8
18887 69 GTCGG QT
ASCFPS
DL
ADI- 243 VH3- VK3- ARDHA QQYGSFP 24 8 10
18888 33 20 STPYY WT
MDV
ADI- 244 VH4- VK1- AGTNV QQSYSVP 3 25 12
18889 34 39 GFVNT LT
HYYFG
MDV
ADI- 245 VH1- VK3- ARDAY QQYGSSF 21 27 10
18890 69 20 EVWTG LT
SYLPPF
DY
ADI- 246 VH1- VK3- ARDAY QQYGSSF 21 22 10
18891 69 20 EVWTG LT
SYLPPF
DY
ADI- 247 VH1- VK2- ARDSFS MQATQW 39 7 1
18892 18 30 LTGAG PRT
FPDY
ADI- 248 VH3- VL1- ARLGY QSYDLSLS 61 8 3
18893 21 40 GGNPE SSRV
LDY
ADI- 249 VH3- VL1- ARGAS QSYDSLS 54 11 5
18894 30 40 YYYVS ASWV
SDLGY
ADI- 250 VH5- VK1- ASVML QPYDNLP 84 12 1
18895 51 33 RGIM PPLT
ADI- 251 VH3- VK3- ARAPY QQYSIWP 16 10 6
18896 30 15 DIWSG QT
YCLDY
ADI- 252 VH3-7 VK4-1 ARDTP QQYYSSP 42 11 8
18897 DVLRH QT
LEWPP
VGAFDI
ADI- 253 VH1- VK2- ARESG MQAIHWP 52 9 8
18898 18 30 ATAAA RT
MFDY
ADI- 254 VH3- VK3- ARAPY QQYSIWP 16 10 6
18899 30 15 DIWSG QT
YCLDY
ADI- 255 VH3- VK1-5 ARDQE QQYYTYY 38 22 7
18900 23 VELIDD S
AFDF
ADI- 256 VH1-2 VL1- ARSSLV GTWDASL 72 18 8
18901 51 GASPNF SAAMV
DF
ADI- 257 VH4- VL3- ARSTW QVWDSSP 73 8 7
18902 59 21 DYGDH DHPYV
FPFDY
ADI- 258 VH1- VK2- ARD VP MQGTHW 46 9 12
18903 18 30 GHGAA PPA
FMDV
ADI- 259 VH1- VK2- ARDPP MQGTHW 36 8 7
18904 18 30 AYAAT PPT
LMDV
ADI- 260 VH4- VK1-5 ACKRA QQYHVYF 1 29 2
18905 39 DADDV PLT
DYVAG
LTGFP
WYFDV
ADI- 261 VH3- VK3- ARDHA QQYGSFP 24 8 10
18906 33 20 STPYY WT
MDV
ADI- 262 VH1- VK3- ARGCC QQRTTGV 55 21 7
18907 69 11 GAVAG T
FQH
ADI- 263 VH3- VL1- VRGVL QSYDYSL 98 16 7
18908 21 40 PGGTG NWV
GGWFD
s
ADI- 264 VH4- VK3- ARDLG QVYSSSPP 27 13 9
18909 304 20 KPLWD IT
GHYYY
GVDV
ADI- 265 VH1- VK2- ARTAA MQTLQTP 74 8 3
18910 69 28 LGPPGT WT
IVGYM
DV
ADI- 266 VH5- VK1- ARLGIG LQFDNLPP 60 12 7
18911 51 33 AAARN T
Y
ADI- 267 VH3- VL1- ARDLLP QSYDSRL 31 6 3
18912 21 40 VERGP GGSV
AFDI
ADI- 268 VH5- VK1- ARQIGG QQSDTTPF 67 13 6
18913 51 39 LVCSSE T
SCYFY
GMDV
ADI- 269 VH3- VL1- ATDSR QSYDDSL 86 4 3
18915 15 40 RLYDS TGWV
RGFYSS
AFDV
ADI- 270 VH5- VK1- ARQIGG QQSDTTPF 67 13 6
18916 51 39 LVCSSE T
SCYFY
GMDV
ADI- 271 VH3- VL1- VRGVL QSYDYSL 98 16 7
18917 21 40 PGDTG NWV
GGWFD
S
ADI- 272 VH5- VK3- ARLPV QQYNNW 62 8 13
18918 51 15 GSYYY LSWT
FNL
ADI- 273 VH4- VK2- ARTSY MQGLQIP 75 22 4
18919 31 28 AGRML WT
DR
ADI- 274 VH3- VL1- AKVRN GTWDTSL 12 10 14
18920 30 51 EAWEL RAGV
LGDAL
DV
ADI- 275 VH1- VK1- ATPTPV QQSYIIPY 88 15 2
18921 24 39 GATDY T
ADI- 276 VH4-b VK3- ASRRGS QQYNNWP 83 22 8
18922 15 GWFFD PGGT
S
ADI- 277 VH3- VL1- ARDWP QSYDSSLS 48 0 0
18923 21 40 NSSSSP GFYV
NWFDP
ADI- 278 VH5- VL1- ARCSLS QSYDSSLS 18 9 11
18924 51 40 CDYYG GFYV
VNL
ADI- 279 VH3- VK3- AKPIVG QQRSNWY 9 8 0
18925 30 11 PTTGYF T
DY
ADI- 280 VH1- VK2- ARDPP MQGTHGR 36 19 8
18926 18 30 ASAAA GIS
MLDY
ADI- 281 VH1-2 VK1- ASQSSP QQSFTPQF 82 21 21
18927 13 YTPGA T
LDV
ADI- 282 VH1- VL7- ARDIE LLSYSGA 25 15 8
18928 69 46 WFVLM RPV
DPITSY
YPMDV
ADI- 283 VH3- VL1- ARDAVI AAWDDSL 19 9 6
18929 11 44 WGPV NGPV
AVHYQ
YYADV
ADI- 284 VH1- VK3- ARDAY QQYGSSF 21 14 8
18930 69 20 EVWTG LT
SYLPPF
DY
ADI- 285 VH3- VK3- TRDDIL QQYDNWP 92 6 6
18931 49 15 TGFYD PYT
RSYYY
GIHV
ADI- 286 VH4- VK3- ARDLG QQRSTWP 29 25 10
18932 304 11 TLAFDP T
YYYYG
IDV
ADI- 287 VH1- VKl- ARRGY QQSYIRPI 69 26 10
18933 46 39 PDSGSY T
PLDY
ADI- 288 VH4- VK3- ARDLG QQRSNGV 30 19 6
18935 304 11 YSSSSP LT
AFYYGI
DF
ADI- 289 VH1-8 VK1- ASQSSP QLNSGAL 82 26 12
18936 39 YTPGA FT
MGV
ADI- 290 VH4- VK3- ARDVG QQYGGSP 45 25 10
18937 304 20 VYSGY PVT
DVFHY
YGMDV
ADI- 291 VH3- VK1-5 ARDLW QQYNSWA 32 15 10
18938 74 TTSPYF
DL
ADI- 292 VH4- VK1- AGTNY QQSYSAP 4 3 7
18939 34 39 GEVNT LT
SNQYFF
GMDV
ADI- 293 VH1-8 VK1- ASQSSP QLNSGAL 82 33 14
18940 39 YTPGA FT
MDV
ADI- 294 VH5- VK3- GQAVA QHYNNWP 90 7 5
18941 51 15 GGEYF RG
HH
ADI- 295 VH4- VK3- ARDLG QQRSNWP 28 19 6
18942 304 11 TANNY PYT
YFGMD
V
ADI- 296 VH4-b VK3- AGAFW QQYSSSPL 2 38 7
18943 20 EVWTG T
LYSPPF
DF
ADI- 297 VH1- VK2- ARDPA MQGTHW 34 20 8
18944 18 30 VDAIP PLT
MLDY
ADI- 298 VH3- VL2- AKEEW SSYSTNSA 7 8 3
18946 30 14 LVPAY P
ADI- 299 VH3- VK3- ARAPY QQYSIWP 16 16 7
18947 30 15 DIWSG QT
YCLDY
ADI- 300 VH3- VK3- ARAPY QQYSIWP 16 13 7
18948 30 15 DIWSG QT
YCLDY
ADI- 301 VH1- VK2- ARDPA MQGTHW 34 20 8
18949 18 30 VDAIP PLT
MLDY
ADI- 302 VH4- VK3- ATAWT QLRGHWP 85 13 2
18950 39 11 FDH PTIT
ADI- 303 VH3- VL2- AKDGL SSYRNGN 5 19 16
18951 23 14 RDVSR ALGV
VYYID
V
ADI- 304 VH3- VL2- AKDGL SSYRNGN 5 18 11
18952 23 14 RDLSR TLGV
VYYID
V
ADI- 305 VH1- VK3- ARDAY QQYGSSF 21 12 11
18953 69 20 EVWTG LT
SYLPPF
DY
ADI- 306 VH3- VK3- ARAPY QQYSIWP 16 11 6
18955 30 15 DIWSG QT
YCLDY
ADI- 307 VH1- VL2- ATRLY CSYAGRYI 89 23 10
18956 69 11 TLGSPF YV
DN
ADI- 308 VH3- VL1- ARVHV QSYDSSLS 78 12 3
18957 21 40 DLVTTI GAI
FGVDF
DF
ADI- 309 VH1- VK2- AREPPS MQGTQW 51 18 3
18958 18 30 DDAAR PVT
LFDY
ADI- 310 VH1- VK1- ATPTPV QQTYIIPY 88 18 4
18959 24 39 GATDF T
ADI- 311 VH4- VL3- AREGP QVWDTSS 50 15 5
18960 39 21 NWELL DHVV
NAFDI
ADI- 312 VH3- VL1- ARVSTE QSYDSSLS 80 1 0
18962 21 40 LGYYY W
MDV
ADI- 313 VH1-3 VK4-1 GRDWD QQYYGNF 91 14 9
18965 GAIRVL PT
DY
ADI- 314 VH3- VK2- ARDPG MQGTHW 35 13 3
18966 30 30 VGSYY PPT
NWGM
DV
ADI- 315 VH1- VK1- ATPLPA QQTYIIPY 88 23 12
18967 24 39 GALDK T
ADI- 316 VH4- VK3- TRDLG QQRTNWP 93 17 8
18968 304 11 YSTSSP IT
SFYYG
MDV
ADI- 317 VHl- VK2- ARDVF MQATDW 43 15 4
18969 18 30 SKTAA PVT
RIFDY
ADI- 318 VH4- VK3- ARDIGY QQRTNWI 26 6 9
18970 304 11 GDHGT T
GSYYY
GIED
ADI- 319 VH3- VL3- AKDRV QVWDSRS 6 17 12
18971 23 21 GWFGE EHVI
FDAFDF
ADI- 320 VH1- VK2- ARDPA MQGTHW 34 20 8
18972 18 30 VDAIP PLT
MLDY
ADI- 321 VH2- VK3- ALMRP QLYHRSP 13 18 14
18973 70 20 FWSRD GSASQTV
DYYYSI WT
AV
ADI- 322 VH1- VK2- ARDTP MQGIFRP 41 22 5
18974 18 30 ATAAP GT
LLDY
ADI- 323 VH1- VK2- ARDSG MQATEFP 40 11 3
18975 18 24 CCSGST PMYT
SDV
ADI- 324 VH4- VK1- ARDNK QQSYTTR 33 5 9
18976 31 39 HHDSG LT
NYYAY
FDH
ADI- 325 VH1-3 VK1- ARQVS QQYDNLP 68 17 6
18977 33 TSGWH LT
ATSHRF
AP
ADI- 326 VH3- VK1-5 AKSSSS QQYYNW 11 9 11
18978 30 HVNSR WT
QDK
ADI- 327 VH1- VK2- ARDSFS MQATHRP 39 11 1
18979 18 30 ETGTGF RT
PDF
ADI- 328 VH5- VK3- AKSNV QEVRNWP 10 8 9
18980 51 11 GNTGW PCT
NY
ADI- 329 VH4- VK3- ARCGN QQYGSSP 17 27 9
18981 30 20 EYGEV WT
HPFDI
ADI- 330 VH1- VK2- ARDSFS MQATHRP 39 7 1
18982 18 30 ETGTGF RT
PDF
ADI- 331 VH3- VK1- AREAY LQHNRYP 49 14 5
18983 30 17 EEWEL FT
TMGNL
DH
ADI- 332 VH4- VK1- ARGEH QQANSFP 56 29 5
18984 61 12 FAYWW RT
GN
ADI- 333 VH1-2 VK1- TSQTSP QQTYNGL 95 22 16
18985 39 YTPGA IA
MGV
ADI- 334 VH3- VL1- ARGAS QSYDSLS 54 12 5
18986 30 40 YYYVS ASWV
SDLGY
ADI- 335 VH1- VK3- ARDAY QQYGSSF 20 12 8
18987 69 20 EVWTG LT
SYLPPF
DD
ADI- 336 VH3- VL1- VREAY QSYDSSLS 97 22 6
18988 21 40 ASSSAL GWV
YWFDP
ADI- 337 VH3- VK2- ARSLGS MQALQTP 71 14 6
18989 48 28 GNYDN YT
EDQTF
YYYYG
MDV
ADI- 338 VH4- VK3- ARDLG QQRSNWP 28 19 6
18990 304 11 TANNY PYT
YFGMD
V
ADI- 339 VH4- VL3- ASGPV QVWDSST 81 22 14
18991 304 21 GMATS DYHVV
NWFDP
ADI- 340 VH1- VL1- ARAPS QSYDSSLS 15 14 7
18992 46 40 HDEWV AWV
AISRNV
VGFDA
ADI- 341 VH3- VL1- AREVLP QSYDISLS 53 10 7
18993 21 40 ATAIGG ASYV
AWLDP
ADI- 342 VH1- VL2- ARIGHV CSYVAGS 58 13 7
18994 18 23 TAVAG TSV
APPDY
ADI- 343 VH4- VL3- ASGPV QVWDSGT 81 18 12
18995 304 21 GMATS DYHVV
NWFDP
ADI- 344 VH1-2 VL1- ARSSLV GTWDASL 72 17 10
18996 51 GASPNF SAAMV
DF
ADI- 345 VH4- VK3- ARVHP QQYAYWP 77 16 9
18997 34 15 SYDFG PYT
WRFFD
F
ADI- 346 VH4- VL3- ASGPV QVWDSST 81 15 15
18998 304 21 GMATS DHHVV
NWFDP
ADI- 347 VH1- VL2- ARPNY CSYAGGL 65 13 3
18999 69 11 DILTGY YV
AFDI
ADI- 348 VH1-8 VL1- VQMDH AAWDDSL 96 10 6
19000 36 CRSTSC NVWV
SEGNW
FDT
ADI- 349 VH3- VL2-8 TRQDD SSYAGSN 94 10 7
19001 49 FWSGH DLGV
PYYFEY
ADI- 350 VH4- VK1- ARQFG QQSYSIPW 66 17 8
19002 59 39 YDKNT T
LSRLDF
DY
ADI- 351 VH4- VL3- AREGP QVWDTSS 50 15 4
19003 39 21 NWELL DHVV
NAFDI
ADI- 352 VH1- VK2- ARDPP MQGTHGR 36 19 7
19004 18 30 ASAAA GIS
MLDY
ADI- 353 VH1- VK1- ASQSSP QLNSGAL 82 21 9
19005 18 39 YTPGA FT
MGV
ADI- 354 VH3- VK3- ARAKT QRYGNSW 14 30 12
19006 11 20 SYYFY P
ALDV
ADI- 355 VH3- VK4-1 AKESL HQYYDTH 8 18 5
19007 23 DFGSGS T
YNWFD
T
ADI- 356 VH3- VK3- ARDPSL QQRSNWP 37 15 6
19008 30 11 GYNNH PMYS
YFDY
ADI- 357 VH1- VK3- ARDAY QQYGSSF 21 19 6
19009 69 20 EVWTG LT
SYLPPF
DY
ADI- 358 VH3- VL1- ARDVQ QSYDSSLS 47 0 0
19010 21 40 YSGYD ALYV
SGYYF
DY
ADI- 359 VH3- VL4- ATIRGI EAWDFNT 87 19 9
19011 30 60 VAGLC GGV
DN
ADI- 360 VH4-4 VK1- ARLSG QQSYNTV 63 12 10
19012 39 NCSGG YT
SCYSPF
DH
ADI- 361 VH5- VK1- ARPMT QQTNSFLP 64 4 2
19013 51 12 TQEGF LT
DL
ADI- 362 VH4- VK3- ARSADI QQYGTSP 70 21 10
19014 304 20 DIVWG WT
SSLYMP
L
ADI- 363 VH3- VL1- ARIGYS QSYDKSL 59 13 5
19016 21 40 SAHHY SGGYV
QYYMD
V
ADI- 364 VH1- VL3- ASQSSP QSADSSG 82 22 0
19017 18 25 YTPGA TYPW
MGV
TABLE 3
Affinity and Neutralization data for anti-RSV antibodies
Neat Neat
IC50 IC50
Antibody Prefusion Postfusion Prefusion Postfusion (ug/ml) (ug/ml)
number subtype A KD subtype A KD subtype B subtype B subtype subtype
Name (Ab #) (M)* (M)* KD (M)* KD (M)* A* B*
ADI- 232 7.36E−10 NB 7.64E−10 NB 0.040 0.035
18875
ADI- 233 7.07E−10 1.71E−09 3.16E−10 1.79E−10 0.037 0.179
18876
ADI- 234 3.03E−10 NB 3.83E−10 NB 0.410 0.130
18877
ADI- 235 4.53E−09 4.83E−10 5.82E−09 3.88E−10 >10 8.308
18878
ADI- 236 3.12E−10 NB 3.58E−10 NB 0.041 0.103
18879
ADI- 237 2.55E−10 NB 3.04E−10 NB 0.041 0.055
18880
ADI- 238 4.27E−10 NB 4.76E−10 NB 0.041 0.057
18882
ADI- 239 4.31E−10 NB 5.66E−10 NB 0.041 0.050
18883
ADI- 240 3.38E−10 NB 2.04E−10 NB 0.073 0.239
18884
ADI- 241 2.18E−09 3.84E−10 3.89E−09 3.07E−10 0.376 8.635
18885
ADI- 242 NB 7.43E−10 1.22E−08 5.49E−10 1.110 >10
18887
ADI- 243 NB 2.54E−08 NB 1.16E−09 >10 >10
18888
ADI- 244 5.54E−10 NB 5.87E−10 NB 0.040 0.019
18889
ADI- 245 4.89E−10 NB 4.58E−10 NB 0.041 0.041
18890
ADI- 246 5.34E−10 NB 5.13E−10 NB 0.012 0.026
18891
ADI- 247 2.17E−10 NB 2.53E−10 NB 0.018 0.117
18892
ADI- 248 2.45E−10 NB 2.78E−10 NB 0.123 0.182
18893
ADI- 249 2.54E−09 NB 3.27E−10 NB 0.345 0.123
18894
ADI- 250 NB 2.37E−09 NB 4.86E−10 2.303 >10
18895
ADI- 251 2.27E−09 2.79E−10 1.81E−09 2.70E−10 1.100 4.722
18896
ADI- 252 1.47E−09 2.19E−10 1.53E−09 1.85E−10 0.288 0.762
18897
ADI- 253 3.05E−10 NB 3.25E−10 NB 0.030 0.097
18898
ADI- 254 1.92E−09 2.66E−10 1.59E−09 2.51E−10 0.742 2.700
18899
ADI- 255 1.19E−09 NB 3.31E−10 NB 0.035 0.059
18900
ADI- 256 2.17E−09 NB NB NB 5.646 5.762
18901
ADI- 257 1.07E−10 NB 1.01E−10 NB 0.024 0.150
18902
ADI- 258 3.24E−10 NB 2.72E−10 NB 0.036 0.118
18903
ADI- 259 2.51E−10 NB 2.37E−10 NB 0.018 0.089
18904
ADI- 260 3.38E−09 NB NB NB 0.685 3.676
18905
ADI- 261 NB 2.33E−08 NB 1.10E−09 >10 >10
18906
ADI- 262 1.74E−10 NB 2.04E−10 NB 3.300 >10
18907
ADI- 263 3.02E−10 NB 3.52E−10 NB 0.018 0.095
18908
ADI- 264 5.08E−10 5.81E−10 2.88E−10 2.25E−10 0.110 0.169
18909
ADI- 265 4.67E−09 NB 1.06E−08 NB >10 0.767
18910
ADI- 266 NB 3.53E−10 NB 2.80E−10 0.301 4.853
18911
ADI- 267 2.58E−10 NB 2.86E−10 NB 0.024 0.061
18912
ADI- 268 5.68E−10 NB 4.71E−10 NB <0.01 <0.01
18913
ADI- 269 2.81E−08 NB 4.21E−10 NB 1.199 0.021
18915
ADI- 270 5.85E−10 NB 4.65E−10 NB <0.01 <0.01
18916
ADI- 271 3.56E−10 NB 3.32E−10 NB 0.024 0.091
18917
ADI- 272 NB 5.67E−10 NB 4.09E−10 0.377 4.590
18918
ADI- 273 2.02E−10 NB 1.63E−10 NB 0.123 0.261
18919
ADI- 274 6.78E−10 NB 9.77E−11 NB 0.041 0.049
18920
ADI- 275 5.75E−09 NB NB NB 1.703 1.172
18921
ADI- 276 3.47E−09 3.22E−10 5.27E−09 2.87E−10 >10 5.051
18922
ADI- 277 5.17E−10 NB 1.79E−09 NB 0.078 0.147
18923
ADI- 278 6.48E−09 4.11E−10 NB 3.21E−10 0.572 1.073
18924
ADI- 279 4.99E−09 NB NB NB >10 >10
18925
ADI- 280 2.52E−10 NB 2.50E−10 NB 0.023 0.092
18926
ADI- 281 3.58E−09 NB 2.99E−09 NB 0.022 0.067
18927
ADI- 282 4.49E−10 NB 5.15E−10 NB 0.034 0.062
18928
ADI- 283 1.61E−09 NB NB NB 0.261 0.369
18929
ADI- 284 3.87E−10 NB 3.72E−10 NB 0.013 0.051
18930
ADI- 285 5.65E−10 NB 4.88E−10 NB >10 >10
18931
ADI- 286 9.17E−10 NB 1.39E−09 NB 0.184 0.351
18932
ADI- 287 NB 2.00E−08 NB 6.16E−10 0.075 0.137
18933
ADI- 288 6.60E−10 NB 5.82E−10 NB 0.779 0.355
18935
ADI- 289 3.03E−10 NB 2.98E−10 NB 0.032 0.035
18936
ADI- 290 2.89E−10 NB 2.73E−10 NB 0.084 0.508
18937
ADI- 291 1.65E−10 2.16E−10 1.50E−10 1.68E−10 0.837 4.255
18938
ADI- 292 5.74E−10 NB 5.60E−10 NB 0.018 0.038
18939
ADI- 293 1.12E−09 NB 1.56E−09 NB 0.023 0.063
18940
ADI- 294 NB 1.91E−08 NB 6.45E−10 >10 >10
18941
ADI- 295 8.65E−10 2.81E−10 5.12E−10 2.58E−10 0.374 0.614
18942
ADI- 296 6.46E−10 NB 7.25E−10 NB 0.027 0.043
18943
ADI- 297 3.09E−10 NB 3.37E−10 NB 0.026 0.074
18944
ADI- 298 1.58E−10 2.06E−10 1.57E−10 1.66E−10 0.093 0.227
18946
ADI- 299 2.45E−09 2.96E−10 2.20E−09 2.82E−10 1.299 3.602
18947
ADI- 300 4.55E−09 2.57E−10 2.10E−09 2.47E−10 1.123 4.346
18948
ADI- 301 3.07E−10 NB 3.08E−10 NB 0.040 0.076
18949
ADI- 302 1.13E−09 3.93E−10 4.18E−09 3.85E−10 >10 >10
18950
ADI- 303 7.52E−10 1.29E−09 5.35E−09 1.13E−09 3.398 >10
18951
ADI- 304 7.15E−10 7.29E−10 1.01E−09 6.33E−10 1.589 2.745
18952
ADI- 305 5.13E−10 NB 4.21E−10 NB 0.034 0.022
18953
ADI- 306 5.99E−10 2.56E−10 2.37E−09 2.50E−10 1.933 3.116
18955
ADI- 307 1.82E−10 NB 2.24E−10 NB >10 >10
18956
ADI- 308 4.69E−10 NB 3.24E−10 NB 1.339 6.084
18957
ADI- 309 2.86E−10 NB 3.02E−10 NB 0.587 3.364
18958
ADI- 310 4.68E−09 NB NB NB 7.214 2.258
18959
ADI- 311 1.78E−10 NB 1.83E−10 NB 0.034 0.107
18960
ADI- 312 8.83E−09 NB 2.28E−08 NB 4.439 >10
18962
ADI- 313 NB NB NB 3.023 6.892
18965
ADI- 314 5.78E−10 NB 5.62E−10 NB 0.044 0.130
18966
ADI- 315 8.09E−10 NB NB NB 6.737 3.651
18967
ADI- 316 1.98E−09 4.38E−10 6.02E−10 3.05E−10 0.909 0.541
18968
ADI- 317 3.03E−10 NB 2.97E−10 NB 0.035 0.187
18969
ADI- 318 1.04E−08 6.84E−09 4.45E−10 4.12E−10 >10 0.333
18970
ADI- 319 1.57E−10 NB 1.68E−10 NB 0.039 0.114
18971
ADI- 320 2.98E−10 NB 3.68E−10 NB 0.016 0.107
18972
ADI- 321 3.78E−09 4.95E−10 2.63E−09 3.94E−10 9.605 6.273
18973
ADI- 322 2.53E−10 NB 2.90E−10 NB 0.030 0.105
18974
ADI- 323 2.67E−10 NB 2.98E−10 NB 0.037 0.174
18975
ADI- 324 4.03E−09 2.36E−09 1.24E−09 2.09E−10 6.290 10.600
18976
ADI- 325 7.86E−10 NB 9.66E−10 NB 0.108 0.117
18977
ADI- 326 3.00E−09 NB NB NB >10 >10
18978
ADI- 327 1.89E−10 NB 1.84E−10 NB 0.012 0.031
18979
ADI- 328 NB 5.33E−10 NB 3.50E−10 3.599 >10
18980
ADI- 329 1.53E−09 3.53E−10 1.15E−09 2.80E−10 >10 >10
18981
ADI- 330 1.92E−10 7.65E−10 1.95E−10 7.47E−10 0.018 0.053
18982
ADI- 331 1.71E−09 NB 5.81E−10 NB 0.028 0.075
18983
ADI- 332 1.29E−08 8.03E−10 6.08E−09 6.59E−10 >10 >10
18984
ADI- 333 5.66E−10 NB 1.70E−09 NB 0.034 0.090
18985
ADI- 334 2.68E−09 NB 2.38E−10 NB 0.464 0.123
18986
ADI- 335 4.49E−10 NB 5.24E−10 NB 0.015 0.027
18987
ADI- 336 2.93E−10 NB 3.70E−10 NB 0.089 0.370
18988
ADI- 337 3.51E−09 3.56E−10 3.92E−09 3.77E−10 >10 >10
18989
ADI- 338 8.90E−10 2.94E−10 4.91E−10 2.52E−10 0.580 0.845
18990
ADI- 339 1.35E−10 1.52E−10 0.028 0.228
18991
ADI- 340 7.66E−10 1.53E−09 9.69E−10 9.07E−10 2.546 5.692
18992
ADI- 341 2.55E−10 NB 2.77E−10 NB 0.078 0.128
18993
ADI- 342 3.10E−10 NB 3.31E−10 NB 0.047 0.108
18994
ADI- 343 1.20E−10 1.23E−08 1.27E−10 0.043 0.125
18995
ADI- 344 2.52E−09 NB 3.60E−09 NB >10 >10
18996
ADI- 345 5.01E−09 NB 5.32E−09 NB >10 >10
18997
ADI- 346 1.57E−10 1.24E−08 1.72E−10 NB 0.055 0.458
18998
ADI- 347 5.92E−10 1.67E−10 1.02E−09 1.41E−10 1.805 6.465
18999
ADI- 348 1.10E−10 1.75E−10 1.04E−10 1.28E−10 0.037 0.129
19000
ADI- 349 1.07E−09 1.93E−10 1.06E−09 1.49E−10 >10 3.259
19001
ADI- 350 1.63E−09 NB NB NB 2.886 4.507
19002
ADI- 351 1.61E−10 NB 1.68E−10 NB 0.047 0.125
19003
ADI- 352 2.28E−10 NB 2.73E−10 NB 0.020 0.128
19004
ADI- 353 9.63E−10 NB 9.64E−10 NB 0.041 0.110
19005
ADI- 354 1.75E−09 NB NB NB 4.891 5.059
19006
ADI- 355 6.18E−10 9.69E−10 6.08E−10 4.57E−10 0.208 0.370
19007
ADI- 356 3.63E−09 NB NB NB 8.293 >10
19008
ADI- 357 4.42E−10 NB 4.66E−10 NB 0.062 0.066
19009
ADI- 358 6.04E−09 NB 2.84E−09 NB >10 0.650
19010
ADI- 359 2.15E−09 NB NB NB >10 6.237
19011
ADI- 360 2.89E−09 3.04E−10 1.14E−09 3.14E−10 >10 >10
19012
ADI- 361 NB 1.61E−08 NB 5.83E−10 9.504 >10
19013
ADI- 362 2.82E−09 3.59E−10 2.21E−09 2.77E−10 1.745 >10
19014
ADI- 363 NB NB NB NB 0.052 0.092
19016
ADI- 364 1.10E−08 NB 7.20E−09 NB 1.562 0.795
19017
*NN; non-neutralizing, NB; non-binding, ND; not determined. IgG KDs were calculated for antibodies with BLI binding responses >0.1 nm. Antibodies with BLI binding responses <0.05 nm were designated as NB.
TABLE 4
Bin, patch, and antigenic site assignments for anti-RSV antibodies
Antibody Antigenic
number Bin Patch Site
Name (Ab #) Assignment Assignment Assignment
ADI-18875 232 D25 1, 2 Ø
ADI-18876 233 Mota 5 II
ADI-18877 234 D25/mota/MPE8 4 V
ADI-18878 235 101F/13390
ADI-18879 236 D25/mota/MPE8 4 V
ADI-18880 237 D25/mota/MPE8 4 V
ADI-18882 238 D25 1, 2 Ø
ADI-18883 239 D25 4 V
ADI-18884 240 14469 I
ADI-18885 241 101F/13390
ADI-18887 242 Mota/13390
ADI-18888 243 Mota/101F/13390
ADI-18889 244 D25 1, 2 Ø
ADI-18890 245 D25 2 Ø
ADI-18891 246 D25 2, 1 Ø
ADI-18892 247 Mota/MPE8 4 V
ADI-18893 248 Mota/MPE8 III
ADI-18894 249 D25
ADI-18895 250 Unknown
ADI-18896 251 101F/13390
ADI-18897 252 Mota/101F/13390 III
ADI-18898 253 D25/mota/MPE8 4 V
ADI-18899 254 101F/13390 I
ADI-18900 255 D25 1 Ø
ADI-18901 256 Unknown
ADI-18902 257 14443 9 IV
ADI-18903 258 D25/mota/MPE8 4, 3 V
ADI-18904 259 D25/mota/MPE8 4 V
ADI-18905 260 MPE8
ADI-18906 261 Mota/101F/13390
ADI-18907 262 UK
ADI-18908 263 Mota/MPE8 III
ADI-18909 264 Mota 5 II
ADI-18910 265 Unknown
ADI-18911 266 Mota
ADI-18912 267 Mota/MPE8 III
ADI-18913 268 D25 1 Ø
ADI-18915 269 D25/mota
ADI-18916 270 D25 1 Ø
ADI-18917 271 Mota/MPE8 III
ADI-18918 272 Mota
ADI-18919 273 UK
ADI-18920 274 101F 9 IV
ADI-18921 275 101F
ADI-18922 276 Mota
ADI-18923 277 Mota/MPE8/101F III
ADI-18924 278 Unknown
ADI-18925 279 101F
ADI-18926 280 D25/mota/MPE8 4 V
ADI-18927 281 D25/mota
ADI-18928 282 D25 1, 2 Ø
ADI-18929 283 101F 1 UK
ADI-18930 284 D25 1, 2 Ø
ADI-18931 285 101F IV
ADI-18932 286 Mota 5 II
ADI-18933 287 Unknown
ADI-18935 288 Mota 6, 5 III
ADI-18936 289 D25/mota 4 V
ADI-18937 290 Mota 5 II
ADI-18938 291 Mota/101F III
ADI-18939 292 D25 9 Ø
ADI-18940 293 D25/mota 1, 2 V
ADI-18941 294 Mota
ADI-18942 295 Mota II
ADI-18943 296 D25 5 UK
ADI-18944 297 D25/mota/MPE8 1, 2 V
ADI-18946 298 101F 4 IV
ADI-18947 299 101F/13390
ADI-18948 300 101F/13390
ADI-18949 301 D25/mota/MPE8 4 V
ADI-18950 302 13390 I
ADI-18951 303 Mota/13390 III
ADI-18952 304 Mota/13390 III
ADI-18953 305 D25 2 Ø
ADI-18955 306 101F/13390 I
ADI-18956 307 14469 I
ADI-18957 308 Mota/MPE8 III
ADI-18958 309 Mota 4 V
ADI-18959 310 14443
ADI-18960 311 14469 9 IV
ADI-18962 312 Mota/MPE8
ADI-18965 313 Unknown
ADI-18966 314 D25/mota/MPE8 4 V
ADI-18967 315 101F 9 IV
ADI-18968 316 Mota 5 II
ADI-18969 317 D25/mota/MPE8 4 V
ADI-18970 318 Mota/MPE8
ADI-18971 319 14469 9 IV
ADI-18972 320 D25/mota/MPE8 4 V
ADI-18973 321 13390
ADI-18974 322 D25/mota/MPE8 4 V
ADI-18975 323 D25/mota/MPE8 4 V
ADI-18976 324 13390
ADI-18977 325 D25/mota 4 V
ADI-18978 326 14469
ADI-18979 327 Mota/MPE8 4 V
ADI-18980 328 Mota
ADI-18981 329 101F/13390 I
ADI-18982 330 Mota/MPE8 4 V
ADI-18983 331 101F 3, 9 Q
ADI-18984 332 13390
ADI-18985 333 D25/mota 4 V
ADI-18986 334 D25
ADI-18987 335 D25 Ø
ADI-18988 336 Mota/MPE8 III
ADI-18989 337 101F/13390
ADI-18990 338 Mota 5 II
ADI-18991 339 14443 9 IV
ADI-18992 340 101F IV
ADI-18993 341 Mota/MPE8 III
ADI-18994 342 Mota/MPE8 III
ADI-18995 343 14443 IV
ADI-18996 344 Unknown
ADI-18997 345 D25/mota
ADI-18998 346 14443 9 IV
ADI-18999 347 101F 9 IV
ADI-19000 348 14443 9 IV
ADI-19001 349 101F/13390 I
ADI-19002 350 Unknown UK
ADI-19003 351 14469 9 IV
ADI-19004 352 D25/mota/MPE8 4 V
ADI-19005 353 D25/mota V
ADI-19006 354 Unknown UK
ADI-19007 355 Mota/MPE8 5 II
ADI-19008 356 Unknown
ADI-19009 357 D25 1 Ø
ADI-19010 358 Mota/MPE8
ADI-19011 359 Unknown
ADI-19012 360 13390
ADI-19013 361 Unknown
ADI-19014 362 101F/13390
ADI-19016 363 Mota/MPE8
ADI-19017 364 D25/mota
TABLE 5
A subset of anti-RSV F antibodies cross-neutralize human metapneumovirus.
Antibody Prefusion Postfusion RSV F
number HMPV-A1 RSV-A2 IC50 RSV F KD RSV F KD Binding
Name (Ab#) IC50 (μg/ml) (μg/ml) (M) (M) Site
ADI- 6.1 2.5 7.6 × 10−10 1.5 × 10−9 IV*
18992
MPE8 N/A 0.07 0.04 — — —
Control
N/A, not applicable
*Binding site assignment based on competition only.
Materials and Methods Study Design To profile the antibody response to RSV F, peripheral blood mononuclear cells were obtained from a adult donor approximately between 20-35 years of age, and monoclonal antibodies from RSV F-reactive B cells were isolated therefrom. The antibodies were characterized by sequencing, binding, epitope mapping, and neutralization assays. All samples for this study were collected with informed consent of volunteers. This study was unblinded and not randomized. At least two independent experiments were performed for each assay.
Generation of RSV F Sorting Probes The soluble prefusion and postfusion probes were based on the RSV F ΔFP and DS-Cav1 constructs that we previously crystallized and determined to be in the pre- and postfusion conformations, respectively (11, 15). To increase the avidity of the probes and to uniformly orient the RSV F proteins, the trimeric RSV F proteins were coupled to tetrameric streptavidin through biotinylation of a C-terminal AviTag. For each probe, both a C-terminal His-Avi tagged version and a C-terminal StrepTagII version were co-transfected into FreeStyle 293-F cells. The secreted proteins were purified first over Ni-NTA resin to remove trimers lacking the His-Avi tag. The elution from the Ni-NTA purification was then purified over Strep-Tactin resin. Due to the low avidity of a single StrepTagII for the Strep-Tactin resin, additional washing steps were able to remove singly StrepTagged trimers. This resulted in the purification of trimers containing two StrepTagII tagged monomers and therefore only one His-Avi tagged monomer. This purification scheme results in a single AviTag per trimer which greatly reduces the aggregation or ‘daisy-chaining’ that occurs when trimeric proteins containing three AviTags are incubated with tetrameric streptavidin. RSV F trimers were biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromotography on a Superdex 200 column (GE Healthcare). Quantification of the number of biotin moieties per RSV F trimer was performed using the Quant*Tag Biotin Kit per the manufacturer's instructions (Vector Laboratories).
Single B-Cell Sorting Peripheral blood mononuclear cells were stained using anti-human IgG (BV605), IgA (FITC), CD27 (BV421), CD8 (PerCP-Cy5.5), CD14 (PerCP-Cy5.5), CD19 (PECy7), CD20 (PECy7) and a mixture of dual-labeled DS-Cav1 and F ΔFP tetramers (50 nM each). Dual-labeled RSV F tetramers were generated by incubating the individual AviTagged RSV F proteins with premium-grade phycoerythrin-labeled streptavidin (Molecular Probes) or premium-grade allophycocyanin-labeled streptavidin for at least 20 minutes on ice at a molar ratio of 4:1. Tetramers were prepared fresh for each experiment. Single cells were sorted on a BD fluorescence-activated cell sorter Aria II into 96-well PCR plates (BioRad) containing 20 μL/well of lysis buffer [5 μL of 5×first strand cDNA buffer (Invitrogen), 0.25 μL RNaseOUT (Invitrogen), 1.25 μL dithiothreitol (Invitrogen), 0.625 μL NP-40 (New England Biolabs), and 12.6 μL dH2O]. Plates were immediately frozen on dry ice before storage at −80° C.
Amplification and Cloning of Antibody Variable Genes Single B cell PCR was performed as described previously (22). Briefly, IgH, Igλ and Igκ variable genes were amplified by RT-PCR and nested PCR reactions using cocktails of IgG and IgA-specific primers (22). The primers used in the second round of PCR contained 40 base pairs of 5′ and 3′ homology to the cut expression vectors to allow for cloning by homologous recombination into Saccharomyces cerevisiae (40). PCR products were cloned into S. cerevisiae using the lithium acetate method for chemical transformation (41). Each transformation reaction contained 20 μL of unpurified heavy chain and light chain PCR product and 200 ng of cut heavy and light chain plasmids. Following transformation, individual yeast colonies were picked for sequencing and characterization.
Expression and Purification of IgGs and Fab Fragments Anti-RSV F IgGs were expressed in S. cerevisiae cultures grown in 24-well plates, as described previously (23). Fab fragments used for competition assays were generated by digesting the IgGs with papain for 2 h at 30° C. The digestion was terminated by the addition of iodoacetamide, and the Fab and Fc mixtures were passed over Protein A agarose to remove Fc fragments and undigested IgG. The flowthrough of the Protein A resin was then passed over CaptureSelect™ IgG-CH1 affinity resin (ThermoFischer Scientific), and eluted with 200 mM acetic acid/50 mM NaCl pH 3.5 into ⅛th volume 2M Hepes pH 8.0. Fab fragments then were buffer-exchanged into PBS pH 7.0.
Biolayer Interferometry Binding Analysis IgG binding to DS-Cav1 and FΔ FP was determined by BLI measurements using a ForteBio Octet HTX instrument (Pall Life Sciences). For high-throughput KD screening, IgGs were immobilized on AHQ sensors (Pall Life Sciences) and exposed to 100 nM antigen in PBS containing 0.1% BSA (PBSF) for an association step, followed by a dissociation step in PBSF buffer. Data was analyzed using the FortéBio Data Analysis Software 7. The data was fit to a 1:1 binding model to calculate an association and dissociation rate, and KD was calculated using the ratio kd/ka.
Antibody Competition Assays Antibody competition assays were performed as previously described (23). Antibody competition was measured by the ability of a control anti-RSV F Fab to inhibit binding of yeast surface-expressed anti-RSV F IgGs to either DS-Cav1 or FΔ FP. 50 nM biotinylated DS-Cav1 or FΔ FP was pre-incubated with 1 μM competitor Fab for 30 min at room temperature and then added to a suspension of yeast expressing anti-RSV F IgG. Unbound antigen was removed by washing with PBS containing 0.1% BSA (PBSF). After washing, bound antigen was detected using streptavidin Alexa Fluor 633 at a 1:500 dilution (Life Technologies) and analyzed by flow cytometry using a FACSCanto II (BD Biosciences). The level of competition was assessed by measuring the fold reduction in antigen binding in the presence of competitor Fab relative to an antigen-only control. Antibodies were considered competitors when a greater than five-fold reduction was observed in the presence of control Fab relative to an antigen-only control.
Expression, Purification and Biotinylation of preF Patch Variants
A panel of 9 patches of 2-4 mutations uniformly covering the surface of the preF molecule was designed based on the structure of prefusion RSV F (10). For known antigenic sites, including those recognized by motavizumab, 101F, D25, AM14 and MPE8, patches incorporated residues associated with viral escape or known to be critical for antibody binding. Residues with high conservation across 184 subtype A, subtype B and bovine RSV F sequences were avoided where possible to minimize the likelihood of disrupting protein structure. The mutations present in each patch variant are shown in FIG. 7A. Mutations for each patch variant were cloned into the prefusion stabilized RSV F (DS-Cav1) construct with a C-terminal AviTag for site specific biotinylation. Proteins were secreted from FreeStyle 293-F cells, purified over Ni-NTA resin and biotinylated using biotin ligase BirA according to the manufacturer's instructions (Avidity, LLC). Biotinylated proteins were separated from excess biotin by size-exclusion chromotography on a Superdex 200 column (GE Healthcare). A deglycosylated version of DS-Cav1 was produced by expressing DS-Cav1 in the presence of 1 μM kifunensine and digesting with 10% (wt/wt) EndoH before biotinylation.
Luminex Assay for Patch Variant Binding Binding of isolated antibodies to the patch variants was determined using a high-throughput Luminex assay. Each biotinylated variant and a DS-Cav1 control were coupled to avidin coated MagPlex beads (Bio-Rad), each with a bead identification number reflecting a unique ratio of red and infrared dyes embedded within the bead. The coupled beads were then mixed with a six-fold serial dilution of each antibody, ranging from 400 nM to 1.4 μM, in a 384-well plate. Beads were washed using a magnetic microplate washer (BioTek) before incubation with a PE conjugated mouse anti-human IgG Fc secondary antibody (Southern Biotech). Beads were classified and binding of PE was measured using a FLEXMAP 3D flow cytometer (Luminex).
RSV Neutralization Assays Viral stocks were prepared and maintained as previously described (61). Recombinant mKate-RSV expressing prototypic subtype A (strain A2) and subtype B (18537) F genes and the Katushka fluorescent protein were constructed as reported by Hotard et al. (62). HEp-2 cells were maintained in Eagle's minimal essential medium containing 10% fetal bovine serum supplemented with glutamine, penicillin and streptomycin. Antibody neutralization was measured by a fluorescence plate reader neutralization assay (15). A 30 μL solution of culture media containing 2.4×104 HEp-2 cells was seeded in 384-well black optical bottom plate (Nunc, Thermo Scientific). IgG samples were serially diluted four-fold from 1:10 to 1:163840 and an equal volume of recombinant mKate-RSV A2 was added. Samples were mixed and incubated at 37° C. for one hour. After incubation, 50 μL mixture of sample and virus was added to cells in 384-well plate, and incubated at 37° C. for 22-24 hours. The assay plate was then measured for fluorescence intensity in a microplate reader at Ex 588 nm and Em 635 nm (SpectraMax Paradigm, molecular devices). IC50 of neutralization for each sample was calculated by curve fitting using Prism (GraphPad Software Inc.).
Human Metapneumovirus Neutralization Assays Predetermined amounts of GFP-expressing hMPV recombinant virus (NL/1/00, A1 sublineage, a kind gift of Bernadette van den Hoogen and Ron Fouchier, Rotterdam, the Netherlands) were mixed with serial dilutions of monoclonal antibodies before being added to cultures of Vero-118 cells growing in 96-well plates with Dulbecco's Modified Eagle's medium supplemented with 10% fetal calf serum. Thirty-six hours later, the medium was removed, PBS was added and the amount of GFP per well was measured with a Tecan microplate reader M200. Fluorescence values were represented as percent of a virus control without antibody.
Polyreactivity Assay Antibody polyreactivity was assessed using a previously described high-throughput assay that measures binding to solubilized CHO cell membrane preparations (SMPs) (43). Briefly, two million IgG-presenting yeast were transferred into a 96-well assay plate and pelleted to remove the supernatant. The pellet was resuspended in 50 μL of 1:10 diluted stock b-SMPs and incubated on ice for 20 minutes. Cells were then washed twice with ice-cold PBSF and the cell pellet was re-suspended in 50 μL of secondary labeling mix (Extravidin-R-PE, anti-human LCFITC, and propidium iodide). The mix was incubated on ice for 20 minutes followed by two washes with ice-cold PBSF. Cells were then re-suspended in 100 μL of ice-cold PBSF, and the plate was run on a FACSCanto II (BD Biosciences) using a HTS sample injector. Flow cytometry data was analyzed for mean fluorescence intensity in the R-PE channel and normalized to proper controls in order to assess non-specific binding.
REFERENCES AND NOTES
- 1. A. L. Rogovik, B. Carleton, A. Solimano, R. D. Goldman, Palivizumab for the prevention of respiratory syncytial virus infection. Can Fam Physician 56, 769-772 (2010).
- 2. B. S. Graham, Biological challenges and technological opportunities for respiratory syncytial virus vaccine development. Immunol Rev 239, 149-166 (2011).
- 3. J. R. Groothuis, E. A. Simoes, V. G. Hemming, Respiratory syncytial virus (RSV) infection in preterm infants and the protective effects of RSV immune globulin (RSVIG). Respiratory Syncytial Virus Immune Globulin Study Group. Pediatrics 95, 463-467 (1995).
- 4. M. Magro, V. Mas, K. Chappell, M. Vazquez, O. Cano, D. Luque, M. C. Terron, J. A. Melero, C. Palomo, Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc Natl Acad Sci USA 109, 3089-3094 (2012).
- 5. S. Johnson, C. Oliver, G. A. Prince, V. G. Hemming, D. S. Pfarr, S. C. Wang, M. Dormitzer, J. O'Grady, S. Koenig, J. K. Tamura, R. Woods, G. Bansal, D. Couchenour, E. Tsao, W. C. Hall, J. F. Young, Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 176, 1215-1224 (1997).
- 6. J. A. Beeler, K. van Wyke Coelingh, Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol 63, 2941-2950 (1989).
- 7. R. A. Karron, D. A. Buonagurio, A. F. Georgiu, S. S. Whitehead, J. E. Adamus, M. L. Clements-Mann, D. O. Harris, V. B. Randolph, S. A. Udem, B. R. Murphy, M. S. Sidhu, Respiratory syncytial virus (RSV) SH and G proteins are not essential for viral replication in vitro: clinical evaluation and molecular characterization of a cold-passaged, attenuated RSV subgroup B mutant. Proc Natl Acad Sci USA 94, 13961-13966 (1997).
- 8. J. O. Ngwuta, M. Chen, K. Modjarrad, M. G. Joyce, M. Kanekiyo, A. Kumar, H. M. Yassine, S. M. Moin, A. M. Killikelly, G. Y. Chuang, A. Druz, I. S. Georgiev, E. J. Rundlet, M. Sastry, G. B. Stewart-Jones, Y. Yang, B. Zhang, M. C. Nason, C. Capella, M. E. Peeples, J. E. Ledgerwood, J. S. McLellan, P. D. Kwong, B. S. Graham, Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med 7, 309ra162 (2015).
- 9. T. I.-R. S. Group, Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102, 531-537 (1998).
- 10. J. S. McLellan, M. Chen, S. Leung, K. W. Graepel, X. Du, Y. Yang, T. Zhou, U. Baxa, E. Yasuda, T. Beaumont, A. Kumar, K. Modjarrad, Z. Zheng, M. Zhao, N. Xia, P. D. Kwong, B. S. Graham, Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340, 1113-1117 (2013).
- 11. J. S. McLellan, Y. Yang, B. S. Graham, P. D. Kwong, Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol 85, 7788-7796 (2011).
- 12. K. A. Swanson, E. C. Settembre, C. A. Shaw, A. K. Dey, R. Rappuoli, C. W. Mandl, P. R. Dormitzer, A. Carfi, Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. Proc Natl Acad Sci USA 108, 9619-9624 (2011).
- 13. L. Liljeroos, M. A. Krzyzaniak, A. Helenius, S. J. Butcher, Architecture of respiratory syncytial virus revealed by electron cryotomography. Proc Natl Acad Sci USA 110, 11133-11138 (2013).
- 14. A. Krarup, D. Truan, P. Furmanova-Hollenstein, L. Bogaert, P. Bouchier, I. J. Bisschop, M. N. Widjojoatmodjo, R. Zahn, H. Schuitemaker, J. S. McLellan, J. P. Langedijk, A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism. Nat Commun 6, 8143 (2015).
- 15. J. S. McLellan, M. Chen, M. G. Joyce, M. Sastry, G. B. Stewart-Jones, Y. Yang, B. Zhang, L. Chen, S. Srivatsan, A. Zheng, T. Zhou, K. W. Graepel, A. Kumar, S. Moin, J. C. Boyington, G. Y. Chuang, C. Soto, U. Baxa, A. Q. Bakker, H. Spits, T. Beaumont, Z. Zheng, N. Xia, S. Y. Ko, J. P. Todd, S. Rao, B. S. Graham, P. D. Kwong, Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592-598 (2013).
- 16. M. J. Kwakkenbos, S. A. Diehl, E. Yasuda, A. Q. Bakker, C. M. van Geelen, M. V. Lukens, G. M. van Bleek, M. N. Widjojoatmodjo, W. M. Bogers, H. Mei, A. Radbruch, F. A. Scheeren, H. Spits, T. Beaumont, Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med 16, 123-128 (2010).
- 17. D. Corti, S. Bianchi, F. Vanzetta, A. Minola, L. Perez, G. Agatic, B. Guarino, C. Silacci, J. Marcandalli, B. J. Marsland, A. Piralla, E. Percivalle, F. Sallusto, F. Baldanti, A. Lanzavecchia, Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 501, 439-443 (2013).
- 18. M. Magro, D. Andreu, P. Gomez-Puertas, J. A. Melero, C. Palomo, Neutralization of human respiratory syncytial virus infectivity by antibodies and low-molecular-weight compounds targeted against the fusion glycoprotein. J Virol 84, 7970-7982 (2010).
- 19. G. Taylor, E. J. Stott, J. Furze, J. Ford, P. Sopp, Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies. J Gen Virol 73 (Pt 9), 2217-2223 (1992).
- 20. L. J. Calder, L. Gonzalez-Reyes, B. Garcia-Barreno, S. A. Wharton, J. J. Skehel, D. C. Wiley, J. A. Melero, Electron microscopy of the human respiratory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies. Virology 271, 122-131 (2000).
- 21. M. S. Gilman, S. M. Moin, V. Mas, M. Chen, N. K. Patel, K. Kramer, Q. Zhu, S. C. Kabeche, A. Kumar, C. Palomo, T. Beaumont, U. Baxa, N. D. Ulbrandt, J. A. Melero, B. S. Graham, J. S. McLellan, Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. PLoS Pathog 11, e1005035 (2015).
- 22. M. G. Joyce, A. K. Wheatley, P. V. Thomas, G. Y. Chuang, C. Soto, R. T. Bailer, A. Druz, I. S. Georgiev, R. A. Gillespie, M. Kanekiyo, W. P. Kong, K. Leung, S. N. Narpala, M. S. Prabhakaran, E. S. Yang, B. Zhang, Y. Zhang, M. Asokan, J. C. Boyington, T. Bylund, S. Darko, C. R. Lees, A. Ransier, C. H. Shen, L. Wang, J. R. Whittle, X. Wu, H. M. Yassine, C. Santos, Y. Matsuoka, Y. Tsybovsky, U. Baxa, J. C. Mullikin, K. Subbarao, D. C. Douek, B. S. Graham, R. A. Koup, J. E. Ledgerwood, M. Roederer, L. Shapiro, P. D. Kwong, J. R. Mascola, A. B. McDermott, Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses. Cell 166, 609-623 (2016).
- 23. J. Truck, M. N. Ramasamy, J. D. Galson, R. Rance, J. Parkhill, G. Lunter, A. J. Pollard, D. F. Kelly, Identification of antigen-specific B cell receptor sequences using public repertoire analysis. J Immunol 194, 252-261 (2015).
- 24. P. Parameswaran, Y. Liu, K. M. Roskin, K. K. Jackson, V. P. Dixit, J. Y. Lee, K. L. Artiles, S. Zompi, M. J. Vargas, B. B. Simen, B. Hanczaruk, K. R. McGowan, M. A. Tariq, N. Pourmand, D. Koller, A. Balmaseda, S. D. Boyd, E. Harris, A. Z. Fire, Convergent antibody signatures in human dengue. Cell host & microbe 13, 691-700 (2013).
- 25. K. J. Jackson, Y. Liu, K. M. Roskin, J. Glanville, R. A. Hoh, K. Seo, E. L. Marshall, T. C. Gurley, M. A. Moody, B. F. Haynes, E. B. Walter, H. X. Liao, R. A. Albrecht, A. Garcia-Sastre, J. Chaparro-Riggers, A. Rajpal, J. Pons, B. B. Simen, B. Hanczaruk, C. L. Dekker, J. Laserson, D. Koller, M. M. Davis, A. Z. Fire, S. D. Boyd, Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements. Cell host & microbe 16, 105-114 (2014).
- 26. F. W. Henderson, A. M. Collier, W. A. Clyde, Jr., F. W. Denny, Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. The New England journal of medicine 300, 530-534 (1979).
- 27. M. A. Moody, B. F. Haynes, Antigen-specific B cell detection reagents: use and quality control. Cytometry A 73, 1086-1092 (2008).
- 28. M. S. Habibi, A. Jozwik, S. Makris, J. Dunning, A. Paras, J. P. DeVincenzo, C. A. de Haan, J. Wrammert, P. J. Openshaw, C. Chiu, I. Mechanisms of Severe Acute Influenza Consortium, Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus. Am J Respir Crit Care Med 191, 1040-1049 (2015).
- 29. T. Tiller, E. Meffre, S. Yurasov, M. Tsuiji, M. C. Nussenzweig, H. Wardemann, Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329, 112-124 (2008).
- 30. Z. A. Bornholdt, H. L. Turner, C. D. Murin, W. Li, D. Sok, C. A. Souders, A. E. Piper, A. Goff, J. D. Shamblin, S. E. Wollen, T. R. Sprague, M. L. Fusco, K. B. Pommert, L. A. Cavacini, H. L. Smith, M. Klempner, K. A. Reimann, E. Krauland, T. U. Gerngross, K. D. Wittrup, E. O. Saphire, D. R. Burton, P. J. Glass, A. B. Ward, L. M. Walker, Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351, 1078-1083 (2016).
- 31. J. F. Scheid, H. Mouquet, N. Feldhahn, M. S. Seaman, K. Velinzon, J. Pietzsch, R. G. Ott, R. M. Anthony, H. Zebroski, A. Hurley, A. Phogat, B. Chakrabarti, Y. Li, M. Connors, F. Pereyra, B. D. Walker, H. Wardemann, D. Ho, R. T. Wyatt, J. R. Mascola, J. V. Ravetch, M. C. Nussenzweig, Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636-640 (2009).
- 32. J. Wrammert, K. Smith, J. Miller, W. A. Langley, K. Kokko, C. Larsen, N. Y. Zheng, I. Mays, L. Garman, C. Helms, J. James, G. M. Air, J. D. Capra, R. Ahmed, P. C. Wilson, Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667-671 (2008).
- 33. S. D. Boyd, B. A. Gaeta, K. J. Jackson, A. Z. Fire, E. L. Marshall, J. D. Merker, J. M. Maniar, L. N. Zhang, B. Sahaf, C. D. Jones, B. B. Simen, B. Hanczaruk, K. D. Nguyen, K. C. Nadeau, M. Egholm, D. B. Miklos, J. L. Zehnder, A. M. Collins, Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements. J Immunol 184, 6986-6992 (2010).
- 34. J. Sui, W. C. Hwang, S. Perez, G. Wei, D. Aird, L. M. Chen, E. Santelli, B. Stec, G. Cadwell, M. Ali, H. Wan, A. Murakami, A. Yammanuru, T. Han, N. J. Cox, L. A. Bankston, R. O. Donis, R. C. Liddington, W. A. Marasco, Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16, 265-273 (2009).
- 35. C. C. Huang, M. Venturi, S. Majeed, M. J. Moore, S. Phogat, M. Y. Zhang, D. S. Dimitrov, W. A. Hendrickson, J. Robinson, J. Sodroski, R. Wyatt, H. Choe, M. Farzan, P. D. Kwong, Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci USA 101, 2706-2711 (2004).
- 36. C. H. Chan, K. G. Hadlock, S. K. Foung, S. Levy, V(H)1-69 gene is preferentially used by hepatitis C virus-associated B cell lymphomas and by normal B cells responding to the E2 viral antigen. Blood 97, 1023-1026 (2001).
- 37. E. E. Godoy-Lozano, J. Tellez-Sosa, G. Sanchez-Gonzalez, H. Samano-Sanchez, A. Aguilar-Salgado, A. Salinas-Rodriguez, B. Cortina-Ceballos, H. Vivanco-Cid, K. Hernandez-Flores, J. M. Pfaff, K. M. Kahle, B. J. Doranz, R. E. Gomez-Barreto, H. Valdovinos-Torres, I. Lopez-Martinez, M. H. Rodriguez, J. Martinez-Barnetche, Lower IgG somatic hypermutation rates during acute dengue virus infection is compatible with a germinal center-independent B cell response. Genome Med 8, 23 (2016).
- 38. J. Wrammert, D. Koutsonanos, G. M. Li, S. Edupuganti, J. Sui, M. Morrissey, M. McCausland, I. Skountzou, M. Hornig, W. I. Lipkin, A. Mehta, B. Razavi, C. Del Rio, N. Y. Zheng, J. H. Lee, M. Huang, Z. Ali, K. Kaur, S. Andrews, R. R. Amara, Y. Wang, S. R. Das, C. D. O'Donnell, J. W. Yewdell, K. Subbarao, W. A. Marasco, M. J. Mulligan, R. Compans, R. Ahmed, P. C. Wilson, Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208, 181-193 (2011).
- 39. S. F. Andrews, Y. Huang, K. Kaur, L. I Popova, I Y. Ho, N. T. Pauli, C. J. Henry Dunand, W. M. Taylor, S. Lim, M. Huang, X. Qu, J. H. Lee, M. Salgado-Ferrer, F. Krammer, P. Palese, J. Wrammert, R. Ahmed, P. C. Wilson, Immune history profoundly affects broadly protective B cell responses to influenza. Sci Transl Med 7, 316ra192 (2015).
- 40. M. Liu, G. Yang, K. Wiehe, N. I. Nicely, N. A. Vandergrift, W. Rountree, M. Bonsignori, S. M. Alam, J. Gao, B. F. Haynes, G. Kelsoe, Polyreactivity and autoreactivity among HIV-1 antibodies. J Virol 89, 784-798 (2015).
- 41. H. Mouquet, J. F. Scheid, M. J. Zoller, M. Krogsgaard, R. G. Ott, S. Shukair, M. N. Artyomov, J. Pietzsch, M. Connors, F. Pereyra, B. D. Walker, D. D. Ho, P. C. Wilson, M. S. Seaman, H. N. Eisen, A. K. Chakraborty, T. J. Hope, J. V. Ravetch, H. Wardemann, M. C. Nussenzweig, Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467, 591-595 (2010).
- 42. R. L. Kelly, T. Sun, T. Jain, I. Caffry, Y. Yu, Y. Cao, H. Lynaugh, M. Brown, M. Vasquez, K. D. Wittrup, Y. Xu, High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice. MAbs, 0 (2015).
- 43. Y. Xu, W. Roach, T. Sun, T. Jain, B. Prinz, T. Y. Yu, J. Torrey, J. Thomas, P. Bobrowicz, M. Vasquez, K. D. Wittrup, E. Krauland, Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. Protein Eng Des Sel 26, 663-670 (2013).
- 44. D. R. Bowley, A. F. Labrijn, M. B. Zwick, D. R. Burton, Antigen selection from an HIV-1 immune antibody library displayed on yeast yields many novel antibodies compared to selection from the same library displayed on phage. Protein Eng Des Sel 20, 81-90 (2007).
- 45. H. Wu, D. S. Pfarr, S. Johnson, Y. A. Brewah, R. M. Woods, N. K. Patel, W. I. White, J. F. Young, P. A. Kiener, Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. Journal of molecular biology 368, 652-665 (2007).
- 46. J. S. McLellan, M. Chen, J. S. Chang, Y. Yang, A. Kim, B. S. Graham, P. D. Kwong, Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F. J Virol 84, 12236-12244 (2010).
- 47. P. W. Parren, D. R. Burton, The antiviral activity of antibodies in vitro and in vivo. Advances in immunology 77, 195-262 (2001).
- 48. J. Foote, H. N. Eisen, Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci USA 92, 1254-1256 (1995).
- 49. F. D. Batista, M. S. Neuberger, Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 8, 751-759 (1998).
- 50. J. E. Schuster, R. G. Cox, A. K. Hastings, K. L. Boyd, J. Wadia, Z. Chen, D. R. Burton, R. A. Williamson, J. V. Williams, A broadly neutralizing human monoclonal antibody exhibits in vivo efficacy against both human metapneumovirus and respiratory syncytial virus. J Infect Dis 211, 216-225 (2015).
- 51. B. F. Fernie, P. J. Cote, Jr., J. L. Gerin, Classification of hybridomas to respiratory syncytial virus glycoproteins. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 171, 266-271 (1982).
- 52. P. J. Cote, Jr., B. F. Fernie, E. C. Ford, J. W. Shih, J. L. Gerin, Monoclonal antibodies to respiratory syncytial virus: detection of virus neutralization and other antigen-antibody systems using infected human and murine cells. Journal of virological methods 3, 137-147 (1981).
- 53. E. E. Walsh, J. Hruska, Monoclonal antibodies to respiratory syncytial virus proteins: identification of the fusion protein. J Virol 47, 171-177 (1983).
- 54. L. J. Anderson, P. Bingham, J. C. Hierholzer, Neutralization of respiratory syncytial virus by individual and mixtures of F and G protein monoclonal antibodies. J Virol 62, 4232-4238 (1988).
- 55. G. E. Scopes, P. J. Watt, P. R. Lambden, Identification of a linear epitope on the fusion glycoprotein of respiratory syncytial virus. J Gen Virol 71 (Pt 1), 53-59 (1990).
- 56. J. Arbiza, G. Taylor, J. A. Lopez, J. Furze, S. Wyld, P. Whyte, E. J. Stott, G. Wertz, W. Sullender, M. Trudel, et al., Characterization of two antigenic sites recognized by neutralizing monoclonal antibodies directed against the fusion glycoprotein of human respiratory syncytial virus. J Gen Virol 73 (Pt 9), 2225-2234 (1992).
- 57. J. A. Lopez, R. Bustos, C. Orvell, M. Berois, J. Arbiza, B. Garcia-Barreno, J. A. Melero, Antigenic structure of human respiratory syncytial virus fusion glycoprotein. J Virol 72, 6922-6928 (1998).
- 58. B. J. DeKosky, T. Kojima, A. Rodin, W. Charab, G. C. Ippolito, A. D. Ellington, G. Georgiou, In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat Med 21, 86-91 (2015).
- 59. U.S. National Library of Medicine, (NCT02290340, https://clinicaltrials.gov/).
- 60. PATH, RSV Vaccine Snapshot (2016 https://sites.path.org/vaccinedevelopment/files/2016/07/RSV-snapshot-July_13_2016.pdf)
- 61. B. S. Graham, M. D. Perkins, P. F. Wright, D. T. Karzon, Primary respiratory syncytial virus infection in mice. Journal of medical virology 26, 153-162 (1988).
- 62. A. L. Hotard, F. Y. Shaikh, S. Lee, D. Yan, M. N. Teng, R. K. Plemper, J. E. Crowe, Jr., M. L. Moore, A stabilized respiratory syncytial virus reverse genetics system amenable to recombination-mediated mutagenesis. Virology 434, 129-136 (2012).
An informal sequence listing is provided in Table 6, below. The informal sequence listing provides the following sixteen (16) sequence elements contained in each of the 133 antibodies, identified as described above and designated as Antibody Numbers (Ab #) 232 through 364, in the following order:
Heavy chain variable region (“HC”) nucleic acid sequence
Heavy chain variable region (“HC”) amino acid sequence
Heavy chain variable region CDR H1 (“H1”) amino acid sequence
Heavy chain variable region CDR H1 (“H1”) nucleic acid sequence
Heavy chain variable region CDR H2 (“H2”) amino acid sequence
Heavy chain variable region CDR H2 (“H2”) nucleic acid sequence
Heavy chain variable region CDR H3 (“H3”) amino acid sequence
Heavy chain variable region CDR H3 (“H3”) nucleic acid sequence
Light chain variable region (“LC”) nucleic acid sequence
Light chain variable region (“LC”) amino acid sequence
Light chain variable region CDR L1 (“L1”) amino acid sequence
Light chain variable region CDR Li (“Li”) nucleic acid sequence
Light chain variable region CDR L2 (“L2”) amino acid sequence
Light chain variable region CDR L2 (“L2”) nucleic acid sequence
Light chain variable region CDR L3 (“L3”) amino acid sequence
Light chain variable region CDR L3 (“L3”) nucleic acid sequence
The informal sequence listing for antibodies 365-372 provides the following ten (10) sequence elements contained in each of the 8 antibodies, identified as described above and designated as Antibody Numbers (Ab #) 365 through 372, in the following order:
Heavy chain variable region (“HC”) nucleic acid sequence
Heavy chain variable region (“HC”) amino acid sequence
Heavy chain variable region CDR H1 (“H1”) amino acid sequence
Heavy chain variable region CDR H2 (“H2”) amino acid sequence
Heavy chain variable region CDR H3 (“H3”) amino acid sequence
Light chain variable region (“LC”) nucleic acid sequence
Light chain variable region (“LC”) amino acid sequence
Light chain variable region CDR L1 (“L1”) amino acid sequence
Light chain variable region CDR L2 (“L2”) amino acid sequence
Light chain variable region CDR L3 (“L3”) amino acid sequence
TABLE 6
Informal Sequence Listing
Seq.
Antibody Ref. SEQ ID
No. No. NO. Sequence
232 3697 1 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTA
TTCCTGGAGCTGGATCCGCCAGACCCCAGGGAAGGGGCTGGAGTGGA
TTGGGGAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTC
AAGAGTCGAGTCACCATGTCAGTGGACACGTCCCAGAACCAGATCTC
CCTGAGGGTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTTCTG
TGCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAGTACTTCT
TCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
232 3698 2 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIRQTPGKGLEWIG
EINHRGSTNYNPSLKSRVTMSVDTSQNQISLRVTSVTAADTAVYFCAGTN
YGEVNTSNQYFFGMDVWGQGTTVTVSS
232 3699 3 GSFSGYSWS
232 3700 4 GGGTCCTTCAGTGGTTATTCCTGGAGC
232 3701 5 EINHRGSTNYNPSLKS
232 3702 6 GAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAG
T
232 3703 7 AGTNYGEVNTSNQYFFGMDV
232 3704 8 GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAGTACTTCTT
CGGTATGGACGTC
232 3705 9 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGGCACCTA
TTTAAATTGGTATCAGCAGAAACCAGGGAAACCCCCTAAACTCCTGA
TCTATGCTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTCAGTG
GCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGTCTGCAAC
CTGAACATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCGC
TCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
232 3706 10 DIQVTQSPSSLSASVGDRVTITCRASQSIGTYLNWYQQKPGKPPKLLIYAA
SNLESGVPSSFSGSGSGTHFTLTISSLQPEHFATYYCQQSYSTPLTFGGGTK
VEIK
232 3707 11 RASQSIGTYLN
232 3708 12 CGGGCAAGTCAGAGCATTGGCACCTATTTAAAT
232 3709 13 AASNLES
232 3710 14 GCTGCATCCAATTTGGAAAGT
232 3711 15 QQSYSTPLT
232 3712 16 CAACAGAGTTACAGTACCCCGCTCACT
233 3713 17 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTCCCTCCATCAGCAGTGG
TGATTACTACTGGACTTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG
AGTGGATTGGCTACATCTATAACAGTGGGAGCACCGACTACAACCCG
TCCCTCAAGAGTCGTATCACCATGTCACTAGACAGGTCCAAGAACCA
GTTCTCCCTGAATCTGAGCTCTGTGACTGCCGCAGACACGGCCGTGTA
TTTCTGTGCCAGGGATGTGGGTACTCTGGTACTACCAACTGTTGCTTA
CTACTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT
CCTCA
233 3714 18 QVQLQESGPGLVKPSQTLSLTCTVSGPSISSGDYYWTWIRQPPGKGLEWI
GYIYNSGSTDYNPSLKSRITMSLDRSKNQFSLNLSSVTAADTAVYFCARD
VGTLVLPTVAYYYGMDVWGQGTTVTVSS
233 3715 19 PSISSGDYYWT
233 3716 20 CCCTCCATCAGCAGTGGTGATTACTACTGGACT
233 3717 21 YIYNSGSTDYNPSLKS
233 3718 22 TACATCTATAACAGTGGGAGCACCGACTACAACCCGTCCCTCAAGAG
T
233 3719 23 ARDVGTLVLPTVAYYYGMDV
233 3720 24 GCCAGGGATGTGGGTACTCTGGTACTACCAACTGTTGCTTACTACTAC
GGCATGGACGTC
233 3721 25 GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCGGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTGAGAGTATTAGCAGCAG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCT
CATCTATGATGCGTCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTG
GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA
CCCCTGGTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
233 3722 26 EIVLTQSPGTLSLSPGERATLSCRASESISSSYLAWYQQKPGQAPRLLIYD
ASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFAVYYCQQYGSSPLVTFGPG
TKVDIK
233 3723 27 RASESISSSYLA
233 3724 28 AGGGCCAGTGAGAGTATTAGCAGCAGCTACTTAGCC
233 3725 29 DASSRAT
233 3726 30 GATGCGTCCAGCAGGGCCACT
233 3727 31 QQYGSSPLVT
233 3728 32 CAGCAGTATGGTAGCTCACCCCTGGTCACT
234 3729 33 CAGGTCCAGCTGGTGCAGTCTGGAACTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGTAAGGCTGCTGGTTACACCTTTAGCAACTA
CGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAG
GTCCAGGGCAGACTCACCATGACCACAGACACATCTACCAGCACAGC
CTACATGGAATTGAGGAACCTCAGATCTGACGACACGGCCGTGTATT
ATTGTGCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC
TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
234 3730 34 QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWVRQAPGQGLEW
MGWISAYNGNTKFAQKVQGRLTMTTDTSTSTAYMELRNLRSDDTAVYY
CARESGATAAAMFDYWGQGTLVTVSS
234 3731 35 YTFSNYGVS
234 3732 36 TACACCTTTAGCAACTACGGTGTCAGT
234 3733 37 WISAYNGNTKFAQKVQG
234 3734 38 TGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCA
GGGC
234 3735 39 ARESGATAAAMFDY
234 3736 40 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC
234 3737 41 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGT
GATGGAAACATCTACTTGAGTTGGTTTCAACAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCGCCAGGGTGGAGGCTGAGGATGTTGCAGTTTATTACTGCATGCAA
GCTATACACTGGCCTCGAACTTTTGGCCAGGGGACCAAAGTGGATAT
CAAA
234 3738 42 ETTLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWFQQRPGQSPRRL
IYKVSHRDSGVPDRFSGSGSGTDFTLKIARVEAEDVAVYYCMQAIHWPR
TFGQGTKVDIK
234 3739 43 RSSQSLEYSDGNIYLS
234 3740 44 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAG
T
234 3741 45 KVSHRDS
234 3742 46 AAGGTTTCTCACCGGGACTCT
234 3743 47 MQAIHWPRT
234 3744 48 ATGCAAGCTATACACTGGCCTCGAACT
235 3745 49 CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCATCTGCGATGTCTCTGGTGGCTCCATCGGCAGTGG
TGACCACTACTGGAGTTGGATCCGCCAGCCCCCCGGGAAGGGCCTCG
AGTGGATTGGGTACATCTATTACAGTGGGACCACTTACTACAACCCGT
CCCTCAAGAGTCGAGTGACCATTTCAGCAGACACGTCCAAGAACCAG
TTGTCCCTGAAATTGAGTTCTGTGACTGCCGCAGACACGGCCATTTAT
TTCTGTGCCAGAGATGGGGGTTATGATCACGTCTGGGGGACTCATCGT
TATTTCGACAAGTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
235 3746 50 QVQLQESGPRLVKPSQTLSLICDVSGGSIGSGDHYWSWIRQPPGKGLEWI
GYIYYSGTTYYNPSLKSRVTISADTSKNQLSLKLSSVTAADTAIYFCARD
GGYDHVWGTHRYFDKWGQGTLVTVSS
235 3747 51 GSIGSGDHYWS
235 3748 52 GGCTCCATCGGCAGTGGTGACCACTACTGGAGT
235 3749 53 YIYYSGTTYYNPSLKS
235 3750 54 TACATCTATTACAGTGGGACCACTTACTACAACCCGTCCCTCAAGAGT
235 3751 55 ARDGGYDHVWGTHRYFDK
235 3752 56 GCCAGAGATGGGGGTTATGATCACGTCTGGGGGACTCATCGTTATTTC
GACAAG
235 3753 57 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAACAG
TTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGGTGTTTCCACCAGGGCCACTGGCATCCCAGACCGGTTCAG
TGGCAGCGGGTCTGGGACAGACTTCACCCTCACCATCAGCAGACTGG
AACCTGAAGATTTTGCAATGTATCACTGTCAGCAGTATGGTGCCTCAC
CTTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA
235 3754 58 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLLIY
GVSTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAMYHCQQYGASPWTFG
QGTKVDIK
235 3755 59 RASQSVSNSYLA
235 3756 60 AGGGCCAGTCAGAGTGTTAGCAACAGTTACTTAGCC
235 3757 61 GVSTRAT
235 3758 62 GGTGTTTCCACCAGGGCCACT
235 3759 63 QQYGASPWT
235 3760 64 CAGCAGTATGGTGCCTCACCTTGGACG
236 3761 65 GAGGTGCAGCTGTTGGAGTCTGGAGGTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAGGGCCTCTGGTTACACCTTTAGAAACTA
TGGCCTCACCTGGGTGCGGCAGGCCCCCGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAG
TTCCAGGGCAGAGTCACACTGACCACGGACACATCCACGAGCACAGC
CTACATGGAACTGAGGAGCCTAAGATCTGACGACACGGCCGTGTATT
TCTGTGCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTCT
GGGGCACAGGGACCACGGTCACCGTCTCCTCA
236 3762 66 EVQLLESGGEVKKPGASVKVSCRASGYTFRNYGLTWVRQAPGQGLEW
MGWISAYNGNTNYAQKFQGRVTLTTDTSTSTAYMELRSLRSDDTAVYF
CARDVPGHGAAFMDVWGTGTTVTVSS
236 3763 67 YTFRNYGLT
236 3764 68 TACACCTTTAGAAACTATGGCCTCACC
236 3765 69 WISAYNGNTNYAQKFQG
236 3766 70 TGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCA
GGGC
236 3767 71 ARDVPGHGAAFMDV
236 3768 72 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTC
236 3769 73 GACATCCAGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGG
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAAGCCAGT
GATACAAATATCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCT
CCAAGGCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGTCCCA
GACAGATTCAGCGGCAGTGGGTCAGGCACTCATTTCACACTGAGAAT
CAGCAGGGTGGAGGCTGACGATGTTGCGGTTTATTACTGCATGCAGG
GTACACACTGGCCTCCGGCGTTCGGCCAGGGGACCAAAGTGGATATC
AAA
236 3770 74 DIQLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWFQQRPGQSPRRL
IYKISNRDSGVPDRFSGSGSGTHFTLRISRVEADDVAVYYCMQGTHWPPA
FGQGTKVDIK
236 3771 75 RSSQSLEASDTNIYLS
236 3772 76 AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAG
T
236 3773 77 KISNRDS
236 3774 78 AAGATTTCTAACCGAGACTCT
236 3775 79 MQGTHWPPA
236 3776 80 ATGCAGGGTACACACTGGCCTCCGGCG
237 3777 81 CAGGTCCAGCTGGTACAGTCTGGATCTGAGGTGAAGAAGCCTGGGGC
CGCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACATCTTTGCCAACTT
TGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAG
TTCCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGCACAGC
CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATT
ATTGTGCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTCT
GGGGCAAAGGGACCACGGTCACTGTCTCCTCA
237 3778 82 QVQLVQSGSEVKKPGAAVKVSCKASGYIFANFGVSWVRQAPGQGLEW
MGWISAYNGNTNYAQKFQGRVIMTTDTSTSTAYMELRSLRSDDTAVYY
CARDPPAYAATLMDVWGKGTTVTVSS
237 3779 83 YIFANFGVS
237 3780 84 TACATCTTTGCCAACTTTGGTGTCAGC
237 3781 85 WISAYNGNTNYAQKFQG
237 3782 86 TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA
GGGC
237 3783 87 ARDPPAYAATLMDV
237 3784 88 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTC
237 3785 89 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAACACAGT
GATACAAACACCTACTTGACTTGGTATCAGCAGAGGCCAGGCCAATC
TCCAAGGCGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAAGTGGATAT
CAAA
237 3786 90 EIVLTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTWYQQRPGQSPRR
LLYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWP
PTFGQGTKVDIK
237 3787 91 RSSQSLEHSDTNTYLT
237 3788 92 AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGAC
T
237 3789 93 KVSNRDS
237 3790 94 AAGGTTTCTAACCGGGACTCT
237 3791 95 MQGTHWPPT
237 3792 96 ATGCAAGGTACACACTGGCCTCCGACG
238 3793 97 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAGGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGGGGCT
ATGGTCTCAGCTGGGTGCGACAGGCCCCTGGACAGGGACTCGAGTGG
ATGGGAGGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCCGAA
GTTCCAGGGCAGACTCACGATCACCGCGGACGCATCCACGGGCACAG
CCTACATGGAGCTGAGCAGCCTGATATCTGAGGACACGGCCGTATAT
TTTTGTGCGAGAGATGCTTACGAAGTGTGGACCGGCTCTTATCTCCCC
CCTTTTGACTACTGGGGCCAGGGAACAATGGTCACCGTCTCTTCA
238 3794 98 QVQLVQSGAEVKKPGSSVRVSCKASGGTFRGYGLSWVRQAPGQGLEW
MGGITHLFGTVSYAPKFQGRLTITADASTGTAYMELSSLISEDTAVYFCA
RDAYEVWTGSYLPPFDYWGQGTMVTVSS
238 3795 99 GTFRGYGLS
238 3796 100 GGCACCTTCAGGGGCTATGGTCTCAGC
238 3797 101 GITHLFGTVSYAPKFQG
238 3798 102 GGGATCACCCATCTTTTTGGGACAGTCAGCTACGCTCCGAAGTTCCAG
GGC
238 3799 103 ARDAYEVWTGSYLPPFDY
238 3800 104 GCGAGAGATGCTTACGAAGTGTGGACCGGCTCTTATCTCCCCCCTTTT
GACTAC
238 3801 105 GATATTGTGATGACTCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGATTATTCCAAGCAG
TTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGGTGCATTCACCAGGGCCACTGACATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATTTTGCAGTATATTATTGTCAGCAGTATGGTAGTTCA
TTTCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
238 3802 106 DIVMTQSPGTLSLSPGERVTLSCRASQIIPSSYLAWYQQKPGQAPRLLIYG
AFTRATDIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGGG
TKVEIK
238 3803 107 RASQIIPSSYLA
238 3804 108 AGGGCCAGTCAGATTATTCCAAGCAGTTACTTAGCC
238 3805 109 GAFTRAT
238 3806 110 GGTGCATTCACCAGGGCCACT
238 3807 111 QQYGSSFLT
238 3808 112 CAGCAGTATGGTAGTTCATTTCTCACT
239 3809 113 CAGGTCCAGCTTGTGCAGTCTGGGCCTGAGGTAAAGAAGCCTGGGTC
CTCAGTGACGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTA
TGGTATTGCTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATCAACAATCCCTATCCTTGGAACAGCAAGCTACAGACAGAGC
TTAAAGGACAGAGTCACAATTACCGCGGACGCTTCCACGACCACAGT
CTACATGGAAATGACTCGCCTCAGAACTGAGGACACGGCCGTCTATT
TTTGTGCGAGAGTTCCGGAGAGTCTTGTGGCATCAAACGCTTATGCTG
TTTGGGGCCAAGGGACGGTGGTCACTGTCTCCTCA
239 3810 114 QVQLVQSGPEVKKPGSSVTVSCKASGGTFSNYGIAWVRQAPGQGLEWM
GSTIPILGTASYRQSLKDRVTITADASTTTVYMEMTRLRTEDTAVYFCAR
VPESLVASNAYAVWGQGTVVTVSS
239 3811 115 GTFSNYGIA
239 3812 116 GGCACCTTCAGCAACTATGGTATTGCT
239 3813 117 STIPILGTASYRQSLKD
239 3814 118 TCAACAATCCCTATCCTTGGAACAGCAAGCTACAGACAGAGCTTAAA
GGAC
239 3815 119 ARVPESLVASNAYAV
239 3816 120 GCGAGAGTTCCGGAGAGTCTTGTGGCATCAAACGCTTATGCTGTT
239 3817 121 GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGTCGGGCGAGCCAGGACATTAGCACCTG
GTTAGCCTGGTATCAGCAGAGACCAGGGAAAGCCCCAAAACTCCTGA
TCTACACTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG
GCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG
CCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTACCAGTTTCCCA
TTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA
239 3818 122 DIQMTQSPSSVSASVGDRVTITCRASQDISTWLAWYQQRPGKAPKLLIYT
ASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGTSFPFTFGPGT
KLEIK
239 3819 123 RASQDISTWLA
239 3820 124 CGGGCGAGCCAGGACATTAGCACCTGGTTAGCC
239 3821 125 TASSLQS
239 3822 126 ACTGCATCCAGTTTGCAAAGT
239 3823 127 QQGTSFPFT
239 3824 128 CAACAGGGTACCAGTTTCCCATTCACT
240 3825 129 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGATGAAGAAGCCTGGGGC
CTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTAACTA
TGCTATACATTGGGTGCGCCAGGCCCCCGGCCAAAGCCTTGAGTGGA
TGGGATGGATCAACGCTGGCAATGGTAACACACAATATTCACAGAAG
TTCCAGGGCAGAGTCACCTTTACCAGGGACACATCCGCGAGCACGGT
CTACATGGACCTGAGCAGCCTGAGATCTGAAGACACGGCTGTCTATT
ACTGTGCGAGAGGCCAAATTGTTGTTATACCACGTGCTAATTTCTGGT
TCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
240 3826 130 EVQLVESGAEMKKPGASVKVSCKASGYTFTNYAIHWVRQAPGQSLEW
MGWINAGNGNTQYSQKFQGRVTFTRDTSASTVYMDLSSLRSEDTAVYY
CARGQIVVIPRANFWFDPWGQGTLVTVSS
240 3827 131 YTFTNYAIH
240 3828 132 TACACCTTCACTAACTATGCTATACAT
240 3829 133 WINAGNGNTQYSQKFQG
240 3830 134 TGGATCAACGCTGGCAATGGTAACACACAATATTCACAGAAGTTCCA
GGGC
240 3831 135 ARGQIVVIPRANFWFDP
240 3832 136 GCGAGAGGCCAAATTGTTGTTATACCACGTGCTAATTTCTGGTTCGAC
CCC
240 3833 137 GATATTGTGCTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGT
CATGGATACAACTATTTGGATTGGTACTTGCAGAAGCCAGGGCAGTC
TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC
TGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA
TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
ACTCTACAAACTCCGATCACCTTCGGCCAAGGGACACGAATGGAGAT
TAAA
240 3834 138 DIVLTQSPLSLPVTPGEPASISCRSSQSLLHSHGYNYLDWYLQKPGQSPQL
LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQTLQTPI
TFGQGTRMEIK
240 3835 139 RSSQSLLHSHGYNYLD
240 3836 140 AGGTCTAGTCAGAGCCTCCTGCATAGTCATGGATACAACTATTTGGAT
240 3837 141 LGSNRAS
240 3838 142 TTGGGTTCTAATCGGGCCTCC
240 3839 143 MQTLQTPIT
240 3840 144 ATGCAAACTCTACAAACTCCGATCACC
241 3841 145 GAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTTACA
GACCCTGTCCGTCACCTGCAGTGTCTCTGGTGGCTCCATCAGCAGTGG
TGATAACTACTGGAGCTGGATCCGCCAGCGCCCAGGGAAGGGCCTGG
AGTGGATTGGGTACATCTATTACAGTGGGACCACCTACTACAATCCGT
CCCTCAAGAGTCGAGTTACCATATCAGCAGACAGGTCTAAGAATCAG
TTTTCTCTGAAGATGAATTCTCTGAGTGCCGCGGACACGGCCGTGTAT
TACTGTGCGAGAGATGGCGGATATGATCACATCTGGGGGACTCATCG
TTATTTCGCCCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
241 3842 146 EVQLQESGPGLVKPLQTLSVTCSVSGGSISSGDNYWSWIRQRPGKGLEWI
GYIYYSGTTYYNPSLKSRVTISADRSKNQFSLKMNSLSAADTAVYYCAR
DGGYDHIWGTHRYFALWGQGTLVTVSS
241 3843 147 GSISSGDNYWS
241 3844 148 GGCTCCATCAGCAGTGGTGATAACTACTGGAGC
241 3845 149 YIYYSGTTYYNPSLKS
241 3846 150 TACATCTATTACAGTGGGACCACCTACTACAATCCGTCCCTCAAGAGT
241 3847 151 ARDGGYDHIWGTHRYFAL
241 3848 152 GCGAGAGATGGCGGATATGATCACATCTGGGGGACTCATCGTTATTT
CGCCCTC
241 3849 153 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAGCGA
CTACTTGGCCTGGTACCAGCAGAAACTTGGCCAGGCTCCCAGGCTCCT
CATTTATGGTGTATCCAACAGGGCCACTGGCATCCCAGACAGGTTTAC
TGGGAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG
AGCCTGAAGATTTTGCAGTCTATCACTGTCAGCAGTATGGTACCTCAC
CGTGGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA
241 3850 154 ETTLTQSPGTLSLSPGERATLSCRASQSVNSDYLAWYQQKLGQAPRLLIY
GVSNRATGIPDRFTGSGSGTDFTLTISRLEPEDFAVYHCQQYGTSPWTFG
QGTKVEIK
241 3851 155 RASQSVNSDYLA
241 3852 156 AGGGCCAGTCAGAGTGTTAACAGCGACTACTTGGCC
241 3853 157 GVSNRAT
241 3854 158 GGTGTATCCAACAGGGCCACT
241 3855 159 QQYGTSPWT
241 3856 160 CAGCAGTATGGTACCTCACCGTGGACG
242 3857 161 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTC
CTCGGTGAAAGTCTCCTGTAAGGCCTCTGGAGGCACCTTCAGTAGTTA
TGCTCTCTCCTGGGTACGGCAGGCCCCTGGACAAGGACTTGAGTGGA
TAGGGGGGATCATCCCTATGCATCGTGTAACAAATTACGCACAGAAA
TTTCGGGGCAGAGTCACAATTTCCGCGGACACATCCACGAGTACGGC
CTACTTGGAGGTGAACAGCCTGAGAGTTGAGGACACGGCCATGTATT
ACTGTGCGAGAGTGTTTTTCGGAACTTGTGGCGGTGCTTCGTGCTTCC
CCTCTGACCTCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
242 3858 162 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYALSWVRQAPGQGLEWI
GGIIPMHRVTNYAQKFRGRVTISADTSTSTAYLEVNSLRVEDTAMYYCA
RVFFGTCGGASCFPSDLWGQGTLVTVSS
242 3859 163 GTFSSYALS
242 3860 164 GGCACCTTCAGTAGTTATGCTCTCTCC
242 3861 165 GIIPMHRVTNYAQKFRG
242 3862 166 GGGATCATCCCTATGCATCGTGTAACAAATTACGCACAGAAATTTCG
GGGC
242 3863 167 ARVFFGTCGGASCFPSDL
242 3864 168 GCGAGAGTGTTTTTCGGAACTTGTGGCGGTGCTTCGTGCTTCCCCTCT
GACCTC
242 3865 169 GAAATTGTGTTGACACAGTCTCCATCCTTCGTGTCTGCTTCTGTCGGA
GACGGGGTCACCATCACTTGCCGGGCCAGTCAGGCCATTAGCAGTTA
TTTAGCCTGGTATCAGCAAAAACCAGGGCAAGCCCCTAAACTCCTGA
TCTATGCTGCATCCACTTTGCAAGGTGGTGTCCCATCAAGGTTCAGCG
GCAGTGGATCTGGGACACATTTCACTCTCACCATCAGCAGCCTGCAGC
CTGAAGATTTTGCAACTTATTACTGTCAGCAACTTCATAGTGATTTTC
AGACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA
242 3866 170 EIVLTQSPSFVSASVGDGVTITCRASQAISSYLAWYQQKPGQAPKLLIYAA
STLQGGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQLHSDFQTFGPGT
KVEIK
242 3867 171 RASQAISSYLA
242 3868 172 CGGGCCAGTCAGGCCATTAGCAGTTATTTAGCC
242 3869 173 AASTLQG
242 3870 174 GCTGCATCCACTTTGCAAGGT
242 3871 175 QQLHSDFQT
242 3872 176 CAGCAACTTCATAGTGATTTTCAGACT
243 3873 177 CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCAGCTTCAGTATGCA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGACAGCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCC
GTGAAGGGCCGATTCACGATCTCCAGAGACAATTCTAGGAACACGCT
GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT
ACTGTGCGAGAGATCATGCCTCAACTCCATACTACATGGACGTCTGG
GGCAAAGGGACCACGGTCACCGTCTCCTCA
243 3874 178 QVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWVRQAPGKGLEW
VTAIWYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYY
CARDHASTPYYMDVWGKGTTVTVSS
243 3875 179 FSFSMHGMH
243 3876 180 TTCAGCTTCAGTATGCATGGCATGCAC
243 3877 181 AIWYDGSNKYYADSVKG
243 3878 182 GCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAA
GGGC
243 3879 183 ARDHASTPYYMDV
243 3880 184 GCGAGAGATCATGCCTCAACTCCATACTACATGGACGTC
243 3881 185 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
GAAAGCGCCACCCTCTCCTGCAGGACCAGTCAGAGGATTAGCAGCAC
CTACTTAGCCTGGTACCGGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATGTATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTG
GAGCCTGAAGATTTTGCACTATATTACTGTCAGCAGTATGGTAGCTTT
CCGTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA
243 3882 186 ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQKPGQAPRLLMY
GASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFALYYCQQYGSFPWTFGQ
GTKLEIK
243 3883 187 RTSQRISSTYLA
243 3884 188 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC
243 3885 189 GASSRAT
243 3886 190 GGTGCATCCAGCAGGGCCACT
243 3887 191 QQYGSFPWT
243 3888 192 CAGCAGTATGGTAGCTTTCCGTGGACG
244 3889 193 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTGGAAGCCTTCGCA
GACCCTGTCCCTCACCTGCGCTGTCCATGGTGGATCCCTCAGTGGCTA
CTCTTGGAGTTGGATCCGCCAGTCCCCAGGGAGGGGACTGGAGTGGA
TCGGCGAAGTCAATCGTAGGGGAACCACCAACTACAACCCCTCCCTC
AAGGGTCGAGTCTCCATATCCTGGGACACGTCCAAGAACCAGGTCTC
CCTGTCCCTGAGGTCTGTGACCGCCGCGGACACGGCTACATATTACTG
TGCGGGGACCAATGTTGGATTCGTTAATACCCATAACGACTACTACTT
CGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
244 3890 194 QVQLQQWGAGLWKPSQTLSLTCAVHGGSLSGYSWSWIRQSPGRGLEWI
GEVNRRGTTNYNPSLKGRVSISWDTSKNQVSLSLRSVTAADTATYYCAG
TNVGFVNTHNDYYFGMDVWGQGTTVTVSS
244 3891 195 GSLSGYSWS
244 3892 196 GGATCCCTCAGTGGCTACTCTTGGAGT
244 3893 197 EVNRRGTTNYNPSLKG
244 3894 198 GAAGTCAATCGTAGGGGAACCACCAACTACAACCCCTCCCTCAAGGG
T
244 3895 199 AGTNVGFVNTHNDYYFGMDV
244 3896 200 GCGGGGACCAATGTTGGATTCGTTAATACCCATAACGACTACTACTTC
GGTATGGACGTC
244 3897 201 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGCATCGGTTGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATAAGCAATTA
TGTAAATTGGTATCAGAAAAAAACAGGTCAAGTCCCTAAACTCCTGA
TCTATGGTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGGTTCAGTG
GCGGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC
CTGAAGATTTTGCAACTTATTACTGTCAACAGAGTTACAGTGTCCCGC
TCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
244 3898 202 DIVMTQSPSSLSASVGDRVTITCRASQSISNYVNWYQKKTGQVPKLLIYG
ASNLESGVPSRFSGGGSGTDFTLTISSLQPEDFATYYCQQSYSVPLTFGGG
TKVEIK
244 3899 203 RASQSISNYVN
244 3900 204 CGGGCAAGTCAGAGCATAAGCAATTATGTAAAT
244 3901 205 GASNLES
244 3902 206 GGTGCATCCAATTTGGAAAGT
244 3903 207 QQSYSVPLT
244 3904 208 CAACAGAGTTACAGTGTCCCGCTCACT
245 3905 209 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGATC
CTCGGTGAAGGTCTCCTGCAAGGCGTCTGGAGGCACCTTCCGCGGCT
ACCATATCAGCTGGCTGCGCCAGGCCCCTGGACAGGGCCTCGAGTGG
CTGGGAGGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAG
TTCCAGGGCAGAGTCACCATCACCGCGGACGCATCCACGGGCACACT
TTACATGGTGTTGAACAGCCTGAAACCTGAGGACACGGCCATTTATTA
TTGTGCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCC
TTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
245 3906 210 QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWLRQAPGQGLEWL
GGITHLFGTVSYAPKFQGRVTITADASTGTLYMVLNSLKPEDTAIYYCAR
DAYEVWTGSYLPPFDYWGQGTLVTVSS
245 3907 211 GTFRGYHIS
245 3908 212 GGCACCTTCCGCGGCTACCATATCAGC
245 3909 213 GITHLFGTVSYAPKFQG
245 3910 214 GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAG
GGC
245 3911 215 ARDAYEVWTGSYLPPFDY
245 3912 216 GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTT
GACTAC
245 3913 217 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGCCACCCTCTCTTGCAGGGCCAGTCAGACTGTTACAAGCAA
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGATGCACTCACCAGGGCCACTGGCATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATTTTGCACTTTATTATTGTCAGCAGTATGGTAGTTCA
TTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA
245 3914 218 ETTLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQKPGQAPRLLIY
DALTRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQQYGSSFLTFGG
GTKVDIK
245 3915 219 RASQTVTSNYLA
245 3916 220 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC
245 3917 221 DALTRAT
245 3918 222 GATGCACTCACCAGGGCCACT
245 3919 223 QQYGSSFLT
245 3920 224 CAGCAGTATGGTAGTTCATTCCTCACT
246 3921 225 CAGGTGCAGCTGCAGGAGTCCGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCGCCTTCAGCAGCTA
TGCTATCAGCTGGGTGCGACAGGCCCCTGGACAGGGCCTCGAGTGGC
TGGGAGGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGT
TCCAGGGCAGAGTCACCATCACCGCGGACGCATCCACGGGCACACTT
TACATGGTGTTGAACAGCCTGAAACCTGAGGACACGGCCATTTATTAT
TGTGCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCT
TTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
246 3922 226 QVQLQESGAEVKKPGSSVKVSCKASGGAFSSYAISWVRQAPGQGLEWL
GGITHLFGTVSYAPKFQGRVTITADASTGTLYMVLNSLKPEDTAIYYCAR
DAYEVWTGSYLPPFDYWGQGTLVTVSS
246 3923 227 GAFSSYAIS
246 3924 228 GGCGCCTTCAGCAGCTATGCTATCAGC
246 3925 229 GITHLFGTVSYAPKFQG
246 3926 230 GGGATCACCCATTTGTTTGGGACAGTTAGTTACGCTCCGAAGTTCCAG
GGC
246 3927 231 ARDAYEVWTGSYLPPFDY
246 3928 232 GCGAGAGATGCTTACGAGGTGTGGACTGGTTCTTATCTCCCCCCTTTT
GACTAC
246 3929 233 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGCCACCCTCTCTTGCAGGGCCAGTCAGACTGTTACAAGCAA
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGATGCACTCACCAGGGCCACTGGCATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATTTTGCACTTTATTATTGTCAGCAGTATGGTAGTTCA
TTCCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA
246 3930 234 EIVLTQSPGTLSLSPGERATLSCRASQTVTSNYLAWYQQKPGQAPRLLIY
DALTRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQQYGSSFLTFGG
GTKLEIK
246 3931 235 RASQTVTSNYLA
246 3932 236 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC
246 3933 237 DALTRAT
246 3934 238 GATGCACTCACCAGGGCCACT
246 3935 239 QQYGSSFLT
246 3936 240 CAGCAGTATGGTAGTTCATTCCTCACT
247 3937 241 CAGGTCCAGCTGGTACAGTCTGGAGCTGAGGTGAAGGAGCCTGGGGC
CTCAGTGAGGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTA
TGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAG
TTCCAGGGCAGAGTCACCGTGACCACAGACACATCCACGAGCGCAGC
CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCATTTATT
ACTGTGCGAGAGATTCATTTTCACTGACTGGTGCTGGATTTCCTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
247 3938 242 QVQLVQSGAEVKEPGASVRVSCKASGYTFTSYGISWVRQAPGQGLEWM
GWISAYNGNTNYAQKFQGRVTVTTDTSTSAAYMELRSLRSDDTAIYYCA
RDSFSLTGAGFPDYWGQGTLVTVSS
247 3939 243 YTFTSYGIS
247 3940 244 TACACCTTTACCAGCTATGGTATCAGC
247 3941 245 WISAYNGNTNYAQKFQG
247 3942 246 TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA
GGGC
247 3943 247 ARDSFSLTGAGFPDY
247 3944 248 GCGAGAGATTCATTTTCACTGACTGGTGCTGGATTTCCTGACTAC
247 3945 249 GAAATTGTAATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGT
GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGACACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GCTACACAGTGGCCTCGCACGTTCGGCCAAGGGACCAAGGTGGAAAT
CAAA
247 3946 250 EIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRR
LIYKVSNRDSGVPDRFSGSGSDTDFTLKISRVEAEDVGVYYCMQATQWP
RTFGQGTKVEIK
247 3947 251 RSSQSLVYSDGNTYLN
247 3948 252 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAA
T
247 3949 253 KVSNRDS
247 3950 254 AAGGTTTCTAACCGGGACTCT
247 3951 255 MQATQWPRT
247 3952 256 ATGCAAGCTACACAGTGGCCTCGCACG
248 3953 257 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTA
TAACATCAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGG
TCTCATCCATTAGTGGTGGTAGTAATTACATAGACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG
TATTTGCAAATGAACAACCTGCGAGCCGAAGACACGGCTGTGTATTA
CTGTGCGAGACTTGGCTATGGTGGTAACCCGGAGCTTGACTATTGGG
GCCAGGGAACCCTGGTCACTGTCTCCTCA
248 3954 258 EVQLLESGGGLVKPGGSLRLSCVASGFTFSSYNINWVRQAPGKGLEWVS
SISGGSNYIDYADSVKGRFTISRDNAKNSLYLQMNNLRAEDTAVYYCAR
LGYGGNPELDYWGQGTLVTVSS
248 3955 259 FTFSSYNIN
248 3956 260 TTCACCTTCAGTAGCTATAACATCAAC
248 3957 261 SISGGSNYIDYADSVKG
248 3958 262 TCCATTAGTGGTGGTAGTAATTACATAGACTACGCAGACTCAGTGAA
GGGC
248 3959 263 ARLGYGGNPELDY
248 3960 264 GCGAGACTTGGCTATGGTGGTAACCCGGAGCTTGACTAT
248 3961 265 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGACA
GAGGGTCACCATCTCCTGCACCGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTACCAGCAACGTCCAGGAACAGCCCCCAAA
CTCCTCATCTATGCTAATAACAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACCTC
AGTCTGAGTAGTTCGAGGGTATTCGGCGGAGGGACCAAGCTGACCGT
CCTC
248 3962 266 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQRPGTAPKLLI
YANNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDLSLSSS
RVFGGGTKLTVL
248 3963 267 TGSSSNIGAGYDVH
248 3964 268 ACCGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC
248 3965 269 ANNNRPS
248 3966 270 GCTAATAACAATCGGCCCTCA
248 3967 271 QSYDLSLSSSRV
248 3968 272 CAGTCCTATGACCTCAGTCTGAGTAGTTCGAGGGTA
249 3969 273 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAAACACTCATGTGCAGCCTCTGGATTCACCTTCAATAACTA
TGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTGGAGTGGG
TGGCAGCTATCTCATATGATGGAAGCAATGAATACTACTCAAACTCC
GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGTACACGCT
GTATCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTGTATT
ACTGTGCGAGAGGCGCCTCCTATTACTATGTGAGTAGTGACCTTGGCT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
249 3970 274 QVQLVQSGGGVVQPGRSLKHSCAASGFTFNNYAIHWVRQAPGKGLEWV
AAISYDGSNEYYSNSVKGRFTISRDNSKYTLYLQMNSLRPEDTAVYYCA
RGASYYYVSSDLGYWGQGTLVTVSS
249 3971 275 FTFNNYAIH
249 3972 276 TTCACCTTCAATAACTATGCTATACAC
249 3973 277 AISYDGSNEYYSNSVKG
249 3974 278 GCTATCTCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAA
GGGC
249 3975 279 ARGASYYYVSSDLGY
249 3976 280 GCGAGAGGCGCCTCCTATTACTATGTGAGTAGTGACCTTGGCTAC
249 3977 281 CAGCCTGTGCTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGTCAG
GTTATGATGTGCACTGGTATCAGCAGCTTCCAGGAACAGCCCCCAAA
GTCGTCATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGAGCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
CTGAGTGCCTCTTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA
249 3978 282 QPVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKVVI
YGNINRPSGVPERFSGSKSGTSASLAITGLQAEDEADYYCQSYDSLSASW
VFGGGTKLTVL
249 3979 283 TGSSSNIGSGYDVH
249 3980 284 ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCAC
249 3981 285 GNINRPS
249 3982 286 GGTAACATCAATCGGCCCTCA
249 3983 287 QSYDSLSASWV
249 3984 288 CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG
250 3985 289 CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAAAGACCAGAGA
GTCTCTGAAGATCTACTGTAAGGGTTCTGGATACAGCTTTATCAGCCA
CTGGATCGGCTGGGTGCGCCAGAAACCCGGGAAAGGCCTGGAGTGGA
TGGGGATCATCTATCCGGGTGACTCTGACACCAGATACAGCCCGTCCT
TCCAAGGCCAGGTCGCCATCTCAGCCGACAAGTCCATCAACACCGCC
TACCTGCAGTGGAGCAGCCTGAAGTCCTCGGACACCGCCATATATTA
CTGTGCGAGTGTAATGCTTCGGGGGATTATGTGGGGCCAGGGAACCC
TGGTCACCGTCTCCTCA
250 3986 290 QVQLVQSGPEVKKTRESLKIYCKGSGYSFISHWIGWVRQKPGKGLEWM
GIIYPGDSDTRYSPSFQGQVAISADKSINTAYLQWSSLKSSDTAIYYCASV
MLRGIMWGQGTLVTVSS
250 3987 291 YSFISHWIG
250 3988 292 TACAGCTTTATCAGCCACTGGATCGGC
250 3989 293 IIYPGDSDTRYSPSFQG
250 3990 294 ATCATCTATCCGGGTGACTCTGACACCAGATACAGCCCGTCCTTCCAA
GGC
250 3991 295 ASVMLRGIM
250 3992 296 GCGAGTGTAATGCTTCGGGGGATTATG
250 3993 297 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAAGTA
TCTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA
TCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGATTCAGT
GGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCA
GCCTGAAGATATTGCAACATATTACTGTCAGCCGTATGATAATCTCCC
TCCGCCGCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA
250 3994 298 DIRLTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYD
ASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQPYDNLPPPLTFGG
GTKLEIK
250 3995 299 QASQDISKYLN
250 3996 300 CAGGCGAGTCAGGACATTAGCAAGTATCTAAAT
250 3997 301 DASNLET
250 3998 302 GATGCATCCAATTTGGAAACA
250 3999 303 QPYDNLPPPLT
250 4000 304 CAGCCGTATGATAATCTCCCTCCGCCGCTCACT
251 4001 305 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAGGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCC
GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACGCT
GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT
ACTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
251 4002 306 EVQLLESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEWV
AGIFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYCA
RAPYDIWSGYCLDYWGQGTLVTVSS
251 4003 307 FTFSDNGMH
251 4004 308 TTCACCTTCAGTGACAATGGCATGCAC
251 4005 309 GIFYDGSNKQYADSVKG
251 4006 310 GGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA
GGGC
251 4007 311 ARAPYDIWSGYCLDY
251 4008 312 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC
251 4009 313 GACATCCAGATGACTCAGACTCCAGCCACCCTGTCTATGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGG
CAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTC
TGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCA
GACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
251 4010 314 DIQMTQTPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIY
GASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ
GTKLEIK
251 4011 315 RASQSVNNNLA
251 4012 316 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC
251 4013 317 GASTRAT
251 4014 318 GGTGCATCTACCAGGGCCACT
251 4015 319 QQYSIWPQT
251 4016 320 CAGCAGTATAGTATCTGGCCTCAGACT
252 4017 321 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACTATTGGAACGTA
CTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TGGCCAACATAAAACCAGATGGAAGTGAGCAATATTATGGGGACTCG
GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAATTCCCT
GTATCTGCAAATGCACAGCCTGAGAGCCGAGGACGCGGCTGTCTTTT
ACTGTGCGAGGGATACTCCCGACGTATTACGACATTTGGAGTGGCCC
CCTGTAGGTGCTTTTGATATCTGGGGCCAAGGGACCACGGTCACCGTC
TCCTCA
252 4018 322 EVQLVESGGGLVQPGGSLRLSCAASGFTIGTYWMSWVRQAPGKGLEWV
ANIKPDGSEQYYGDSVKGRFTISRDNAKNSLYLQMHSLRAEDAAVFYCA
RDTPDVLRHLEWPPVGAFDIWGQGTTVTVSS
252 4019 323 FTIGTYWMS
252 4020 324 TTCACTATTGGAACGTACTGGATGAGC
252 4021 325 NIKPDGSEQYYGDSVKG
252 4022 326 AACATAAAACCAGATGGAAGTGAGCAATATTATGGGGACTCGGTGAA
GGGC
252 4023 327 ARDTPDVLRHLEWPPVGAFDI
252 4024 328 GCGAGGGATACTCCCGACGTATTACGACATTTGGAGTGGCCCCCTGT
AGGTGCTTTTGATATC
252 4025 329 GAAATTGTAATGACGCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTCTTTTCTACAG
CTCCACCAATCAGCACTACTTGGCTTGGTACCAGCAGAAACCAGGAC
AGCCTCCTGAGCTGCTCATTTACTGGGCATCTATCCGGGAATCCGGGG
TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA
CCATCAGCAGCCTGCAGGCCGCAGATGTGGCAGTTTATTACTGTCAGC
AGTATTATAGTAGTCCTCAAACTTTTGGCCAGGGGACCAAGGTGGAA
ATCAAA
252 4026 330 EIVMTQSPDSLAVSLGERATINCKSSQSLFYSSTNQHYLAWYQQKPGQPP
ELLIYWASIRESGVPDRFSGSGSGTDFTLTISSLQAADVAVYYCQQYYSSP
QTFGQGTKVEIK
252 4027 331 KSSQSLFYSSTNQHYLA
252 4028 332 AAGTCCAGCCAGAGTCTTTTCTACAGCTCCACCAATCAGCACTACTTG
GCT
252 4029 333 WASIRES
252 4030 334 TGGGCATCTATCCGGGAATCC
252 4031 335 QQYYSSPQT
252 4032 336 CAGCAGTATTATAGTAGTCCTCAAACT
253 4033 337 CAGGTCCAGCTTGTGCAGTCTGGAACTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGTAAGGCTGCTGGTTACACCTTTAGCAACTA
CGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAG
GTCCAGGGCAGACTCACCATGACCACAGACACATCTACCAGCACAGC
CTACATGGAATTGAGGAACCTCAGATCTGACGACACGGCCGTGTATT
ATTGTGCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC
TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
253 4034 338 QVQLVQSGTEVKKPGASVKVSCKAAGYTFSNYGVSWVRQAPGQGLEW
MGWISAYNGNTKFAQKVQGRLTMTTDTSTSTAYMELRNLRSDDTAVYY
CARESGATAAAMFDYWGQGTLVTVSS
253 4035 339 YTFSNYGVS
253 4036 340 TACACCTTTAGCAACTACGGTGTCAGT
253 4037 341 WISAYNGNTKFAQKVQG
253 4038 342 TGGATCAGCGCTTATAATGGTAACACAAAATTTGCACAGAAGGTCCA
GGGC
253 4039 343 ARESGATAAAMFDY
253 4040 344 GCGAGAGAATCAGGGGCAACAGCGGCTGCTATGTTTGACTAC
253 4041 345 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGT
GATGGAAACATCTACTTGAGTTGGTTTCAACAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCGCCAGGGTGGAGGCTGAGGATGTTGCAGTTTATTACTGCATGCAA
GCTATACACTGGCCTCGAACTTTTGGCCAGGGGACCAAGGTGGAGAT
CAAA
253 4042 346 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNIYLSWFQQRPGQSPRRL
IYKVSHRDSGVPDRFSGSGSGTDFTLKIARVEAEDVAVYYCMQAIHWPR
TFGQGTKVEIK
253 4043 347 RSSQSLEYSDGNIYLS
253 4044 348 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACATCTACTTGAG
T
253 4045 349 KVSHRDS
253 4046 350 AAGGTTTCTCACCGGGACTCT
253 4047 351 MQAIHWPRT
253 4048 352 ATGCAAGCTATACACTGGCCTCGAACT
254 4049 353 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAGGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCC
GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACGCT
GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT
ACTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
254 4050 354 EVQLVESGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEWV
AGIFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYCA
RAPYDIWSGYCLDYWGQGTLVTVSS
254 4051 355 FTFSDNGMH
254 4052 356 TTCACCTTCAGTGACAATGGCATGCAC
254 4053 357 GIFYDGSNKQYADSVKG
254 4054 358 GGTATATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA
GGGC
254 4055 359 ARAPYDIWSGYCLDY
254 4056 360 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC
254 4057 361 GACATCCGGTTGACCCAGTCTCCAGCCACCCTGTCTATGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGG
CAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTC
TGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCA
GACTTTTGGCCAGGGGACCAAAGTGGATATCAAA
254 4058 362 DIRLTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIYG
ASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQG
TKVDIK
254 4059 363 RASQSVNNNLA
254 4060 364 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC
254 4061 365 GASTRAT
254 4062 366 GGTGCATCTACCAGGGCCACT
254 4063 367 QQYSIWPQT
254 4064 368 CAGCAGTATAGTATCTGGCCTCAGACT
255 4065 369 GAGGTGCAGCTGTTGGAGTCTGGGGGAGCCTTGGTCGAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTTAACACGTA
TTCCATGAACTGGGTCCGCCAGGGTCCAGGGAAGGGACTGGAGTGGG
TCGCAACGATAAGTACGAGTACTGCTGGCTCATACTACGCAGACTCC
GTGAGGGGCCGGTTCACCATCTCTAGAGACAATTCCAAGAACACGTT
ATATCTGCAAATGAACAGTCTGAGAGTCGAAGACACGGCCGTATATT
ACTGTGCGAGAGATCAGGAAGTGGAACTGATCGATGATGCTTTTGAT
TTCTGGGGCCGGGGGACAATGGTCACCGTCTCTTCA
255 4066 370 EVQLLESGGALVEPGGSLRLSCAASGFSFNTYSMNWVRQGPGKGLEWV
ATISTSTAGSYYADSVRGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCA
RDQEVELIDDAFDFWGRGTMVTVSS
255 4067 371 FSFNTYSMN
255 4068 372 TTCTCCTTTAACACGTATTCCATGAAC
255 4069 373 TISTSTAGSYYADSVRG
255 4070 374 ACGATAAGTACGAGTACTGCTGGCTCATACTACGCAGACTCCGTGAG
GGGC
255 4071 375 ARDQEVELIDDAFDF
255 4072 376 GCGAGAGATCAGGAAGTGGAACTGATCGATGATGCTTTTGATTTC
255 4073 377 GATATTGTGATGACTCAGACACATTCCTCCCTGTCTGCATCTGTGGGA
GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTATCTG
GGTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA
TCTATAAGGCGTCTAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCG
GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG
CCTGATGACTCTGCAACTTATTACTGCCAACAGTATTACACCTATTAC
AGTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
255 4074 378 DIVMTQTHSSLSASVGDRVTITCRASQSISIWVAWYQQKPGKAPNLLIYK
ASSLQSGVPSRFSGSGSGTEFTLTISSLQPDDSATYYCQQYYTYYSFGQGT
KLEIK
255 4075 379 RASQSISIWVA
255 4076 380 CGGGCCAGTCAGAGTATTAGTATCTGGGTGGCC
255 4077 381 KASSLQS
255 4078 382 AAGGCGTCTAGTTTACAAAGT
255 4079 383 QQYYTYYS
255 4080 384 CAACAGTATTACACCTATTACAGT
256 4081 385 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAGGCCTGGGGC
CTCAGTGAAAATCTCCTGCAAGGCTTCTGAATACGCCTTCACCGCCCA
CTATCTTCACTGGGTGCGACAGGCCCCTGATCAAGGACTTGAGTGGAT
GGGATGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGT
TTCACGGCAGGGTCAGCATGACCAGTGACACGTCCATCAGTACAGTC
TATATGGAACTGAGCAGCCTGACATCTGACGACACGGCCGTCTATTA
CTGTGCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCT
GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
256 4082 386 EVQLVESGAEVKRPGASVKISCKASEYAFTAHYLHWVRQAPDQGLEWM
GWISPKSGGTNYAQKFHGRVSMTSDTSISTVYMELSSLTSDDTAVYYCA
RSSLVGASPNFDFWGQGTLVTVSS
256 4083 387 YAFTAHYLH
256 4084 388 TACGCCTTCACCGCCCACTATCTTCAC
256 4085 389 WISPKSGGTNYAQKFHG
256 4086 390 TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCA
CGGC
256 4087 391 ARSSLVGASPNFDF
256 4088 392 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTC
256 4089 393 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACA
GAGGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATA
ATTATGTATCCTGGTACCAGCAACTCCCAGGAACTACCCCCAAAGTCC
TCATTTACGACAATAATCAGCGACCCTCAGGGATTCCTGACCGTTTCT
CTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCC
AGACTGGCGACGAGGCCGTCTATTATTGCGGAACATGGGATGCCAGC
CTGAGTGCTGCTATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCTA
256 4090 394 QSVLTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQLPGTTPKVLIYD
NNQRPSGIPDRFSGSKSGTSATLAISGLQTGDEAVYYCGTWDASLSAAM
VFGGGTKLTVL
256 4091 395 SGSSSNIGNNYVS
256 4092 396 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCC
256 4093 397 DNNQRPS
256 4094 398 GACAATAATCAGCGACCCTCA
256 4095 399 GTWDASLSAAMV
256 4096 400 GGAACATGGGATGCCAGCCTGAGTGCTGCTATGGTT
257 4097 401 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCGGATA
TTACTGGAGCTGGATCCGGCAGCCCCCAGGGAGGGGACTGGAGTGGA
TTGGGTTTATTTATTATAGTGGGAGTACCAGCTACGACTCCTCCCTCA
AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC
CTAAACCTGAGCTCTGTGACCGCTGCGGACACGGCCGTATATTACTGT
GCGAGAAGTACATGGGACTACGGTGACCACTTTCCGTTTGACTACTG
GGGCCAGGGAACCCTGGTCACCGTCTCCTCA
257 4098 402 QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGRGLEWIGFI
YYSGSTSYDSSLKSRVTISVDTSKNQFSLNLSSVTAADTAVYYCARSTWD
YGDHFPFDYWGQGTLVTVSS
257 4099 403 GSISGYYWS
257 4100 404 GGCTCCATCAGCGGATATTACTGGAGC
257 4101 405 FIYYSGSTSYDSSLKS
257 4102 406 TTTATTTATTATAGTGGGAGTACCAGCTACGACTCCTCCCTCAAGAGT
257 4103 407 ARSTWDYGDHFPFDY
257 4104 408 GCGAGAAGTACATGGGACTACGGTGACCACTTTCCGTTTGACTAC
257 4105 409 TCCTATGAGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAA
GACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAATTAAAGATG
TGCACTGGTACCAACTGAGGCCAGGCCAGGCCCCTGTGTTGGTCATCT
CTTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT
CCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCC
GGGGATGAGGCCGACTATTTCTGTCAGGTGTGGGATAGTAGTCCTGA
TCATCCTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA
257 4106 410 SYELTQPPSVSVAPGKTARITCGGNNIGIKDVHWYQLRPGQAPVLVISYD
SDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYFCQVWDSSPDHPYVF
GTGTKLTVL
257 4107 411 GGNNIGIKDVH
257 4108 412 GGGGGAAACAACATTGGAATTAAAGATGTGCAC
257 4109 413 YDSDRPS
257 4110 414 TATGATAGCGACCGGCCCTCA
257 4111 415 QVWDSSPDHPYV
257 4112 416 CAGGTGTGGGATAGTAGTCCTGATCATCCTTATGTC
258 4113 417 GAGGTGCAGCTGGTGGAGTCTGGAGGTGAGGTGAAGAAGCCTGGGG
CCTCAGTGAAGGTCTCCTGCAGGGCCTCTGGTTACACCTTTAGAAACT
ATGGCCTCACCTGGGTGCGGCAGGCCCCCGGACAAGGGCTTGAGTGG
ATGGGATGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAA
GTTCCAGGGCAGAGTCACACTGACCACGGACACATCCACGAGCACAG
CCTACATGGAACTGAGGAGCCTAAGATCTGACGACACGGCCGTGTAT
TTCTGTGCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTC
TGGGGCACAGGGACCACGGTCACCGTCTCCTCA
258 4114 418 EVQLVESGGEVKKPGASVKVSCRASGYTFRNYGLTWVRQAPGQGLEW
MGWISAYNGNTNYAQKFQGRVTLTTDTSTSTAYMELRSLRSDDTAVYF
CARDVPGHGAAFMDVWGTGTTVTVSS
258 4115 419 YTFRNYGLT
258 4116 420 TACACCTTTAGAAACTATGGCCTCACC
258 4117 421 WISAYNGNTNYAQKFQG
258 4118 422 TGGATCAGCGCTTACAATGGAAACACAAACTATGCACAGAAGTTCCA
GGGC
258 4119 423 ARDVPGHGAAFMDV
258 4120 424 GCGAGAGACGTCCCCGGCCACGGCGCTGCCTTCATGGACGTC
258 4121 425 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGG
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAAGCCAGT
GATACAAATATCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATCT
CCAAGGCGCCTAATTTATAAGATTTCTAACCGAGACTCTGGGGTCCCA
GACAGATTCAGCGGCAGTGGGTCAGGCACTCATTTCACACTGAGAAT
CAGCAGGGTGGAGGCTGACGATGTTGCGGTTTATTACTGCATGCAGG
GTACACACTGGCCTCCGGCGTTCGGCCAGGGGACCAAGCTGGAGATC
AAA
258 4122 426 ETTLTQSPLSLPVTLGQPASISCRSSQSLEASDTNIYLSWFQQRPGQSPRRL
IYKISNRDSGVPDRFSGSGSGTHFTLRISRVEADDVAVYYCMQGTHWPPA
FGQGTKLEIK
258 4123 427 RSSQSLEASDTNIYLS
258 4124 428 AGGTCTAGTCAAAGCCTCGAAGCCAGTGATACAAATATCTACTTGAG
T
258 4125 429 KISNRDS
258 4126 430 AAGATTTCTAACCGAGACTCT
258 4127 431 MQGTHWPPA
258 4128 432 ATGCAGGGTACACACTGGCCTCCGGCG
259 4129 433 GAGGTGCAGCTGGTGGAGTCTGGATCTGAGGTGAAGAAGCCTGGGGC
CGCAGTGAAGGTATCCTGCAAGGCTTCTGGTTACATCTTTGCCAACTT
TGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAG
TTCCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGCACAGC
CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATT
ATTGTGCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTCT
GGGGCAAAGGGACCACGGTCACCGTCTCCTCA
259 4130 434 EVQLVESGSEVKKPGAAVKVSCKASGYIFANFGVSWVRQAPGQGLEWM
GWISAYNGNTNYAQKFQGRVIMTTDTSTSTAYMELRSLRSDDTAVYYC
ARDPPAYAATLMDVWGKGTTVTVSS
259 4131 435 YIFANFGVS
259 4132 436 TACATCTTTGCCAACTTTGGTGTCAGC
259 4133 437 WISAYNGNTNYAQKFQG
259 4134 438 TGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCA
GGGC
259 4135 439 ARDPPAYAATLMDV
259 4136 440 GCGAGAGACCCCCCCGCCTACGCCGCTACATTGATGGACGTC
259 4137 441 GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAACACAGT
GATACAAACACCTACTTGACTTGGTATCAGCAGAGGCCAGGCCAATC
TCCAAGGCGGCTACTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGCTGGAGAT
CAAA
259 4138 442 DIVMTQSPLSLPVTLGQSASISCRSSQSLEHSDTNTYLTWYQQRPGQSPRR
LLYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWP
PTFGQGTKLEIK
259 4139 443 RSSQSLEHSDTNTYLT
259 4140 444 AGGTCTAGTCAAAGCCTCGAACACAGTGATACAAACACCTACTTGAC
T
259 4141 445 KVSNRDS
259 4142 446 AAGGTTTCTAACCGGGACTCT
259 4143 447 MQGTHWPPT
259 4144 448 ATGCAAGGTACACACTGGCCTCCGACG
260 4145 449 GAGGTGCAGCTGGTGGAGTCTGGCCCAACACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCGTTGTCTCTGGTGGCTCCGTCTACAGGAG
TAGTAACTACTGGGCCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG
AGTGGATCGGGAGTGTCTATCATAGTGGGAACCCCTACTCCAACCCG
TCCCTTCAGAGTCGAGTCTCCGTCTCCATTGACACGTCCAAGAACCAG
TTCTCCCTGAAGCTGTACTCTGTGACCGCCGCAGACTCGGCTATTTAT
TATTGTGCGTGTAAAAGAGCGGACGCTGACGACGTAGATTACGTGGC
GGGCCTCACCGGTTTCCCCTGGTACTTCGATGTCTGGGGCCGTGGCAC
CCTGGTCACCGTCTCCTCA
260 4146 450 EVQLVESGPTLVKPSETLSLTCVVSGGSVYRSSNYWAWIRQPPGKGLEWI
GSVYHSGNPYSNPSLQSRVSVSIDTSKNQFSLKLYSVTAADSAIYYCACK
RADADDVDYVAGLTGFPWYFDVWGRGTLVTVSS
260 4147 451 GSVYRSSNYWA
260 4148 452 GGCTCCGTCTACAGGAGTAGTAACTACTGGGCC
260 4149 453 SVYHSGNPYSNPSLQS
260 4150 454 AGTGTCTATCATAGTGGGAACCCCTACTCCAACCCGTCCCTTCAGAGT
260 4151 455 ACKRADADDVDYVAGLTGFPWYFDV
260 4152 456 GCGTGTAAAAGAGCGGACGCTGACGACGTAGATTACGTGGCGGGCCT
CACCGGTTTCCCCTGGTACTTCGATGTC
260 4153 457 GAAATTGTGTTGACGCAGTCTCCGTCCACCCTGTCTGCATCTGTGGGA
GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGTTG
GTTGGCCTGGTATCAGCAGAAACCAGGGAAAACCCCTAAGTTGCTCA
TCTATAAGGCGTCTACTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCG
GCAGCGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG
CCTGATGATTTCGCAACCTACTACTGCCAACAGTATCATGTTTATTTC
CCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
260 4154 458 EIVLTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKTPKLLIYKA
STLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYHVYFPLTFGGG
TKVEIK
260 4155 459 RASQSISSWLA
260 4156 460 CGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCC
260 4157 461 KASTLES
260 4158 462 AAGGCGTCTACTTTAGAAAGT
260 4159 463 QQYHVYFPLT
260 4160 464 CAACAGTATCATGTTTATTTCCCGCTCACT
261 4161 465 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCAGCTTCAGTATGCA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGACAGCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCC
GTGAAGGGCCGATTCACGATCTCCAGAGACAATTCTAGGAACACGCT
GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT
ACTGTGCGAGAGATCATGCCTCAACTCCATACTACATGGACGTCTGG
GGCAAAGGGACCACGGTCACCGTCTCTTCA
261 4162 466 EVQLVESGGGVVQPGRSLRLSCVASGFSFSMHGMHWVRQAPGKGLEW
VTAIWYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYY
CARDHASTPYYMDVWGKGTTVTVSS
261 4163 467 FSFSMHGMH
261 4164 468 TTCAGCTTCAGTATGCATGGCATGCAC
261 4165 469 AIWYDGSNKYYADSVKG
261 4166 470 GCTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCCGTGAA
GGGC
261 4167 471 ARDHASTPYYMDV
261 4168 472 GCGAGAGATCATGCCTCAACTCCATACTACATGGACGTC
261 4169 473 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
GAAAGCGCCACCCTCTCCTGCAGGACCAGTCAGAGGATTAGCAGCAC
CTACTTAGCCTGGTACCGGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATGTATGGTGCATCCAGCAGGGCCACTGGCATCCCGGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCTG
GAGCCTGAAGATTTTGCACTATATTACTGTCAGCAGTATGGTAGCTTT
CCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
261 4170 474 ETTLTQSPGTLSLSPGESATLSCRTSQRISSTYLAWYRQKPGQAPRLLMY
GASSRATGIPDRFSGSGSGTDFTLTISSLEPEDFALYYCQQYGSFPWTFGQ
GTKVEIK
261 4171 475 RTSQRISSTYLA
261 4172 476 AGGACCAGTCAGAGGATTAGCAGCACCTACTTAGCC
261 4173 477 GASSRAT
261 4174 478 GGTGCATCCAGCAGGGCCACT
261 4175 479 QQYGSFPWT
261 4176 480 CAGCAGTATGGTAGCTTTCCGTGGACG
262 4177 481 CAGGTCCAGCTGGTGCAGTCTGGGCCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTA
TGCTATCACGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGGGGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACGGAACT
TCAAGGGGAGAGTCACCTTTACCGCGGACAAATCCGCGAACACGGCC
TACATGGAACTGACCAATGTGAGATCCGACGACACGGCCGTGTATTA
CTGTGCGAGAGGCTGTTGTGGGGCTGTGGCTGGATTCCAGCACTGGG
GCCAGGGCACCGGGGTCACCGTCTCCTCA
262 4178 482 QVQLVQSGPEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWM
GGIIPSFDRVDYSRNFKGRVTFTADKSANTAYMELTNVRSDDTAVYYCA
RGCCGAVAGFQHWGQGTGVTVSS
262 4179 483 GTFSSYAIT
262 4180 484 GGCACCTTCAGCAGTTATGCTATCACG
262 4181 485 GIIPSFDRVDYSRNFKG
262 4182 486 GGGATCATCCCTTCCTTTGATAGAGTGGACTATTCACGGAACTTCAAG
GGG
262 4183 487 ARGCCGAVAGFQH
262 4184 488 GCGAGAGGCTGTTGTGGGGCTGTGGCTGGATTCCAGCAC
262 4185 489 GATATTGTGCTGACGCAGACTCCAGCCACCCTGTCTTTATCTCCAGGG
GAAACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCACCTA
CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCCAACAGGGCCACTGGCGTCCCAACCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAG
CCTGAAGATTATGCGATTTATTACTGTCAGCAACGTACTACCGGGGTC
ACTTTCGGCGGGGGGACCAAGGTGGAAATCAAA
262 4186 490 DIVLTQTPATLSLSPGETATLSCRASQSVTTYLAWYQQKPGQAPRLLIYD
ASNRATGVPTRFSGSGSGTDFTLTISSLEPEDYAIYYCQQRTTGVTFGGGT
KVEIK
262 4187 491 RASQSVTTYLA
262 4188 492 AGGGCCAGTCAGAGTGTTACCACCTACTTAGCC
262 4189 493 DASNRAT
262 4190 494 GATGCATCCAACAGGGCCACT
262 4191 495 QQRTTGVT
262 4192 496 CAGCAACGTACTACCGGGGTCACT
263 4193 497 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGTTTT
GGCATGCATTGGGTCCGCCAGGCTCCAGGGCAGGGACTGGAGTGGGT
CGCATCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCACTG
TCTCTGCAAATGAAGAACCTGAGAGCCGAGGACACGGCTGAGTATTA
CTGTGTGCGAGGAGTCCTACCAGGTGGTACTGGGGGGGGCTGGTTCG
ACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
263 4194 498 QVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVRQAPGQGLEWV
ASITGGSSYINYADSVKGRFTISRDNAKKSLSLQMKNLRAEDTAEYYCVR
GVLPGGTGGGWFDSWGQGTLVTVSS
263 4195 499 FTFSSFGMH
263 4196 500 TTCACCTTCAGTAGTTTTGGCATGCAT
263 4197 501 SITGGSSYINYADSVKG
263 4198 502 TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAA
GGGC
263 4199 503 VRGVLPGGTGGGWFDS
263 4200 504 GTGCGAGGAGTCCTACCAGGTGGTACTGGGGGGGGCTGGTTCGACTC
C
263 4201 505 CAGTCTGTCCTGACTCAGCCGCCCTCAATGTCTGGGGCCCCAGGGCAG
AGGGTCACCATCTCCTGCACTGGGACCAGCTCCAACATCGGGGCGGG
TTATGATGTACAGTGGTATCAGCAGTTTCCAGGAACAGCCCCCAAACT
CCTCATCTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGATT
CTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGCCATCACTGGGCT
CCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACTACA
GCCTGAATTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA
263 4202 506 QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQQFPGTAPKLLI
SGNNNRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDYSLNW
VFGGGTKLTVL
263 4203 507 TGTSSNIGAGYDVQ
263 4204 508 ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAG
263 4205 509 GNNNRPS
263 4206 510 GGTAACAACAATCGGCCCTCA
263 4207 511 QSYDYSLNWV
263 4208 512 CAGTCCTATGACTACAGCCTGAATTGGGTG
264 4209 513 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCGCTCACCTGCACTGTCTCTGGTCGCTTCCTCAATAGTGG
TGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGG
AGTGGCTTGGTTACATCCATCACAGTGGGAACACCTACTACAACCCGT
CCCTCAAGAGTCGACTTACCATATCACTAGACATGTCCAAGAACCAG
TTCTCCCTGAAGTTGAGCTCTGTGACAGCCGCAGACACGGCCGTCTAT
TACTGTGCCAGAGATTTGGGAAAGCCGCTTTGGGACGGCCACTATTA
CTACGGAGTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT
CA
264 4210 514 QVQLQESGPGLVKPSQTLSLTCTVSGRFLNSGDYYWSWIRQSPGKGLEW
LGYIHHSGNTYYNPSLKSRLTISLDMSKNQFSLKLSSVTAADTAVYYCAR
DLGKPLWDGHYYYGVDVWGQGTTVTVSS
264 4211 515 RFLNSGDYYWS
264 4212 516 CGCTTCCTCAATAGTGGTGATTACTACTGGAGT
264 4213 517 YIHHSGNTYYNPSLKS
264 4214 518 TACATCCATCACAGTGGGAACACCTACTACAACCCGTCCCTCAAGAG
T
264 4215 519 ARDLGKPLWDGHYYYGVDV
264 4216 520 GCCAGAGATTTGGGAAAGCCGCTTTGGGACGGCCACTATTACTACGG
AGTGGACGTC
264 4217 521 GATATTGTGATGACTCAGTCTCCAGGCACTCTGTCTTTGTCTCCAGGA
GAAAGAGCCACCCTCTCCTGCAGGACCAGTCAGAATGTTAACAGCAA
CTACTTAGCCTGGTACCAGCATAAACCTGGGCAGGCTCCCAGGCTCCT
CATCTATGGTGCATCCAGCAGGGTCACTGGCATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCACCAGAGTG
GAGTCTGAAGATTTTGCAGTGTATTACTGTCAGGTGTATAGTAGTTCA
CCTCCGATCACCTTCGGCCAGGGGACCAAGGTGGAGATCAAA
264 4218 522 DIVMTQSPGTLSLSPGERATLSCRTSQNVNSNYLAWYQHKPGQAPRLLIY
GASSRVTGIPDRFSGSGSGTDFTLTITRVESEDFAVYYCQVYSSSPPITFGQ
GTKVEIK
264 4219 523 RTSQNVNSNYLA
264 4220 524 AGGACCAGTCAGAATGTTAACAGCAACTACTTAGCC
264 4221 525 GASSRVT
264 4222 526 GGTGCATCCAGCAGGGTCACT
264 4223 527 QVYSSSPPIT
264 4224 528 CAGGTGTATAGTAGTTCACCTCCGATCACC
265 4225 529 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTA
TGCTATCAGCTGGGTGCGTCAGGCCCCAGGACAAGGGCTTGAGTGGA
TGGGAGGAATCATCCCTATGTTTGATATAGTCGACTACGCACAGAAG
TTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAACACAGC
CTACATGGAGCTGACCAGCCTGAGATCTGAGGACACGGCCGTGTATT
ACTGTGCGAGAACTGCGGCTTTAGGACCACCTGGGACTATAGTGGGG
TACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA
265 4226 530 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWM
GGIIPMFDIVDYAQKFQGRVTITADESTNTAYMELTSLRSEDTAVYYCAR
TAALGPPGTIVGYMDVWGKGTTVTVSS
265 4227 531 GTFSSYAIS
265 4228 532 GGCACCTTCAGCAGTTATGCTATCAGC
265 4229 533 GIIPMFDIVDYAQKFQG
265 4230 534 GGAATCATCCCTATGTTTGATATAGTCGACTACGCACAGAAGTTCCAG
GGC
265 4231 535 ARTAALGPPGTIVGYMDV
265 4232 536 GCGAGAACTGCGGCTTTAGGACCACCTGGGACTATAGTGGGGTACAT
GGACGTC
265 4233 537 GATATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
GAGCCGGCCTCCATCTCCTGCCGGTCTAGTCAGAGCCTCCTGCAAAGT
AATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGGC
TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC
TGACAAGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA
TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
ACTCTACAAACTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT
CAAA
265 4234 538 DIVMTQSPLSLPVTPGEPASISCRSSQSLLQSNGYNYLDWYLQKPGQAPQ
LLIYLGSNRASGVPDKFSGSGSGTDFTLKISRVEAEDVGVYYCMQTLQTP
WTFGQGTKVEIK
265 4235 539 RSSQSLLQSNGYNYLD
265 4236 540 CGGTCTAGTCAGAGCCTCCTGCAAAGTAATGGATACAACTATTTGGAT
265 4237 541 LGSNRAS
265 4238 542 TTGGGTTCTAATCGGGCCTCC
265 4239 543 MQTLQTPWT
265 4240 544 ATGCAAACTCTACAAACTCCGTGGACG
266 4241 545 CAGGTGCAGCTGGTGGAGTCTGGAGCAGAGGCGAGAAAGCCCGGGG
AGTCTCTGAAGATCTCCTGTAAGGCTTCTGGATACAGCTTTACCAATT
ATTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG
ATGGGGGTCATCTATCCTGCTGACTCCGATACCAGATATAGCCCGTCC
TTCAAAGGCCAGGTCACCATCTCAGCCGACAAATCCATCAGCACCGC
CTACCTCCAGTGGACCAGACTGAAGGCCTCGGACACCGCCGTGTATTT
CTGTGCGAGACTTGGAATAGGAGCTGCTGCCCGGAACTACTGGGGCC
AGGGAACCCTGGTCACCGTCTCTTCA
266 4242 546 QVQLVESGAEARKPGESLKISCKASGYSFTNYWIGWVRQMPGKGLEWM
GVIYPADSDTRYSPSFKGQVTISADKSISTAYLQWTRLKASDTAVYFCAR
LGIGAAARNYWGQGTLVTVSS
266 4243 547 YSFTNYWIG
266 4244 548 TACAGCTTTACCAATTATTGGATCGGC
266 4245 549 VIYPADSDTRYSPSFKG
266 4246 550 GTCATCTATCCTGCTGACTCCGATACCAGATATAGCCCGTCCTTCAAA
GGC
266 4247 551 ARLGIGAAARNY
266 4248 552 GCGAGACTTGGAATAGGAGCTGCTGCCCGGAACTAC
266 4249 553 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCGACAG
TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA
TCTACGATGCATCCAAGTCGGAAACAGGGGTCCCATCAAGATTCAGT
GGAAGCGGATCTGGGACAGATTTCACTTTCACCATCAGTAGCCTGCA
GCCTGAAGATCTTGCAACATATTACTGTCTACAGTTTGATAATCTCCC
TCCGACCTTCGGCCAAGGGACACGACTGGAGATTAAA
266 4250 554 DIQVTQSPSSLSASVGDRVTITCQASQDISDSLNWYQQKPGKAPNLLIYD
ASKSETGVPSRFSGSGSGTDFTFTISSLQPEDLATYYCLQFDNLPPTFGQG
TRLEIK
266 4251 555 QASQDISDSLN
266 4252 556 CAGGCGAGTCAGGACATTAGCGACAGTTTAAAT
266 4253 557 DASKSET
266 4254 558 GATGCATCCAAGTCGGAAACA
266 4255 559 LQFDNLPPT
266 4256 560 CTACAGTTTGATAATCTCCCTCCGACC
267 4257 561 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
267 4258 562 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
267 4259 563 FSFRSYSMN
267 4260 564 TTCAGCTTCAGGAGCTATAGCATGAAC
267 4261 565 SISSSSNYINYADSVKG
267 4262 566 TCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAGTGAA
GGGC
267 4263 567 ARDLLPVERGPAFDI
267 4264 568 GCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATATC
267 4265 569 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
267 4266 570 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
VFGGGTKVTVL
267 4267 571 TGSSSNIGAGYDVH
267 4268 572 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC
267 4269 573 ANSNRPS
267 4270 574 GCTAACAGCAATCGGCCCTCA
267 4271 575 QSYDSRLGGSV
267 4272 576 CAGTCCTATGACAGCAGACTGGGTGGTTCGGTA
268 4273 577 CAGGTCCAGCTTGTGCAGTCTGGACCAGAGGTGAAAAAGCCCGGGGA
GTCTCTGACGATCTCCTGTAAGGGTTCTGGATACGACTTTTCCAATAA
CTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGA
TGGGAATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGT
TCCAAGGCCAGGTCACCCTCTCAGTCGACAAGTCCATTAGTACCGCCT
ACCTACAGTGGAGGAGCCTGAAGGCCTCGGACAGCGGCATCTACTAC
TGTGCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTA
CTTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCT
CCTCA
268 4274 578 QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVRQMPGKGLEWM
GIIYPGDSDTRYSPSFQGQVTLSVDKSISTAYLQWRSLKASDSGIYYCARQ
IGGLVCSSESCYFYGMDVWGQGTTVTVSS
268 4275 579 YDFSNNWIG
268 4276 580 TACGACTTTTCCAATAACTGGATCGGC
268 4277 581 IIYPGDSDTRYSPSFQG
268 4278 582 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAA
GGC
268 4279 583 ARQIGGLVCSSESCYFYGMDV
268 4280 584 GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTC
TACGGCATGGACGTC
268 4281 585 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGA
GGCAGAGTGACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTA
TTTAAATTGGTATCAACACAAACCGGGGAAAGCCCCTGAACTCCTGA
TCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG
GCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAA
CCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTGACACTACCCCG
TTCACTTTCGGCCAGGGGACCAAAGTGGATATCAAA
268 4282 586 DIQLTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKPGKAPELLIYGA
SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPFTFGQGT
KVDIK
268 4283 587 RASQSISNYLN
268 4284 588 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT
268 4285 589 GASSLQS
268 4286 590 GGTGCATCCAGTTTGCAAAGT
268 4287 591 QQSDTTPFT
268 4288 592 CAACAGAGTGACACTACCCCGTTCACT
269 4289 593 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTAAAGCCGGGGGG
GTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAAGGC
CTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TTGGCCGTATTAGAAGCAAAACTGATGGTGGGACAGCAGACTACGCG
GCACCCGTGAAAGGCAGATTCACCATGTCAAGAGATGATTCAAAAAA
CACGCTGTATTTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCG
TGTATTACTGTGCCACAGATTCTCGCCGACTCTATGATAGTCGTGGTT
TTTATTCAAGTGCTTTTGATGTCTGGGGCCAAGGGACCACGGTCACCG
TCTCCTCA
269 4290 594 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSKAWMNWVRQAPGKGLEW
VGRIRSKTDGGTADYAAPVKGRFTMSRDDSKNTLYLQMNSLKTEDTAV
YYCATDSRRLYDSRGFYSSAFDVWGQGTTVTVSS
269 4291 595 FTFSKAWMN
269 4292 596 TTCACTTTCAGTAAGGCCTGGATGAAC
269 4293 597 RIRSKTDGGTADYAAPVKG
269 4294 598 CGTATTAGAAGCAAAACTGATGGTGGGACAGCAGACTACGCGGCACC
CGTGAAAGGC
269 4295 599 ATDSRRLYDSRGFYSSAFDV
269 4296 600 GCCACAGATTCTCGCCGACTCTATGATAGTCGTGGTTTTTATTCAAGT
GCTTTTGATGTC
269 4297 601 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCGG
GTTATGATGTACACTGGTACCAACACCTTCCAGGAACAGCCCCCAAA
GTCCTCATCTATGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACGAC
AGCCTGACTGGTTGGGTGTTCGGCGGAGGGACCAAGGTCACCGTCCT
A
269 4298 602 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQHLPGTAPKVLI
YGNNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDDSLTG
WVFGGGTKVTVL
269 4299 603 TGSSSNIGAGYDVH
269 4300 604 ACTGGGAGCAGCTCCAACATCGGGGCGGGTTATGATGTACAC
269 4301 605 GNNNRPS
269 4302 606 GGTAACAACAATCGGCCCTCA
269 4303 607 QSYDDSLTGWV
269 4304 608 CAGTCCTATGACGACAGCCTGACTGGTTGGGTG
270 4305 609 CAGGTGCAGCTGGTGCAATCTGGACCAGAGGTGAAAAAGCCCGGGG
AGTCTCTGACGATCTCCTGTAAGGGTTCTGGATACGACTTTTCCAATA
ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG
ATGGGAATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCG
TTCCAAGGCCAGGTCACCCTCTCAGTCGACAAGTCCATTAGTACCGCC
TACCTACAGTGGAGGAGCCTGAAGGCCTCGGACAGCGGCATCTACTA
CTGTGCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCT
ACTTCTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTC
TCCTCA
270 4306 610 QVQLVQSGPEVKKPGESLTISCKGSGYDFSNNWIGWVRQMPGKGLEWM
GIIYPGDSDTRYSPSFQGQVTLSVDKSISTAYLQWRSLKASDSGIYYCARQ
IGGLVCSSESCYFYGMDVWGQGTTVTVSS
270 4307 611 YDFSNNWIG
270 4308 612 TACGACTTTTCCAATAACTGGATCGGC
270 4309 613 IIYPGDSDTRYSPSFQG
270 4310 614 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGTTCCAA
GGC
270 4311 615 ARQIGGLVCSSESCYFYGMDV
270 4312 616 GCGAGACAAATTGGCGGTTTGGTTTGTAGCAGTGAGAGCTGCTACTTC
TACGGCATGGACGTC
270 4313 617 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGA
GGCAGAGTGACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTA
TTTAAATTGGTATCAACACAAACCGGGGAAAGCCCCTGAACTCCTGA
TCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG
GCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAA
CCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTGACACTACCCCG
TTCACTTTCGGCCAGGGGACCAAGCTGGAGATCAAA
270 4314 618 DIRVTQSPSSLSASVGGRVTITCRASQSISNYLNWYQHKPGKAPELLIYGA
SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPFTFGQGT
KLEIK
270 4315 619 RASQSISNYLN
270 4316 620 CGGGCAAGTCAGAGCATTAGCAACTATTTAAAT
270 4317 621 GASSLQS
270 4318 622 GGTGCATCCAGTTTGCAAAGT
270 4319 623 QQSDTTPFT
270 4320 624 CAACAGAGTGACACTACCCCGTTCACT
271 4321 625 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCTTGTGCAGCCTCTGGATTCACCTTCAGTAGTTTT
GGCATGCATTGGGTCCGCCAGGCTCCAGGGCAGGGACTGGAGTGGGT
CGCATCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCACTG
TCTCTGCAAATGAAGAACCTGAGAGCCGAGGACACGGCTGAGTATTA
CTGTGTGCGAGGAGTCCTACCAGGTGATACTGGGGGGGGCTGGTTCG
ACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
271 4322 626 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSFGMHWVRQAPGQGLEWV
ASITGGSSYINYADSVKGRFTISRDNAKKSLSLQMKNLRAEDTAEYYCVR
GVLPGDTGGGWFDSWGQGTLVTVSS
271 4323 627 FTFSSFGMH
271 4324 628 TTCACCTTCAGTAGTTTTGGCATGCAT
271 4325 629 SITGGSSYINYADSVKG
271 4326 630 TCCATTACTGGTGGCAGCAGTTACATAAACTACGCAGACTCAGTGAA
GGGC
271 4327 631 VRGVLPGDTGGGWFDS
271 4328 632 GTGCGAGGAGTCCTACCAGGTGATACTGGGGGGGGCTGGTTCGACTC
C
271 4329 633 CAGTCTGTGCTGACGCAGCCGCCCTCAATGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGACCAGCTCCAACATCGGGGCGG
GTTATGATGTACAGTGGTATCAGCAGTTTCCAGGAACAGCCCCCAAA
CTCCTCATCTCTGGTAACAACAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACTAC
AGCCTGAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
271 4330 634 QSVLTQPPSMSGAPGQRVTISCTGTSSNIGAGYDVQWYQQFPGTAPKLLI
SGNNNRPSGVPDRFSGSKSGASASLAITGLQAEDEADYYCQSYDYSLNW
VFGGGTKLTVL
271 4331 635 TGTSSNIGAGYDVQ
271 4332 636 ACTGGGACCAGCTCCAACATCGGGGCGGGTTATGATGTACAG
271 4333 637 GNNNRPS
271 4334 638 GGTAACAACAATCGGCCCTCA
271 4335 639 QSYDYSLNWV
271 4336 640 CAGTCCTATGACTACAGCCTGAATTGGGTG
272 4337 641 CAGGTCCAGCTTGTACAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGA
GTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTT
CTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGA
TGGGCATCATATATCCTGGTGACTCTGATACCAGATATAGCCCGTCTT
TCCAAGGCCAGGTCACCATGTCAGCCGACACGTCCATAAACACCGCC
TACCTGCAGTGGAACAGCGTGAAGGCCTCGGACACCGCCATTTATTA
CTGTGCGAGACTTCCAGTTGGTAGTTATTATTACTTCAATCTCTGGGG
CCGTGGCACCCTGGTCACCGTCTCCTCA
272 4338 642 QVQLVQSGAEVKKPGESLKISCKGSGYSFSSFWIGWVRQMPGKGLEWM
GIIYPGDSDTRYSPSFQGQVTMSADTSINTAYLQWNSVKASDTAIYYCAR
LPVGSYYYFNLWGRGTLVTVSS
272 4339 643 YSFSSFWIG
272 4340 644 TACAGCTTTAGCAGTTTCTGGATCGGC
272 4341 645 IIYPGDSDTRYSPSFQG
272 4342 646 ATCATATATCCTGGTGACTCTGATACCAGATATAGCCCGTCTTTCCAA
GGC
272 4343 647 ARLPVGSYYYFNL
272 4344 648 GCGAGACTTCCAGTTGGTAGTTATTATTACTTCAATCTC
272 4345 649 GAAATTGTGATGACACAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
GAAAGCGCCACCCTATTTTGCAGGGCCAGTCAGAGTATTAGTAGCGA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCCACCAGGGCCACTGGTGTCCCTGCCAGGTTCAGTGC
CACTGGGTCTGAGGCAGAGTTCACTCTCACCATCAGCGGCCTGCAGTC
TGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCTTTC
GTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA
272 4346 650 EIVMTQSPATLSVSPGESATLFCRASQSISSDLAWYQQRPGQAPRLLIYDA
STRATGVPARFSATGSEAEFTLTISGLQSEDFAVYYCQQYNNWLSWTFG
QGTKLEIK
272 4347 651 RASQSISSDLA
272 4348 652 AGGGCCAGTCAGAGTATTAGTAGCGACTTAGCC
272 4349 653 DASTRAT
272 4350 654 GATGCATCCACCAGGGCCACT
272 4351 655 QQYNNWLSWT
272 4352 656 CAGCAGTATAATAACTGGCTTTCGTGGACG
273 4353 657 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGAGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTCGTGGCTCCATCAGAATTGG
TGGTTACTTCTGGAGTTGGATCCGCCAGCACCCAGGGAAGGGTCTGG
AGTGGCTTGGATACATCTCTAACGATGGGGCCACCGACTACAACCCG
TCCCTCAGGAGTCGACTTGCCATATCAGCAGACACATCTAAGAACCA
GTTTTCCCTGACCCTGAGGTCTGTGACTGCCGCGGACACGGCCATCTA
TTACTGTGCGAGAACTTCTTATGCAGGGCGCATGCTCGACCGCTGGGG
CCAGGGAATCCTGGTCACCGTCTCCTCA
273 4354 658 QVQLQESGPGLEKPSQTLSLTCTVSRGSIRIGGYFWSWIRQHPGKGLEWL
GYISNDGATDYNPSLRSRLAISADTSKNQFSLTLRSVTAADTAIYYCARTS
YAGRMLDRWGQGILVTVSS
273 4355 659 GSIRIGGYFWS
273 4356 660 GGCTCCATCAGAATTGGTGGTTACTTCTGGAGT
273 4357 661 YISNDGATDYNPSLRS
273 4358 662 TACATCTCTAACGATGGGGCCACCGACTACAACCCGTCCCTCAGGAG
T
273 4359 663 ARTSYAGRMLDR
273 4360 664 GCGAGAACTTCTTATGCAGGGCGCATGCTCGACCGC
273 4361 665 GACATCCGGGTGACCCAGTCTCCAGTCTCCCTGCCCGTCACCCCTGGA
GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGTCTCCTGCATAGT
AATGGAAACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC
TCCACAACTCCTGATCTATATGGGTTCTTATCGGGCCTCCGGGGTCCC
TGACAGGTTCAGCGGCAGTGGATCAGGCACAGATTTTACACTGAAAA
TCAGCAGAGTGGAGGCTGAGGATGTTGGTGTTTATTACTGCATGCAA
GGTCTACAAATTCCTTGGACGTTCGGCCAAGGGACCAAGCTGGAGAT
CAAA
273 4362 666 DIRVTQSPVSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQL
LIYMGSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLQIP
WTFGQGTKLEIK
273 4363 667 RSSQSLLHSNGNNYLD
273 4364 668 AGGTCTAGTCAGAGTCTCCTGCATAGTAATGGAAACAACTATTTGGAT
273 4365 669 MGSYRAS
273 4366 670 ATGGGTTCTTATCGGGCCTCC
273 4367 671 MQGLQIPWT
273 4368 672 ATGCAAGGTCTACAAATTCCTTGGACG
274 4369 673 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTCAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA
TGCCATGCACTGGGTCCGCCAGACTCCAGACAAGGGGCTGGAGTGGG
TGGCACTTATATCCGATGATGGAAGAAATGAATATTATGCAGATTCC
GTGCAGGGCCGATTCACCATCTCCAGAGACAAATCCAAGAACACGCT
GCATCTGGAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTTTATT
ACTGTGCGAAAGTACGAAATGAGGCGTGGGAGCTCCTGGGTAATGAT
GATGCTCTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
274 4370 674 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQTPDKGLEWV
ALISDDGRNEYYADSVQGRFTISRDKSKNTLHLEMNSLRAEDTAVYYCA
KVRNEAWELLGNDDALDVWGQGTMVTVSS
274 4371 675 FTFSSYAMH
274 4372 676 TTCACCTTCAGTAGCTATGCCATGCAC
274 4373 677 LISDDGRNEYYADSVQG
274 4374 678 CTTATATCCGATGATGGAAGAAATGAATATTATGCAGATTCCGTGCA
GGGC
274 4375 679 AKVRNEAWELLGNDDALDV
274 4376 680 GCGAAAGTACGAAATGAGGCGTGGGAGCTCCTGGGTAATGATGATGC
TCTTGATGTC
274 4377 681 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACA
GAAAGTCACCATCTCCTGCTCTGGAACTAGCTTCAACATTGGCAGTAA
TTACGTATCCTGGTACCAGCTACTCCCAGGAACAGCCCCCAAACTCCT
CATTTTTGACAATTATAAGCGACCCTCAGGGATTCCTGACCGATTCTC
TGGCTCCTGGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCCA
GACTGGGGACGAGGCCGAATACTTCTGCGGAACTTGGGACACCAGCC
TGAGAGCTGGAGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA
274 4378 682 QSVLTQPPSVSAAPGQKVTISCSGTSFNIGSNYVSWYQLLPGTAPKLLIFD
NYKRPSGIPDRFSGSWSGTSATLAISGLQTGDEAEYFCGTWDTSLRAGVF
GGGTKLTVL
274 4379 683 SGTSFNIGSNYVS
274 4380 684 TCTGGAACTAGCTTCAACATTGGCAGTAATTACGTATCC
274 4381 685 DNYKRPS
274 4382 686 GACAATTATAAGCGACCCTCA
274 4383 687 GTWDTSLRAGV
274 4384 688 GGAACTTGGGACACCAGCCTGAGAGCTGGAGTG
275 4385 689 CAGGTCCAGCTGGTGCAGTCTGGGTCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGCTCTCCTGCAAGGTTGCCGGTTACAGCCTCAGTGAGTT
ATCCATGCACTGGGTGCGACAGTCTCCTGGAAAAGGGCTTGAGTGGT
TGGGAGCTTTTGACCATGAAGATGCTGAAGCAATCTATGCACCGAGG
TTCCAGGGCAGAATCACCATGACCGCGGACACATCTACGGACACAGC
CTACATGGAACTGAGCAGCCTGAGATCTGAGGACACGGCCGTTTATT
ACTGTGCAACACCGACCCCAGTTGGAGCTACGGACTACTGGGGCCAG
GGAACCCTGGTCACCGTCTCCTCA
275 4386 690 QVQLVQSGSEVKKPGASVRLSCKVAGYSLSELSMHWVRQSPGKGLEWL
GAFDHEDAEAIYAPRFQGRITMTADTSTDTAYMELSSLRSEDTAVYYCA
TPTPVGATDYWGQGTLVTVSS
275 4387 691 YSLSELSMH
275 4388 692 TACAGCCTCAGTGAGTTATCCATGCAC
275 4389 693 AFDHEDAEAIYAPRFQG
275 4390 694 GCTTTTGACCATGAAGATGCTGAAGCAATCTATGCACCGAGGTTCCA
GGGC
275 4391 695 ATPTPVGATDY
275 4392 696 GCAACACCGACCCCAGTTGGAGCTACGGACTAC
275 4393 697 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGTATTAGTAGTTA
TTTAAATTGGTATCAACAAAAACCAGGAAAAGCCCCTAAGCTCCTGA
TCTATGCTGCATCCAGTTTGCAAAGGGGGGGCCCATCAAGATTCAGT
GGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCA
ACCTGAAGATTTTGCAACTTACTATTGTCAACAGAGTTACATTATTCC
GTACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA
275 4394 698 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQRGGPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYIIPYTFGQGT
KVDIK
275 4395 699 RASQSISSYLN
275 4396 700 CGGGCAAGTCAGAGTATTAGTAGTTATTTAAAT
275 4397 701 AASSLQR
275 4398 702 GCTGCATCCAGTTTGCAAAGG
275 4399 703 QQSYIIPYT
275 4400 704 CAACAGAGTTACATTATTCCGTACACT
276 4401 705 CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACGGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCAGTGTCGCTGATGGCTCAATCAGTAGTGG
TCATTACTACTGGGGCTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGG
AGTGGATTGCGACAATCCATGATAGTGGGGCCACGTACTACAACCCG
TCCCTCCAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCA
GTTCTCCCTGAAAGTGAATTCTGTGACCGCCGCAGACACGGCTGTCTA
TTACTGTGCGAGTCGAAGGGGCAGTGGCTGGTTTTTCGACTCCTGGGG
CCAGGGAACCCTGGTCACCGTCTCCTCA
276 4402 706 QVQLQESGPGRVKPSETLSLTCSVADGSISSGHYYWGWVRQPPGKGLEW
IATIHDSGATYYNPSLQSRVTISVDTSKNQFSLKVNSVTAADTAVYYCAS
RRGSGWFFDSWGQGTLVTVSS
276 4403 707 GSISSGHYYWG
276 4404 708 GGCTCAATCAGTAGTGGTCATTACTACTGGGGC
276 4405 709 TIHDSGATYYNPSLQS
276 4406 710 ACAATCCATGATAGTGGGGCCACGTACTACAACCCGTCCCTCCAGAG
T
276 4407 711 ASRRGSGWFFDS
276 4408 712 GCGAGTCGAAGGGGCAGTGGCTGGTTTTTCGACTCC
276 4409 713 GATATTGTGCTGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCACAGTGTTAACTACAA
TTTAGCCTGGTACCAGCAGAAACCTGGTCAGGCTCCCAGGCTCCTCAT
CTATGGTTCATCTACCAGGGCCACTGGTCTCCCAGCCAGGTTCAGTGG
CAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGT
CTGAAGATTTTGCAATTTATTACTGTCAGCAGTATAATAACTGGCCTC
CGGGAGGCACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA
276 4410 714 DIVLTQSPATLSVSPGERVTLSCRASHSVNYNLAWYQQKPGQAPRLLIYG
SSTRATGLPARFSGSGSGTEFTLTISSLQSEDFAIYYCQQYNNWPPGGTFG
QGTKVEIK
276 4411 715 RASHSVNYNLA
276 4412 716 AGGGCCAGTCACAGTGTTAACTACAATTTAGCC
276 4413 717 GSSTRAT
276 4414 718 GGTTCATCTACCAGGGCCACT
276 4415 719 QQYNNWPPGGT
276 4416 720 CAGCAGTATAATAACTGGCCTCCGGGAGGCACT
277 4417 721 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA
TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CTGTGCGAGAGATTGGCCGAATAGCAGCTCGTCGCCGAACTGGTTCG
ACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
277 4418 722 EVQLLESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWV
SSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DWPNSSSSPNWFDPWGQGTLVTVSS
277 4419 723 FTFSSYSMN
277 4420 724 TTCACCTTCAGTAGCTATAGCATGAAC
277 4421 725 SISSSSSYIYYADSVKG
277 4422 726 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG
GGC
277 4423 727 ARDWPNSSSSPNWFDP
277 4424 728 GCGAGAGATTGGCCGAATAGCAGCTCGTCGCCGAACTGGTTCGACCC
C
277 4425 729 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA
CTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGCCTGAGTGGTTTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTC
CTA
277 4426 730 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLI
YGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGF
YVFGTGTKLTVL
277 4427 731 TGSSSNIGAGYDVH
277 4428 732 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC
277 4429 733 GNSNRPS
277 4430 734 GGTAACAGCAATCGGCCCTCA
277 4431 735 QSYDSSLSGFYV
277 4432 736 CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC
278 4433 737 CAGGTCCAGCTGGTACAGTCTGGGGCAGAGGTGAAAAAGCCCGGGG
AGTCTCTGAAGATCTCCTGTCAGGGTTCTGGATACAGCTTTAGCAGTT
TCTGGATCGTCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG
ATGGGGAGCATCTATCCTGGTGACTCTGACACCAGATACACCCCGTCC
TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCACCAGCACCGC
CTATTTGCAGTGGAACAGCCTGAAGCCCTCGGACACCGCCATGTATTA
CTGTGCGAGGTGTAGTCTCAGCTGCGACTACTACGGAGTGAACCTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA
278 4434 738 QVQLVQSGAEVKKPGESLKISCQGSGYSFSSFWIVWVRQMPGKGLEWM
GSIYPGDSDTRYTPSFQGQVTISADKSTSTAYLQWNSLKPSDTAMYYCAR
CSLSCDYYGVNLWGQGTTVTVSS
278 4435 739 YSFSSFWIV
278 4436 740 TACAGCTTTAGCAGTTTCTGGATCGTC
278 4437 741 SIYPGDSDTRYTPSFQG
278 4438 742 AGCATCTATCCTGGTGACTCTGACACCAGATACACCCCGTCCTTCCAA
GGC
278 4439 743 ARCSLSCDYYGVNL
278 4440 744 GCGAGGTGTAGTCTCAGCTGCGACTACTACGGAGTGAACCTC
278 4441 745 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGACA
GAGGGTCACCATCTCCTGCTCTGGGAGCAGCTCCAACATCGGGGCAC
GTTCTGATGTACACTGGTACCAGCAGCTTCCAGGAAAAGCCCCCAAA
CTCCTCATCTATGGTAACACCAATCGGCCCTTAGGGGTCCCTGACCGA
TTCTCTGGCTCCACGTCTGGCACCTCAGCCTCCCTGGCCATCTCTGGG
CTCCAGGCTGAGGATGAGGGATATTATTACTGTCAGTCCTATGACAGC
AGCCTGAGTGGTTTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTC
CTA
278 4442 746 QSVVTQPPSVSGAPGQRVTISCSGSSSNIGARSDVHWYQQLPGKAPKLLI
YGNTNRPLGVPDRFSGSTSGTSASLAISGLQAEDEGYYYCQSYDSSLSGF
YVFGTGTKLTVL
278 4443 747 SGSSSNIGARSDVH
278 4444 748 TCTGGGAGCAGCTCCAACATCGGGGCACGTTCTGATGTACAC
278 4445 749 GNTNRPL
278 4446 750 GGTAACACCAATCGGCCCTTA
278 4447 751 QSYDSSLSGFYV
278 4448 752 CAGTCCTATGACAGCAGCCTGAGTGGTTTTTATGTC
279 4449 753 CAGGTGCAGCTGGTGGAATCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCCCCTTCAGTCTCTAT
GCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT
GGCATTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGT
GAAGGGCCGATTCACCATCTCCAGAGACAGTTCCAAGAACACGCTGT
ATCTGCAAATGGACAGCCTGACACCTGAAGACACGGCTGTGTATTAC
TGTGCGAAACCTATAGTGGGGCCTACAACGGGTTACTTTGACTACTGG
GGCCCGGGAACCCTGGTCACCGTCTCCTCA
279 4450 754 QVQLVESGGGVVQPGRSLRLSCAASGFPFSLYAMHWVRQAPGKGLEWV
AFISYDGSNKYYADSVKGRFTISRDSSKNTLYLQMDSLTPEDTAVYYCA
KPIVGPTTGYFDYWGPGTLVTVSS
279 4451 755 FPFSLYAMH
279 4452 756 TTCCCCTTCAGTCTCTATGCCATGCAC
279 4453 757 FISYDGSNKYYADSVKG
279 4454 758 TTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAG
GGC
279 4455 759 AKPIVGPTTGYFDY
279 4456 760 GCGAAACCTATAGTGGGGCCTACAACGGGTTACTTTGACTAC
279 4457 761 GAAATTGTGTTGACTCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG
CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGTAC
ACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA
279 4458 762 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD
ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWYTFGQG
TKVEIK
279 4459 763 RASQSVSSYLA
279 4460 764 AGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCC
279 4461 765 DASNRAT
279 4462 766 GATGCATCCAACAGGGCCACT
279 4463 767 QQRSNWYT
279 4464 768 CAGCAGCGTAGCAACTGGTACACT
280 4465 769 GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCCAGACTTCTGGTTACACCTTTAGTCATTT
CGGTGTCACCTGGATACGACAGGCCCCAGGACAAGGGCTTGAGTGGC
TGGGATGGATCAGCGCTTACAATGGTAACACAGACTATGCAGACAAA
CTGCAGGGCAGACTCACCATGACCACAGACACATCCACGAACACCGC
CTACATGGAATTGAGGAGCCTCAGATCTGACGACACGGCCGTCTATT
ACTGTGCGAGAGATCCCCCCGCATCAGCTGCTGCGATGCTTGACTACT
GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
280 4466 770 EVQLVESGAEVKKPGASVKVSCQTSGYTFSHFGVTWIRQAPGQGLEWL
GWISAYNGNTDYADKLQGRLTMTTDTSTNTAYMELRSLRSDDTAVYYC
ARDPPASAAAMLDYWGQGTLVTVSS
280 4467 771 YTFSHFGVT
280 4468 772 TACACCTTTAGTCATTTCGGTGTCACC
280 4469 773 WISAYNGNTDYADKLQG
280 4470 774 TGGATCAGCGCTTACAATGGTAACACAGACTATGCAGACAAACTGCA
GGGC
280 4471 775 ARDPPASAAAMLDY
280 4472 776 GCGAGAGATCCCCCCGCATCAGCTGCTGCGATGCTTGACTAC
280 4473 777 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAAGGCCTCGAATACACT
GATGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTCATTTATAAGATTTCTAACCGGGACTCTGGGGTTCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAGAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACGGGCGGGGAATCTCTTTCGGTCCTGGGACCAAAGTGGA
TATCAAA
280 4474 778 DIVMTQSPLSLAVTLGQPASISCKSSQGLEYTDGNTYLSWFQQRPGQSPR
RLIYKISNRDSGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCMQGTHGR
GISFGPGTKVDIK
280 4475 779 KSSQGLEYTDGNTYLS
280 4476 780 AAGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAG
T
280 4477 781 KISNRDS
280 4478 782 AAGATTTCTAACCGGGACTCT
280 4479 783 MQGTHGRGIS
280 4480 784 ATGCAAGGTACACACGGGCGGGGAATCTCT
281 4481 785 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTA
CTTTATACACTGGGTGCGCCAGGCCCCTGGAGAAGGGCTTGAGTGGA
TGGGTTGGGTCAACCCTCTCAGTGACAACACAAAATATTCACAGAAG
TTTCAGGGCAGGGTCACCATGAGCACGGACACGTCCATCACCACGGC
CTACATGTACCTGAGCAGGCTGCGATTTGACGACACGGCCGTGTATTT
TTGTGCGAGCCAATCTTCCCCCTATACCCCGGGCGCTCTGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA
281 4482 786 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYFIHWVRQAPGEGLEWM
GWVNPLSDNTKYSQKFQGRVTMSTDTSITTAYMYLSRLRFDDTAVYFC
ASQSSPYTPGALDVWGQGTTVTVSS
281 4483 787 YTFTDYFIH
281 4484 788 TACACCTTCACCGACTACTTTATACAC
281 4485 789 WVNPLSDNTKYSQKFQG
281 4486 790 TGGGTCAACCCTCTCAGTGACAACACAAAATATTCACAGAAGTTTCA
GGGC
281 4487 791 ASQSSPYTPGALDV
281 4488 792 GCGAGCCAATCTTCCCCCTATACCCCGGGCGCTCTGGACGTC
281 4489 793 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGCCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTGGGAACAA
TTTAGCTTGGTATCAGCAGAAAGCAGGAAGAGCCCCCAAACTCCTGA
TCTATAGTGCGTCTAATTTCCATAGTGGGGTCCCATCAAGATTCATTG
GCAGTGGATCTGGGACAGTTTTCACTCTCACCATCAGCAGTCTGCAAC
CTGAAGATTTTGCAACCTACTTCTGTCAACAGAGTTTCACTCCCCAAT
TCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA
281 4490 794 DIQLTQSPSSLPASVGDRVTITCRASQNIGNNLAWYQQKAGRAPKLLIYS
ASNFHSGVPSRFIGSGSGTVFTLTISSLQPEDFATYFCQQSFTPQFTFGPGT
KVEIK
281 4491 795 RASQNIGNNLA
281 4492 796 CGGGCAAGTCAGAACATTGGGAACAATTTAGCT
281 4493 797 SASNFHS
281 4494 798 AGTGCGTCTAATTTCCATAGT
281 4495 799 QQSFTPQFT
281 4496 800 CAACAGAGTTTCACTCCCCAATTCACT
282 4497 801 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTC
CTCGGTGAGGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGGAAGT
ATGCTATCAGTTGGGTGCGACAGGCCCGTGGACAAGGGCTTGAGTGG
ATGGGAGGCATCATCCCTATGTCCGGACCACCAAGCTACGCACAGAA
GTTTCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAG
TCTACATGGAGCTGAGCAGCCTGAGATTTGAGGACACGGCCGTGTAT
TTCTGTGCGAGGGATATCGAGTGGTTCGTACTCATGGACCCTATCACA
TCCTACTACCCTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT
CTCCTCA
282 4498 802 QVQLVQSGAEVKRPGSSVRVSCKASGGTFRKYAISWVRQARGQGLEWM
GGIIPMSGPPSYAQKFQGRVTITADESTSTVYMELSSLRFEDTAVYFCARD
IEWFVLMDPITSYYPMDVWGQGTTVTVSS
282 4499 803 GTFRKYAIS
282 4500 804 GGCACCTTCAGGAAGTATGCTATCAGT
282 4501 805 GIIPMSGPPSYAQKFQG
282 4502 806 GGCATCATCCCTATGTCCGGACCACCAAGCTACGCACAGAAGTTTCA
GGGC
282 4503 807 ARDIEWFVLMDPITSYYPMDV
282 4504 808 GCGAGGGATATCGAGTGGTTCGTACTCATGGACCCTATCACATCCTAC
TACCCTATGGACGTC
282 4505 809 CAGTCTGTGGTGACCCAGGAGCCCTCACTGACTGTGTCCCCAGGAGG
GACAGTCACTCTCACCTGTGGCTCCAGCACTGGAGGTGTCACCAGTG
GTCATCATACATACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGG
ACACTGATCTATGATACGACCAACACACACTCCTGGACACCAGCCCG
GTTCGCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACCCTTTCGGG
TGCGCAGCCTGAGGATGAGGCTGACTATTACTGCCTCCTCTCCTATAG
TGGTGCGCGGCCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
282 4506 810 QSVVTQEPSLTVSPGGTVTLTCGSSTGGVTSGHHTYWFQQKPGQAPRTLI
YDTTNTHSWTPARFAGSLLGGKAALTLSGAQPEDEADYYCLLSYSGARP
VFGGGTKLTVL
282 4507 811 GSSTGGVTSGHHTY
282 4508 812 GGCTCCAGCACTGGAGGTGTCACCAGTGGTCATCATACATAC
282 4509 813 DTTNTHS
282 4510 814 GATACGACCAACACACACTCC
282 4511 815 LLSYSGARPV
282 4512 816 CTCCTCTCCTATAGTGGTGCGCGGCCGGTG
283 4513 817 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAATGATTA
CTACATGAATTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGG
TTTCATACATTAGTAGTAGTGGTGAGACCAAATACTACGCAGACTCTG
TGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTG
TATCTGGAAATGAACAGCCTGAGAGTCGAGGACACGGCCGTCTACTA
CTGTGCGAGAGACGCGGTCATTGTAGTAGGACCGGTTGCTGTTCACTA
CCAATACTACGCGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCT
CTTCA
283 4514 818 QVQLVQSGGGLVKPGGSLRLSCAASGFTFNDYYMNWIRQAPGKGLEWV
SYISSSGETKYYADSVKGRFTISRDNAKNSLYLEMNSLRVEDTAVYYCA
RDAVIVVGPVAVHYQYYADVWGKGTTVTVSS
283 4515 819 FTFNDYYMN
283 4516 820 TTCACCTTCAATGATTACTACATGAAT
283 4517 821 YISSSGETKYYADSVKG
283 4518 822 TACATTAGTAGTAGTGGTGAGACCAAATACTACGCAGACTCTGTGAA
GGGC
283 4519 823 ARDAVIVVGPVAVHYQYYADV
283 4520 824 GCGAGAGACGCGGTCATTGTAGTAGGACCGGTTGCTGTTCACTACCA
ATACTACGCGGACGTC
283 4521 825 CAGCCAGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
GAGGGTCACCATCTCTTGTTCTGGAAGCACCTCCAACATCGGAAGTA
ACACTGTACACTGGTACCAGCAACTCCCAGGAACGGCCCCCAGACTC
CTCATCTATGTTATTAATCAGCGGCCCTCAGGGGTCCCAGACCGATTC
TCCGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC
CAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG
CCTGAATGGTCCGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA
283 4522 826 QPVLTQPPSASGTPGQRVTISCSGSTSNIGSNTVHWYQQLPGTAPRLLIYV
INQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGPVF
GGGTKLTVL
283 4523 827 SGSTSNIGSNTVH
283 4524 828 TCTGGAAGCACCTCCAACATCGGAAGTAACACTGTACAC
283 4525 829 VINQRPS
283 4526 830 GTTATTAATCAGCGGCCCTCA
283 4527 831 AAWDDSLNGPV
283 4528 832 GCAGCATGGGATGACAGCCTGAATGGTCCGGTG
284 4529 833 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCT
ACCATATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGG
ATGGGAGGGATCATCCATCTATTTGGGACAGTTAACTACGCTCCGAA
GTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAG
CCTACATGGAGTTAAACAGCCTGATGTCTGAAGACACGGCCGTTTATT
ATTGTGCGAGAGATGCCTACGAAGTGTGGACTGGTTCTTATCTCCCCC
CTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
284 4530 834 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYHISWVRQAPGQGLEWM
GGIIHLFGTVNYAPKFQGRVTITADASTGTAYMELNSLMSEDTAVYYCA
RDAYEVWTGSYLPPFDYWGQGTLVTVSS
284 4531 835 GTFSGYHIS
284 4532 836 GGCACCTTCAGCGGCTACCATATCAGC
284 4533 837 GIIHLFGTVNYAPKFQG
284 4534 838 GGGATCATCCATCTATTTGGGACAGTTAACTACGCTCCGAAGTTCCAG
GGC
284 4535 839 ARDAYEVWTGSYLPPFDY
284 4536 840 GCGAGAGATGCCTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTT
GACTAC
284 4537 841 GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGGTGCATTCACCAGGGCCACTGACATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATTCTGCAGTATATTATTGTCAGCAGTATGGTAGCTCA
TTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA
284 4538 842 EIVLTQSPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIYG
AFTRATDIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYGSSFLTFGGG
TKVDIK
284 4539 843 RASQTVTSSYLA
284 4540 844 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC
284 4541 845 GAFTRAT
284 4542 846 GGTGCATTCACCAGGGCCACT
284 4543 847 QQYGSSFLT
284 4544 848 CAGCAGTATGGTAGCTCATTCCTCACT
285 4545 849 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGCAAAAGCCCGGGCG
GTCCCTGCGACTCTCATGTTCAGCTTCTGGATTCACCTTTGGTGATTAT
GCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGGT
TGGTTTCATTAGAAGTAAAGCTTATGTTGGGACCGCAGAATACGCCG
CGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGC
ATCGCCTATCTGCACATGAACAGCCTGAAGACCGAGGACACAGCCGT
GTATTACTGTACTAGAGATGATATTTTGACTGGTTTTTATGACCGCTCT
TACTATTACGGTATACACGTCTGGGGCCAAGGGACCACGGTCACCGT
CTCCTCA
285 4546 850 EVQLVESGGGLQKPGRSLRLSCSASGFTFGDYAMSWFRQAPGKGLEWV
GFIRSKAYVGTAEYAASVKGRFTISRDDSKSIAYLHMNSLKTEDTAVYYC
TRDDILTGFYDRSYYYGIHVWGQGTTVTVSS
285 4547 851 FTFGDYAMS
285 4548 852 TTCACCTTTGGTGATTATGCTATGAGC
285 4549 853 FIRSKAYVGTAEYAASVKG
285 4550 854 TTCATTAGAAGTAAAGCTTATGTTGGGACCGCAGAATACGCCGCGTCT
GTGAAAGGC
285 4551 855 TRDDILTGFYDRSYYYGIHV
285 4552 856 ACTAGAGATGATATTTTGACTGGTTTTTATGACCGCTCTTACTATTAC
GGTATACACGTC
285 4553 857 GAAATTGTAATGACGCAGTCTCCAGTCACCCTGTCTGTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAGCAA
CTTAGCCTGGTACCAGAAGAAACCTGGCCAGGCTCCCAGGCTCCTCA
TCTATAGTGCATCCACCAGGGCCACTGGTGTCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGAGTTCACTCTCACCGTCAGCAGCCTTCAGT
CTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGATAACTGGCCTC
CGTACACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA
285 4554 858 EIVMTQSPVTLSVSPGERATLSCRASQSVNSNLAWYQKKPGQAPRLLIYS
ASTRATGVPARFSGSGSGTEFTLTVSSLQSEDFAVYYCQQYDNWPPYTF
GQGTKVEIK
285 4555 859 RASQSVNSNLA
285 4556 860 AGGGCCAGTCAGAGTGTTAACAGCAACTTAGCC
285 4557 861 SASTRAT
285 4558 862 AGTGCATCCACCAGGGCCACT
285 4559 863 QQYDNWPPYT
285 4560 864 CAGCAGTATGATAACTGGCCTCCGTACACT
286 4561 865 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAGGCCTTCACA
GACCCTGTCCCTCACCTGCTCCGCCTCTGGTGCAGCCATCAATAGTGG
TGATTATTACTGGAGTTGGATCCGCCAGGCCCCTGGGAGGGGCCTAG
AGTGGATTGGGTCCATTTCCAACCGTGGGGTCACCGACTACAACCCGT
CCCTCAAGAGTCGAGTTATCATATCAGCGGACACGTCCAAGAATCAG
TTCTCCCTGAGGCTGACCTCTGTGACTGCCACAGACACGGCCGTGTAT
TATTGTGCCAGAGATTTGGGTACTTTGGCCTTTGATCCCTACTACTATT
ACGGTATTGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
286 4562 866 QVQLQESGPGLVRPSQTLSLTCSASGAAINSGDYYWSWIRQAPGRGLEW
IGSISNRGVTDYNPSLKSRVIISADTSKNQFSLRLTSVTATDTAVYYCARD
LGTLAFDPYYYYGIDVWGQGTTVTVSS
286 4563 867 AAINSGDYYWS
286 4564 868 GCAGCCATCAATAGTGGTGATTATTACTGGAGT
286 4565 869 SISNRGVTDYNPSLKS
286 4566 870 TCCATTTCCAACCGTGGGGTCACCGACTACAACCCGTCCCTCAAGAGT
286 4567 871 ARDLGTLAFDPYYYYGIDV
286 4568 872 GCCAGAGATTTGGGTACTTTGGCCTTTGATCCCTACTACTATTACGGT
ATTGACGTC
286 4569 873 GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGCA
TTTAGCCTGGTACCAACAAAAACCTGGCCAGGCTCCCCGGCTCCTCAT
CTATGATGCATCATACAGGGTCACTGGCGTCCCAGACAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGGAG
TCTGAAGATTTTGCAATTTATTTCTGTCAGCAGCGTAGCACCTGGCCG
ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
286 4570 874 DIRMTQSPATLSLSPGERATLSCRASQSVSRHLAWYQQKPGQAPRLLIYD
ASYRVTGVPDRFSGSGSGTDFTLTISSLESEDFAIYFCQQRSTWPTFGQGT
KVEIK
286 4571 875 RASQSVSRHLA
286 4572 876 AGGGCCAGTCAGAGTGTTAGCAGGCATTTAGCC
286 4573 877 DASYRVT
286 4574 878 GATGCATCATACAGGGTCACT
286 4575 879 QQRSTWPT
286 4576 880 CAGCAGCGTAGCACCTGGCCGACG
287 4577 881 CAGGTGCAGCTGGTGGAATCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTTGCCTGCACGGCGTCTGGATACGCCTTCACCAATTA
CAACATCCACTGGGTGCGACTGGCCCCTGGACAGGGACTTGAGTGGA
TGGCAATTATCAACCCCGGTAGTGGTGGCACAGACTACTCAGAGAAG
TTCCAGGGCAGGCTCACCTTGACCAGTGACACGTCCACGAGCACGGT
GTACATGACGCTGGGCAGCCTGAGATATGAAGACACGGCCTTTTATT
ACTGTGCGAGAAGGGGTTACCCTGATTCGGGGAGTTACCCCCTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
287 4578 882 QVQLVESGAEVKKPGASVKVACTASGYAFTNYNIHWVRLAPGQGLEW
MAIINPGSGGTDYSEKFQGRLTLTSDTSTSTVYMTLGSLRYEDTAFYYCA
RRGYPDSGSYPLDYWGQGTLVTVSS
287 4579 883 YAFTNYNIH
287 4580 884 TACGCCTTCACCAATTACAACATCCAC
287 4581 885 IINPGSGGTDYSEKFQG
287 4582 886 ATTATCAACCCCGGTAGTGGTGGCACAGACTACTCAGAGAAGTTCCA
GGGC
287 4583 887 ARRGYPDSGSYPLDY
287 4584 888 GCGAGAAGGGGTTACCCTGATTCGGGGAGTTACCCCCTTGACTAC
287 4585 889 GATATTGTGATGACGCAGTCTCCATCCTCCCTGTCTGCATCTCTGGGA
GACAGAGTCACCATCACTTGCCGGGCAGGTCGGAGCATTGCCACTTA
CTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA
TCTATGGTGCATCCAGTTTGCAAAGTGGCGTCCCATCAAGGTTCAGTG
GCAGTGGCTCTGGGACACATTTCACTCTCACCATCAGCAGTCTGCAAC
CTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACATCCGCCCTA
TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
287 4586 890 DIVMTQSPSSLSASLGDRVTITCRAGRSIATYLNWYQQKPGKAPKLLIYG
ASSLQSGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSYIRPITFGGGT
KVEIK
287 4587 891 RAGRSIATYLN
287 4588 892 CGGGCAGGTCGGAGCATTGCCACTTACTTAAAT
287 4589 893 GASSLQS
287 4590 894 GGTGCATCCAGTTTGCAAAGT
287 4591 895 QQSYIRPIT
287 4592 896 CAACAGAGTTACATCCGCCCTATCACT
288 4593 897 CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTCGTCTCCTCAGCAGTGG
TGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAGGGGCCTGG
AGTGGATTGGCTACGTCTATCACAGTGGGACCACCTCGTACAACCCGT
CCCTCAAGAGTCGAATTACCATGACAGTGGACACGTCCAAGAACCAG
TTCAACCTGAGGTTGACCTCTGTAACGGCCGCAGACACGGCCGTGTAT
TACTGTGCCAGAGATCTCGGATATAGCAGTTCCTCTCCCGCCTTTTAT
TACGGTATAGACTTCTGGGGCCCAGGGACCATGGTCACCGTCTCTTCA
288 4594 898 QVQLQESGPGLVKPSQTLSLTCTVSGRLLSSGDYYWSWIRQSPGRGLEWI
GYVYHSGTTSYNPSLKSRITMTVDTSKNQFNLRLTSVTAADTAVYYCAR
DLGYSSSSPAFYYGIDFWGPGTMVTVSS
288 4595 899 RLLSSGDYYWS
288 4596 900 CGTCTCCTCAGCAGTGGTGATTACTACTGGAGT
288 4597 901 YVYHSGTTSYNPSLKS
288 4598 902 TACGTCTATCACAGTGGGACCACCTCGTACAACCCGTCCCTCAAGAGT
288 4599 903 ARDLGYSSSSPAFYYGIDF
288 4600 904 GCCAGAGATCTCGGATATAGCAGTTCCTCTCCCGCCTTTTATTACGGT
ATAGACTTC
288 4601 905 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
CAAAGAGCGACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAACTA
CTTAGCCTGGTACCAACAAAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCCAACAGGGTCACTGGCATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGGCTAGAG
TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACGGGGTC
CTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA
288 4602 906 EIVLTQSPATLSLSPGQRATLSCRASQSVGNYLAWYQQKPGQAPRLLIYD
ASNRVTGIPARFSGSGSGTDFTLTISRLESEDFAVYYCQQRSNGVLTFGGG
TKVDIK
288 4603 907 RASQSVGNYLA
288 4604 908 AGGGCCAGTCAGAGTGTTGGCAACTACTTAGCC
288 4605 909 DASNRVT
288 4606 910 GATGCATCCAACAGGGTCACT
288 4607 911 QQRSNGVLT
288 4608 912 CAGCAGCGTAGCAACGGGGTCCTCACT
289 4609 913 GAGGTGCAGCTGTTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTA
CTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGA
TGGGGTGGGTCAATCCTCTCAGTGGAGCCACAAAATATGCACAGAAG
TTTCAGGGCAGGGTCACCATGACCACGGACACGTCCATCACCACAGG
GTACCTGGACTTGAGGAGCCTGAGAGTTGACGACACGGCCATCTATT
TTTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCTATGGGCGTCT
GGGGCCAAGGGACCACGGTCACCGTCTCTTCA
289 4610 914 EVQLLESGAEVKKPGASVRVSCKASGYTFTDYFMNWVRQAPGGGLEW
MGWVNPLSGATKYAQKFQGRVTMTTDTSITTGYLDLRSLRVDDTAIYFC
ASQSSPYTPGAMGVWGQGTTVTVSS
289 4611 915 YTFTDYFMN
289 4612 916 TACACCTTCACCGACTACTTTATGAAC
289 4613 917 WVNPLSGATKYAQKFQG
289 4614 918 TGGGTCAATCCTCTCAGTGGAGCCACAAAATATGCACAGAAGTTTCA
GGGC
289 4615 919 ASQSSPYTPGAMGV
289 4616 920 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCTATGGGCGTC
289 4617 921 GACATCCAGGTGACCCAGTCTCCATCCTCCCTGTCTGCCTCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTA
TTTAAGTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA
TCTATGCTACATCCAATTTATACAGTGGGGTCCCATCAAGGTTCAGTG
GCCGTGATTCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAAC
CTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTAT
TCACTTTCGGCCCTGGGACCAAGGTGGAGATCAAA
289 4618 922 DIQVTQSPSSLSASVGDRVTITCRASQSISGYLSWYQQKPGKAPNLLIYAT
SNLYSGVPSRFSGRDSGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPGT
KVEIK
289 4619 923 RASQSISGYLS
289 4620 924 CGGGCAAGTCAGAGCATTAGCGGCTATTTAAGT
289 4621 925 ATSNLYS
289 4622 926 GCTACATCCAATTTATACAGT
289 4623 927 QLNSGALFT
289 4624 928 CAACTGAATTCCGGTGCCCTATTCACT
290 4625 929 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTCCCTCCATCAGCGCTGG
AGATTACAACTGGAATTGGATCCGCCAGGCCCCAGGGAAGGGCCTGG
AGTGGGTTGGATACATCGATTACAGGGGCCTCACCCACTACAACCCG
TCCCTCAAGGGTCGACTTTCCATATTAATGGACAGGTCGGCGAACCA
GTTCTCCCTGGAGCTGAATTCTGTGACTGCCGCAGACACGGCCGTCTA
CTACTGTGCCAGGGACGTGGGGGTCTATAGTGGCTACGATGTCTTTCA
CTACTACGGCATGGACGTCTGGGGCCAGGGGACCACGGTCACCGTCT
CCTCA
290 4626 930 QVQLQESGPGLVKPSQTLSLTCTVSGPSISAGDYNWNWIRQAPGKGLEW
VGYIDYRGLTHYNPSLKGRLSILMDRSANQFSLELNSVTAADTAVYYCA
RDVGVYSGYDVFHYYGMDVWGQGTTVTVSS
290 4627 931 PSISAGDYNWN
290 4628 932 CCCTCCATCAGCGCTGGAGATTACAACTGGAAT
290 4629 933 YIDYRGLTHYNPSLKG
290 4630 934 TACATCGATTACAGGGGCCTCACCCACTACAACCCGTCCCTCAAGGGT
290 4631 935 ARDVGVYSGYDVFHYYGMDV
290 4632 936 GCCAGGGACGTGGGGGTCTATAGTGGCTACGATGTCTTTCACTACTAC
GGCATGGACGTC
290 4633 937 GAAACGACACTCACGCAGTCTCCAGTCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGTATGTTAGGAACAA
CTACTTAGCCTGGTACCAACACAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATAGTGCTTCCAGCAGGGTCACTGGCACCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGACTTTGCAGTGTATTACTGTCAGCAGTATGGTGGCTCA
CCTCCGGTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
290 4634 938 ETTLTQSPVTLSLSPGERATLSCRASQYVRNNYLAWYQHKPGQAPRLLIY
SASSRVTGTPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGGSPPVTFG
PGTKVDIK
290 4635 939 RASQYVRNNYLA
290 4636 940 AGGGCCAGTCAGTATGTTAGGAACAACTACTTAGCC
290 4637 941 SASSRVT
290 4638 942 AGTGCTTCCAGCAGGGTCACT
290 4639 943 QQYGGSPPVT
290 4640 944 CAGCAGTATGGTGGCTCACCTCCGGTCACT
291 4641 945 GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCTTAGTTCAGCCTGGGGG
GTCCCTGAGACTATCCTGTGCAGCCTCTGGATTCACCTTCAGTAATTA
CTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGG
TCTCACGTATTAGCGGTGATGGAAGTGACACAACCTACGCGGACTCC
GTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAGGAGTACACT
GTATCTTCAACTGAATAGTCTCACAGGCGACGACACGGCTGTGTATTA
TTGTGCAAGAGATTTGTGGACCACCTCGCCCTACTTTGACCTCTGGGG
CCAGGGAACCCTGGTCACCGTCTCCTCA
291 4642 946 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYWMHWVRQAPGKGLVW
VSRISGDGSDTTYADSVEGRFTISRDNARSTLYLQLNSLTGDDTAVYYCA
RDLWTTSPYFDLWGQGTLVTVSS
291 4643 947 FTFSNYWMH
291 4644 948 TTCACCTTCAGTAATTACTGGATGCAC
291 4645 949 RISGDGSDTTYADSVEG
291 4646 950 CGTATTAGCGGTGATGGAAGTGACACAACCTACGCGGACTCCGTGGA
GGGC
291 4647 951 ARDLWTTSPYFDL
291 4648 952 GCAAGAGATTTGTGGACCACCTCGCCCTACTTTGACCTC
291 4649 953 GAAATTGTATTGACACAGTCTCCTGGCACCCTGTCTGCATCTATTGGA
GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTCTTAATGGCTG
GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAGGCTCCTCA
TCTATAAGTCGTCTAGTTTAGAAAGCGGGGTCCCATCAAGGTTCAGCG
GCAGTGCATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG
CCTGACGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTGGGCG
TTCGGCCAAGGGACCAAGGTGGACGTCAAA
291 4650 954 EIVLTQSPGTLSASIGDRVTITCRASQSLNGWLAWYQQKPGKAPRLLIYK
SSSLESGVPSRFSGSASGTEFTLTISSLQPDDFATYYCQQYNSWAFGQGTK
VDVK
291 4651 955 RASQSLNGWLA
291 4652 956 CGGGCCAGTCAGAGTCTTAATGGCTGGTTGGCC
291 4653 957 KSSSLES
291 4654 958 AAGTCGTCTAGTTTAGAAAGC
291 4655 959 QQYNSWA
291 4656 960 CAACAGTATAATAGTTGGGCG
292 4657 961 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTA
CTCCTGGAGCTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGA
TTGGAGAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTC
AAGAGTCGAGTCACCATATCAGTAGACACGTCGAAGAACCAGTTCTC
CCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTACTACT
GTGCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAATACTTC
TTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTC
A
292 4658 962 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYSWSWIRQSPGKGLEWIG
EINHRGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAGTN
YGEVNTSNQYFFGMDVWGQGTTVTVSS
292 4659 963 GSFSGYSWS
292 4660 964 GGGTCCTTCAGTGGTTACTCCTGGAGC
292 4661 965 EINHRGSTNYNPSLKS
292 4662 966 GAAATCAATCATAGAGGAAGCACCAACTACAACCCGTCCCTCAAGAG
T
292 4663 967 AGTNYGEVNTSNQYFFGMDV
292 4664 968 GCGGGGACCAATTATGGAGAGGTTAATACGAGTAACCAATACTTCTT
CGGTATGGACGTC
292 4665 969 GACATCCGGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTACCACCTA
TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGA
TCTATGCTGCATCCAATTTGGAAAGTGGGGTCCCATCAAGTTTCAGTG
GCAGTGGATTTGGGACAGACTTCACTCTCACCATCAGCAGTCTGCAAC
CTGACGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTGCCCCGC
TCACCTTCGGCGGAGGGACCAAAGTGGATATCAAA
292 4666 970 DIRLTQSPSSLSASVGDRVTITCRASQSITTYLNWYQQKPGKAPKLLIYAA
SNLESGVPSSFSGSGFGTDFTLTISSLQPDDFATYYCQQSYSAPLTFGGGT
KVDIK
292 4667 971 RASQSITTYLN
292 4668 972 CGGGCAAGTCAGAGCATTACCACCTATTTAAAT
292 4669 973 AASNLES
292 4670 974 GCTGCATCCAATTTGGAAAGT
292 4671 975 QQSYSAPLT
292 4672 976 CAACAGAGTTACAGTGCCCCGCTCACC
293 4673 977 CAGGTCCAGCTGGTACAGTCTGGGGCTGGGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCTCATGCACGGCCTCTGGATACACCTTCACCGACTA
CTTTATAAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGA
TGGGGTGGGTCAATCCTCTCAGTGGAGCCACAAGATACGCCCAGAAC
TTTGCGGGCAGGGTCACCATGACCACGGACACGTCCATCACCACAGG
ATATCTGGACTTACGGAACCTGCGACTTGACGACACGGCCGTCTATTT
TTGTGCGAGCCAGTCTTCACCTTACACGCCGGGCGCTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA
293 4674 978 QVQLVQSGAGVKKPGASVRVSCTASGYTFTDYFINWVRQAPGGGLEW
MGWVNPLSGATRYAQNFAGRVTMTTDTSITTGYLDLRNLRLDDTAVYF
CASQSSPYTPGAMDVWGQGTTVTVSS
293 4675 979 YTFTDYFIN
293 4676 980 TACACCTTCACCGACTACTTTATAAAC
293 4677 981 WVNPLSGATRYAQNFAG
293 4678 982 TGGGTCAATCCTCTCAGTGGAGCCACAAGATACGCCCAGAACTTTGC
GGGC
293 4679 983 ASQSSPYTPGAMDV
293 4680 984 GCGAGCCAGTCTTCACCTTACACGCCGGGCGCTATGGACGTC
293 4681 985 GATATTGTGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCTCCATCACTTGCCGGACAAGTCAGACCATTAGTGGCTA
TATAAGTTGGTATCAGAAGAAACCAGGAAAAGCCCCTAAACTCCTGA
TCTATGCTGCATCAAATATGTACAGTGGGGTCCCATCAAGGTTCAGTG
GCAGTGAATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAAC
CTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTAT
TCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
293 4682 986 DIVMTQSPSSLSASVGDRVSITCRTSQTISGYISWYQKKPGKAPKLLIYAA
SNMYSGVPSRFSGSESGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPGT
KVDIK
293 4683 987 RTSQTISGYIS
293 4684 988 CGGACAAGTCAGACCATTAGTGGCTATATAAGT
293 4685 989 AASNMYS
293 4686 990 GCTGCATCAAATATGTACAGT
293 4687 991 QLNSGALFT
293 4688 992 CAACTGAATTCCGGTGCCCTATTCACT
294 4689 993 GAGGTGCAGCTGGTGGAGTCTGCAGCAGAGGTGAAAAAGCCCGGGG
AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGTTTTGCCAGCC
ACTGGATCGGTTGGGTCCGCCAAATGCCCGGGAAAGGCCTGGAGTTG
ATGGGATTCATCTATCCTGGTGACTCTGATACCAGATACAACCCGTCC
TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGC
CTACCTGCAGTGGACCAGGCTGAAGGCCTCGGACACCGCCATGTACT
ACTGTGGCCAGGCAGTGGCGGGGGGTGAATATTTCCACCACTGGGGC
CAGGGCACCCTGGTCACCGTCTCCTCA
294 4690 994 EVQLVESAAEVKKPGESLKISCKGSGYSFASHWIGWVRQMPGKGLELM
GFIYPGDSDTRYNPSFQGQVTISADKSISTAYLQWTRLKASDTAMYYCG
QAVAGGEYFHHWGQGTLVTVSS
294 4691 995 YSFASHWIG
294 4692 996 TACAGTTTTGCCAGCCACTGGATCGGT
294 4693 997 FIYPGDSDTRYNPSFQG
294 4694 998 TTCATCTATCCTGGTGACTCTGATACCAGATACAACCCGTCCTTCCAA
GGC
294 4695 999 GQAVAGGEYFHH
294 4696 1000 GGCCAGGCAGTGGCGGGGGGTGAATATTTCCACCAC
294 4697 1001 GATATTGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTGGCAGCGA
CTTAGCCTGGTACCAGCAGAAACCTGGCCAGACTCCCAGGCTCCTCAT
CTATGATGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG
TCTGAAGATTTTGCAGTTTATTACTGTCAGCACTATAATAATTGGCCC
CGGGGGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
294 4698 1002 DIVMTQSPATLSVSPGERATLSCRASQSLGSDLAWYQQKPGQTPRLLIYD
ASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQHYNNWPRGFGQ
GTKVEIK
294 4699 1003 RASQSLGSDLA
294 4700 1004 AGGGCCAGTCAGAGTCTTGGCAGCGACTTAGCC
294 4701 1005 DASTRAT
294 4702 1006 GATGCATCCACCAGGGCCACT
294 4703 1007 QHYNNWPRG
294 4704 1008 CAGCACTATAATAATTGGCCCCGGGGG
295 4705 1009 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGTCTCCGTCACCATTAAT
GATTACTACTGGACTTGGCTCCGCCAGTCCCCAGGGAAAGGCCTGGA
GTGGATTGGAAACATCTATAACAGTGGGAGCACCTACCAGAACCCGT
CCCTCCAGAGTCGAGTTACCATGTCAGTGGACACGGCCAAGAACCAC
TTCTCCCTGAAGCTGACCTCTGTCACTGCCGCAGATACGGCCGTCTAT
TACTGTGCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATG
GACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTCA
295 4706 1010 QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTWLRQSPGKGLEW
IGNIYNSGSTYQNPSLQSRVTMSVDTAKNHFSLKLTSVTAADTAVYYCA
RDLGTANNYYFGMDVWGLGTTVTVSS
295 4707 1011 VSVTINDYYWT
295 4708 1012 GTCTCCGTCACCATTAATGATTACTACTGGACT
295 4709 1013 NIYNSGSTYQNPSLQS
295 4710 1014 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAG
T
295 4711 1015 ARDLGTANNYYFGMDV
295 4712 1016 GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGT
C
295 4713 1017 GAAATTGTGATGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACTCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCACCTA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATAATGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCGTAGAG
CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCT
CCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA
295 4714 1018 EIVMTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQKPGQAPRLLIYN
GSNRVTGTPARFSGSGSGTDFTLTISSVEPEDFAVYYCQQRSNWPPYTFG
QGTKVEIK
295 4715 1019 RASQSVSTYLA
295 4716 1020 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC
295 4717 1021 NGSNRVT
295 4718 1022 AATGGATCCAACAGGGTCACT
295 4719 1023 QQRSNWPPYT
295 4720 1024 CAGCAGCGTAGCAACTGGCCTCCGTACACT
296 4721 1025 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCTCGGTCTCTGGTGCCTCCGTCACCAGTAG
GGAATACTACTGGGGCTGGATCCGCCAGGCCCCCGGGAAGGGTCTGC
AGTGGATTGCCAGCATTCATCACAGTCCTTTTCAAAGTGACGGCAACC
CGTCCCTGACGAGTCGCGTCTCCAGTTCCGTAGTCACGTCCAAGAACC
AGTTGGCCCTGAGGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTA
TATTACTGTGCGGGCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTCA
CCGCCGTTTGACTTTTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCA
296 4722 1026 QVQLQESGPGLVKPSETLSLTCSVSGASVTSREYYWGWIRQAPGKGLQW
IASIHHSPFQSDGNPSLTSRVSSSVVTSKNQLALRLSSVTAADTAVYYCAG
AFWEVWTGLYSPPFDFWGQGILVTVSS
296 4723 1027 ASVTSREYYWG
296 4724 1028 GCCTCCGTCACCAGTAGGGAATACTACTGGGGC
296 4725 1029 SIHHSPFQSDGNPSLTS
296 4726 1030 AGCATTCATCACAGTCCTTTTCAAAGTGACGGCAACCCGTCCCTGACG
AGT
296 4727 1031 AGAFWEVWTGLYSPPFDF
296 4728 1032 GCGGGCGCGTTTTGGGAGGTTTGGACTGGCCTTTATTCACCGCCGTTT
GACTTT
296 4729 1033 GAAATTGTAATGACACAGTCTCCAGGGACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCTGGGCCAGTCAGACTGTTAGCAGCGG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGGTGCATCTACCAGGGCCACTGACATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGGCTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATCTTGCAGTCTATTACTGTCAGCAGTATAGCAGTTCA
CCACTCACTTTCGGCGGCGGGACCAAGGTGGAAATCAAA
296 4730 1034 EIVMTQSPGTLSLSPGERATLSCWASQTVSSGYLAWYQQKPGQAPRLLIY
GASTRATDIPDRFSGSGSGTGFTLTISRLEPEDLAVYYCQQYSSSPLTFGG
GTKVEIK
296 4731 1035 WASQTVSSGYLA
296 4732 1036 TGGGCCAGTCAGACTGTTAGCAGCGGCTACTTAGCC
296 4733 1037 GASTRAT
296 4734 1038 GGTGCATCTACCAGGGCCACT
296 4735 1039 QQYSSSPLT
296 4736 1040 CAGCAGTATAGCAGTTCACCACTCACT
297 4737 1041 CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTA
CGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGG
TTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGC
CCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATT
ACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
TGGGGCCAGGGAACCACGGTCACCGTCTCCTCA
297 4738 1042 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWM
AWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCA
RDPAVDAIPMLDYWGQGTTVTVSS
297 4739 1043 YTFSNYGIS
297 4740 1044 TACACCTTTTCCAACTACGGTATCAGC
297 4741 1045 WISPYNGNTKSAQRFQG
297 4742 1046 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA
GGGC
297 4743 1047 ARDPAVDAIPMLDY
297 4744 1048 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
297 4745 1049 GACATCCAGGTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACT
GATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAA
TCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAAT
CAAA
297 4746 1050 DIQVTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRR
LIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL
TFGGGTKVEIK
297 4747 1051 RSSQSLVYTDGNTYLS
297 4748 1052 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG
C
297 4749 1053 RVSHRDS
297 4750 1054 AGGGTTTCTCACCGGGACTCT
297 4751 1055 MQGTHWPLT
297 4752 1056 ATGCAAGGTACACACTGGCCTCTCACT
298 4753 1057 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACGTTCAGTGACTA
TGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAATCATATCATATGATGCAAATAATAAATATTATGCAGACTCCG
TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGTG
TATCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTATATTA
CTGTGCGAAAGAAGAGTGGCTGGTGCCAGCCTACTGGGGCCAGGGAA
TCCTGGTCACCGTCTCCTCA
298 4754 1058 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSDYAMHWVRQAPGKGLEW
VAIISYDANNKYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYC
AKEEWLVPAYWGQGILVTVSS
298 4755 1059 FTFSDYAMH
298 4756 1060 TTCACGTTCAGTGACTATGCCATGCAC
298 4757 1061 IISYDANNKYYADSVKG
298 4758 1062 ATCATATCATATGATGCAAATAATAAATATTATGCAGACTCCGTGAA
GGGC
298 4759 1063 AKEEWLVPAY
298 4760 1064 GCGAAAGAAGAGTGGCTGGTGCCAGCCTAC
298 4761 1065 CAGTCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGATAT
AATTACGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT
CTTAATTTATGAGGTCTCTAATCGGCCCTCAGGGGTTTCTAATCGCTT
CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT
CCAGCCTGAGGACGAGGCTGATTATTACTGCAGCTCATATTCAACCA
ATAGTGCCCCCTTTGGAACTGGGACCAAGCTCACCGTCCTA
298 4762 1066 QSVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLLI
YEVSNRPSGVSNRFSGSKSGNTASLTISGLQPEDEADYYCSSYSTNSAPFG
TGTKLTVL
298 4763 1067 TGTSSDVGGYNYVS
298 4764 1068 ACTGGAACCAGCAGTGACGTTGGTGGATATAATTACGTCTCC
298 4765 1069 EVSNRPS
298 4766 1070 GAGGTCTCTAATCGGCCCTCA
298 4767 1071 SSYSTNSAP
298 4768 1072 AGCTCATATTCAACCAATAGTGCCCCC
299 4769 1073 CAGGTCCAGCTTGTGCAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGACAA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAGGAATCTTTCATGATGGGAGTAATAAACAATATGCAGAATCC
GTGAAGGGCCGATTCATCATCTCCAGAGACAATTCCAAGAACACTCT
CTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTCTATATT
TCTGTGCGAGAGCCCCTTACGATATTTGGAGCGGATATTGTCTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
299 4770 1074 QVQLVQSGGGVVQSGRSLRLSCAASGFTFSDNGMHWVRQAPGKGLEW
VAGIFHDGSNKQYAESVKGRFIISRDNSKNTLYLQMNSLRAEDTALYFCA
RAPYDIWSGYCLDYWGQGTLVTVSS
299 4771 1075 FTFSDNGMH
299 4772 1076 TTCACCTTCAGTGACAATGGCATGCAC
299 4773 1077 GIFHDGSNKQYAESVKG
299 4774 1078 GGAATCTTTCATGATGGGAGTAATAAACAATATGCAGAATCCGTGAA
GGGC
299 4775 1079 ARAPYDIWSGYCLDY
299 4776 1080 GCGAGAGCCCCTTACGATATTTGGAGCGGATATTGTCTTGACTAC
299 4777 1081 GACATCCGGATGACCCAGTCTCCAGCCACCCTGTCTCTGTCTCCAGGG
GAAAGCGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTATCAACAA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGG
CAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTC
TGAAGATTTCGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCA
GACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
299 4778 1082 DIRMTQSPATLSLSPGESATLSCRASQSVINNLAWYQQRPGQAPRLLIYG
ASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQG
TKLEIK
299 4779 1083 RASQSVINNLA
299 4780 1084 AGGGCCAGTCAGAGTGTTATCAACAACTTAGCC
299 4781 1085 GASTRAT
299 4782 1086 GGTGCATCTACCAGGGCCACT
299 4783 1087 QQYSIWPQT
299 4784 1088 CAGCAGTATAGTATCTGGCCTCAGACT
300 4785 1089 GAGGTGCAGCTGTTGGAGTCCGGGGGAGGCGTGGTCCAGTCTGGGAG
GTCCCTGAGACTCTCCTGTGTAGCGTCTGGATTCACCTTCAGTGACAG
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAGGTTTATTTTATGATGGAAGTAATAAACAATATGCAGACTCCG
TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAGCACACTG
TATCTGCAGATGAACAGCCTGAGGGCCGAGGACACGGCTGTTTATTA
CTGTGCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTA
CTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
300 4786 1090 EVQLLESGGGVVQSGRSLRLSCVASGFTFSDSGMHWVRQAPGKGLEWV
AGLFYDGSNKQYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYC
ARAPYDIWSGYCLDYWGQGTLVTVSS
300 4787 1091 FTFSDSGMH
300 4788 1092 TTCACCTTCAGTGACAGTGGCATGCAC
300 4789 1093 GLFYDGSNKQYADSVKG
300 4790 1094 GGTTTATTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA
GGGC
300 4791 1095 ARAPYDIWSGYCLDY
300 4792 1096 GCGAGAGCCCCTTACGATATTTGGAGTGGTTATTGTCTTGACTAC
300 4793 1097 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTATATGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGGTGCATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGG
CAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAGTC
TGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCTCA
GACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
300 4794 1098 EIVLTQSPATLYMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIY
GASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ
GTKLEIK
300 4795 1099 RASQSVNNNLA
300 4796 1100 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC
300 4797 1101 GASTRAT
300 4798 1102 GGTGCATCTACCAGGGCCACT
300 4799 1103 QQYSIWPQT
300 4800 1104 CAGCAGTATAGTATCTGGCCTCAGACT
301 4801 1105 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTA
CGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGG
TTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGC
CCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATT
ACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
TGGGGCCAGGGAACCATGGTCACCGTCTCCTCA
301 4802 1106 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWM
AWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCA
RDPAVDAIPMLDYWGQGTMVTVSS
301 4803 1107 YTFSNYGIS
301 4804 1108 TACACCTTTTCCAACTACGGTATCAGC
301 4805 1109 WISPYNGNTKSAQRFQG
301 4806 1110 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA
GGGC
301 4807 1111 ARDPAVDAIPMLDY
301 4808 1112 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
301 4809 1113 GAAATTGTGTTGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACT
GATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAA
TCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAAT
CAAA
301 4810 1114 EIVLTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRR
LIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL
TFGGGTKVEIK
301 4811 1115 RSSQSLVYTDGNTYLS
301 4812 1116 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG
C
301 4813 1117 RVSHRDS
301 4814 1118 AGGGTTTCTCACCGGGACTCT
301 4815 1119 MQGTHWPLT
301 4816 1120 ATGCAAGGTACACACTGGCCTCTCACT
302 4817 1121 GAGGTGCAGCTGGTGGAGTCGGGCCCAAGACTGGTGAGGCCTTCGGA
GACCCTGTCCCTCACCTGCACTGTCTCTGGAGGCTTCATCAAAACTAG
TAGTTACTACTGGGGCTGGATCCGTCAGCCCCCAGGGAAGGGGCTAG
AGTGGATTGGGAGTATCTATTATGCTGGGACCACCTACTACAACCCGT
CCCTCCAGAGTCGAGTCACCATGTCCGTTGACACGTCGAACAACCAG
TTCTCCCTGAAGCTGAACTCTGTGACCGCCGCAGACACGGCTGTATAT
TACTGTGCGACCGCCTGGACTTTTGACCACTGGGGCCAGGGAACCCT
GGTCACTGTCTCCTCA
302 4818 1122 EVQLVESGPRLVRPSETLSLTCTVSGGFIKTSSYYWGWIRQPPGKGLEWI
GSIYYAGTTYYNPSLQSRVTMSVDTSNNQFSLKLNSVTAADTAVYYCAT
AWTFDHWGQGTLVTVSS
302 4819 1123 GFIKTSSYYWG
302 4820 1124 GGCTTCATCAAAACTAGTAGTTACTACTGGGGC
302 4821 1125 SIYYAGTTYYNPSLQS
302 4822 1126 AGTATCTATTATGCTGGGACCACCTACTACAACCCGTCCCTCCAGAGT
302 4823 1127 ATAWTFDH
302 4824 1128 GCGACCGCCTGGACTTTTGACCAC
302 4825 1129 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCCTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTAGCAACTA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG
CCTGAAGATTTTGCAGTTTATTACTGTCAGCTGCGTGGCCACTGGCCC
CCCACGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
302 4826 1130 EIVLTQSPATLSLSPGERATLSCRASQSLSNYLAWYQQKPGQAPRLLIYD
ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQLRGHWPPTITFG
QGTRLEIK
302 4827 1131 RASQSLSNYLA
302 4828 1132 AGGGCCAGTCAGAGTCTTAGCAACTACTTAGCC
302 4829 1133 DASNRAT
302 4830 1134 GATGCATCCAACAGGGCCACT
302 4831 1135 QLRGHWPPTIT
302 4832 1136 CAGCTGCGTGGCCACTGGCCCCCCACGATCACC
303 4833 1137 CAGGTCCAGCTTGTACAGTCTGGGGGAGGCTTGGTTCAGCCGGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCGACTA
TACCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCAAGTGTTAGTGGCACGGGTGGTACCTCATACTACGCAGACTCCG
TGAATGGCCGGTTCGCCATCTCCAGAGAGAATTCCAAGAACACGCTG
TTTCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCCACTTACTA
CTGTGCCAAAGATGGGTTGAGGGACGTATCGAGGGTTTATTACATCG
ACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA
303 4834 1138 QVQLVQSGGGLVQPGGSLRLSCAASGFAFSDYTMSWVRQAPGKGLEWV
SSVSGTGGTSYYADSVNGRFAISRENSKNTLFLQMDSLRAEDTATYYCA
KDGLRDVSRVYYIDVWGKGTTVTVSS
303 4835 1139 FAFSDYTMS
303 4836 1140 TTCGCCTTTAGCGACTATACCATGAGC
303 4837 1141 SVSGTGGTSYYADSVNG
303 4838 1142 AGTGTTAGTGGCACGGGTGGTACCTCATACTACGCAGACTCCGTGAA
TGGC
303 4839 1143 AKDGLRDVSRVYYIDV
303 4840 1144 GCCAAAGATGGGTTGAGGGACGTATCGAGGGTTTATTACATCGACGT
C
303 4841 1145 CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
TCGATCACCATCTCCTGCACTGGAACCAGCCGTGACATTGGTTCTCAT
GACTCTGTCTCCTGGTACCAACAAAAGCCAGGCAAAGCCCCCAAACT
CATCATTTATGCAGTCAGAAATCGGCCCTCAGGGCTTTCTAATCGCTT
CTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT
CCAGACTGAAGACGAAGGTGACTATTACTGCAGCTCATATAGAAACG
GCAACGCTCTGGGGGTCTTCGGAACTGGGACCAAGGTCACCGTCCTC
303 4842 1146 QPVLTQPASVSGSPGQSITISCTGTSRDIGSHDSVSWYQQKPGKAPKLIIY
AVRNRPSGLSNRFSGSKSGNTASLTISGLQTEDEGDYYCSSYRNGNALGV
FGTGTKVTVL
303 4843 1147 TGTSRDIGSHDSVS
303 4844 1148 ACTGGAACCAGCCGTGACATTGGTTCTCATGACTCTGTCTCC
303 4845 1149 AVRNRPS
303 4846 1150 GCAGTCAGAAATCGGCCCTCA
303 4847 1151 SSYRNGNALGV
303 4848 1152 AGCTCATATAGAAACGGCAACGCTCTGGGGGTC
304 4849 1153 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCGGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCAACTA
TGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGG
TCTCAAGTGTTAGTGGCACGGGTGGTACCACATACTACGCAGACTCC
GTGAACGGGCGGTTCGCCATCTCCAGAGAGAATTCCAGGAACACCCT
CTATCTGCAAATGGATAGCCTGAGAGTCGAGGACACGGCCACTTATT
ACTGTGCCAAAGATGGGTTGAGGGACTTATCGAGGGTCTATTACATC
GACGTCTGGGGCAAAGGGGCCACGGTCACCGTCTCTTCA
304 4850 1154 QVQLVESGGGLVQPGGSLRLSCAASGFAFSNYAMSWVRQAPGKGLEWV
SSVSGTGGTTYYADSVNGRFAISRENSRNTLYLQMDSLRVEDTATYYCA
KDGLRDLSRVYYIDVWGKGATVTVSS
304 4851 1155 FAFSNYAMS
304 4852 1156 TTCGCCTTTAGCAACTATGCCATGAGC
304 4853 1157 SVSGTGGTTYYADSVNG
304 4854 1158 AGTGTTAGTGGCACGGGTGGTACCACATACTACGCAGACTCCGTGAA
CGGG
304 4855 1159 AKDGLRDLSRVYYIDV
304 4856 1160 GCCAAAGATGGGTTGAGGGACTTATCGAGGGTCTATTACATCGACGT
C
304 4857 1161 CAGTCTGTCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
TCGATCACCATCTCCTGCACTGGAACCAGCCGTGACATTGGTAGTCAT
GACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT
CATCATTTATGGGGTCAATAATCGGCCCTCAGGACTTTCTAATCGCTT
CTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT
CCAGACTGAAGACGAAGGTGACTATTACTGCAGCTCATATAGAAACG
GCAACACTCTGGGGGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA
304 4858 1162 QSVLTQPASVSGSPGQSITISCTGTSRDIGSHDYVSWYQQHPGKAPKLIIY
GVNNRPSGLSNRFSGSKSGNTASLTISGLQTEDEGDYYCSSYRNGNTLGV
FGTGTKLTVL
304 4859 1163 TGTSRDIGSHDYVS
304 4860 1164 ACTGGAACCAGCCGTGACATTGGTAGTCATGACTATGTCTCC
304 4861 1165 GVNNRPS
304 4862 1166 GGGGTCAATAATCGGCCCTCA
304 4863 1167 SSYRNGNTLGV
304 4864 1168 AGCTCATATAGAAACGGCAACACTCTGGGGGTC
305 4865 1169 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCT
ACGCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGG
ATGGGAGGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAA
GTTCCAGGGCAGACTCACGATAACCGCGGACGCATCCACGGGCACAG
CCTACATGGAATTGAGCAGCCTGATGTCTGAGGACACGGCCCTATATT
ATTGTGCGAGAGATGCTTACGAAGTGTGGACCGGTTCTTATCTCCCCC
CTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
305 4866 1170 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYAINWVRQAPGQGLEW
MGGIIHIFGTVNYAPKFQGRLTITADASTGTAYMELSSLMSEDTALYYCA
RDAYEVWTGSYLPPFDYWGQGTLVTVSS
305 4867 1171 GTFSGYAIN
305 4868 1172 GGCACCTTCAGCGGCTACGCTATCAAC
305 4869 1173 GIIHIFGTVNYAPKFQG
305 4870 1174 GGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCA
GGGC
305 4871 1175 ARDAYEVWTGSYLPPFDY
305 4872 1176 GCGAGAGATGCTTACGAAGTGTGGACCGGTTCTTATCTCCCCCCTTTT
GACTAC
305 4873 1177 GAAACGACACTCACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAA
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGATGCATTCACCAGGGCCACTGGCGTCCCAGCCAGGTTCAG
TGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG
AGCCTGAAGATTTTGCAGTTTACTATTGTCAGCAGTATGGTAGCTCAT
TCCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
305 4874 1178 ETTLTQSPGTLSLSPGERVTLSCRASQTVTSNYLAWYQQKPGQAPRLLIY
DAFTRATGVPARFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGG
GTKVEIK
305 4875 1179 RASQTVTSNYLA
305 4876 1180 AGGGCCAGTCAGACTGTTACAAGCAACTACTTAGCC
305 4877 1181 DAFTRAT
305 4878 1182 GATGCATTCACCAGGGCCACT
305 4879 1183 QQYGSSFLT
305 4880 1184 CAGCAGTATGGTAGCTCATTCCTCACT
306 4881 1185 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGTCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCATCTTCAGTGACAA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCAGGTATTTTTTATGATGGAAGTAATAAACAATATGCAGACTCCG
TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACACTG
TATCTGCAAATGAAGAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CTGTGCGAGAGCCCCTTACGATATCTGGAGTGGTTATTGTCTTGACTA
CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
306 4882 1186 EVQLVESGGGVVQSGRSLRLSCAASGFIFSDNGMHWVRQAPGKGLEWV
AGIFYDGSNKQYADSVKGRFTISRDNSKNTLYLQMKSLRAEDTAVYYCA
RAPYDIWSGYCLDYWGQGTLVTVSS
306 4883 1187 FIFSDNGMH
306 4884 1188 TTCATCTTCAGTGACAATGGCATGCAC
306 4885 1189 GIFYDGSNKQYADSVKG
306 4886 1190 GGTATTTTTTATGATGGAAGTAATAAACAATATGCAGACTCCGTGAA
GGGC
306 4887 1191 ARAPYDIWSGYCLDY
306 4888 1192 GCGAGAGCCCCTTACGATATCTGGAGTGGTTATTGTCTTGACTAC
306 4889 1193 GACATCCAGGTGACCCAGTCTCCAGCCACCCTGTCTATGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAA
CTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGGTGCATCTACGAGGGCCACTGGTATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGAGACAGAGTTCACTCTCACTATCAGCAGCCTGCAG
TCTGAAGATTTTGCGGTTTATCACTGTCAGCAGTATAGTATCTGGCCT
CAGACTTTTGGCCAGGGGACCAAGGTGGAAATCAAA
306 4890 1194 DIQVTQSPATLSMSPGERATLSCRASQSVNNNLAWYQQRPGQAPRLLIY
GASTRATGIPARFSGSGSETEFTLTISSLQSEDFAVYHCQQYSIWPQTFGQ
GTKVEIK
306 4891 1195 RASQSVNNNLA
306 4892 1196 AGGGCCAGTCAGAGTGTTAACAACAACTTAGCC
306 4893 1197 GASTRAT
306 4894 1198 GGTGCATCTACGAGGGCCACT
306 4895 1199 QQYSIWPQT
306 4896 1200 CAGCAGTATAGTATCTGGCCTCAGACT
307 4897 1201 CAGGTCCAGCTTGTACAGTCTGGGGCTGAACTAAAGAAGCCTGGCTC
CTCGGTGAAAGTCTCCTGCAAGGCTTCTGCAGACACCTTCAAAAGTTA
TGCTATCAACTGGGTGCGGCAGGCCCCTGGACAAGGACTTGAGTGGA
TGGGAGAGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACAGAAGT
TCCAGGGCAGAGTCACCATTACCGCGGACAGATCCACGTCCACAGCC
TACATGGAGTTGAGCAGCCTGAAATCTGATGACTCGGCCATTTATTAC
TGTGCGACACGTCTGTATACGTTGGGGTCCCCTTTTGACAATTGGGGC
CAGGGGACCACGGTCACCGTCTCCTCA
307 4898 1202 QVQLVQSGAELKKPGSSVKVSCKASADTFKSYAINWVRQAPGQGLEWM
GEFIPIFGVSPSAQKFQGRVTITADRSTSTAYMELSSLKSDDSAIYYCATRL
YTLGSPFDNWGQGTTVTVSS
307 4899 1203 DTFKSYAIN
307 4900 1204 GACACCTTCAAAAGTTATGCTATCAAC
307 4901 1205 EFIPIFGVSPSAQKFQG
307 4902 1206 GAGTTCATCCCAATCTTTGGTGTCTCACCCTCCGCACAGAAGTTCCAG
GGC
307 4903 1207 ATRLYTLGSPFDN
307 4904 1208 GCGACACGTCTGTATACGTTGGGGTCCCCTTTTGACAAT
307 4905 1209 CAGCCTGTGCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
TCAGTCACCATCTCCTGCACTGGAACCAGTAGTGATGTTGGTGATTAT
GACTATGTCTCCTGGTACCAACACCTCCCAGGCGAAGTCCCCAAACTC
ATAGTTTATAATGTCATTAAGCGGCCCTCTGGGGTCCCTGATCGCTTC
TCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTC
CAGGCTGAGGATGAGGCTGACTATTACTGCTGCTCATATGCAGGCAG
GTATATTTATGTCTTCGGCAGTGGGACCAAGCTCACCGTCCTA
307 4906 1210 QPVLTQPRSVSGSPGQSVTISCTGTSSDVGDYDYVSWYQHLPGEVPKLIV
YNVIKRPSGVPDRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGRYIYV
FGSGTKLTVL
307 4907 1211 TGTSSDVGDYDYVS
307 4908 1212 ACTGGAACCAGTAGTGATGTTGGTGATTATGACTATGTCTCC
307 4909 1213 NVIKRPS
307 4910 1214 AATGTCATTAAGCGGCCCTCT
307 4911 1215 CSYAGRYIYV
307 4912 1216 TGCTCATATGCAGGCAGGTATATTTATGTC
308 4913 1217 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGA
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCTTAGTGGCTA
CTACATGAATTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGG
TCTCCTCCATTAGTGGTGGTAGTAATTACATAAACTACGCCGACTCAG
TGAAGGGCCGGTTCACCATCTCCAGAGACAACGCCAAGAACTCACTC
TATCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGCTGTCTATTA
CTGTGCGAGGGTCCACGTGGATTTAGTGACTACGATTTTTGGGGTTGA
CTTTGACTTCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
308 4914 1218 EVQLLESGGGLVKPGESLRLSCAASGFTLSGYYMNWVRQAPGRGLEWV
SSISGGSNYINYADSVKGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCAR
VHVDLVTTIFGVDFDFWGQGTLVTVSS
308 4915 1219 FTLSGYYMN
308 4916 1220 TTCACCCTTAGTGGCTACTACATGAAT
308 4917 1221 SISGGSNYINYADSVKG
308 4918 1222 TCCATTAGTGGTGGTAGTAATTACATAAACTACGCCGACTCAGTGAA
GGGC
308 4919 1223 ARVHVDLVTTIFGVDFDF
308 4920 1224 GCGAGGGTCCACGTGGATTTAGTGACTACGATTTTTGGGGTTGACTTT
GACTTC
308 4921 1225 CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GGTATGATGTACACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAA
CTCCTCATCTATGGTAACACCAATCGGCCCGCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCGTATGACAG
CAGCCTGAGTGGTGCGATCTTCGGCGGAGGGACCAAGCTCACCGTCC
TA
308 4922 1226 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLI
YGNTNRPAGVPDRFSGSKSGSSASLAITGLQAEDEADYYCQSYDSSLSGA
IFGGGTKLTVL
308 4923 1227 TGSSSNIGAGYDVH
308 4924 1228 ACTGGGAGCAGCTCCAACATCGGGGCAGGGTATGATGTACAC
308 4925 1229 GNTNRPA
308 4926 1230 GGTAACACCAATCGGCCCGCA
308 4927 1231 QSYDSSLSGAI
308 4928 1232 CAGTCGTATGACAGCAGCCTGAGTGGTGCGATC
309 4929 1233 CAGGTGCAGCTGCAGGAGTCCGGAGCTGAGGTGAAGATGCGTGGGGC
CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTAGTCACTA
TGGTATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGA
TGGGATTTATCAGCGCTTACAATCATAACACAAAGTATGCACAGACC
GTCCAGGGCAGAGTCACCTTGAGCACAGACACATCCACGAGCACAGC
CTACATGGAGCTGAGGAGCCTGAGACCTGACGACACGGCCATGTATT
ACTGTGCGAGAGAACCCCCGAGTGACGATGCTGCAAGGCTCTTTGAC
TACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
309 4930 1234 QVQLQESGAEVKMRGASVKVSCKASGYTFSHYGISWVRQAPGQGLEW
MGFISAYNHNTKYAQTVQGRVTLSTDTSTSTAYMELRSLRPDDTAMYY
CAREPPSDDAARLFDYWGQGTLVTVSS
309 4931 1235 YTFSHYGIS
309 4932 1236 TACACCTTTAGTCACTATGGTATCAGT
309 4933 1237 FISAYNHNTKYAQTVQG
309 4934 1238 TTTATCAGCGCTTACAATCATAACACAAAGTATGCACAGACCGTCCA
GGGC
309 4935 1239 AREPPSDDAARLFDY
309 4936 1240 GCGAGAGAACCCCCGAGTGACGATGCTGCAAGGCTCTTTGACTAC
309 4937 1241 GAAACGACACTCACGCAGTCTCCACGCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACAGT
GAAGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTATTGCATGCAA
GGTACACAGTGGCCTGTGACATTCGGCCAAGGGACCAAGGTGGAAAT
CAAA
309 4938 1242 ETTLTQSPRSLPVTLGQPASISCRSSQSLVYSEGNTYLSWFQQRPGQSPRR
LIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTQWP
VTFGQGTKVEIK
309 4939 1243 RSSQSLVYSEGNTYLS
309 4940 1244 AGGTCTAGTCAAAGCCTCGTGTACAGTGAAGGAAACACCTACTTGAG
T
309 4941 1245 KVSNRDS
309 4942 1246 AAGGTTTCTAACCGGGACTCT
309 4943 1247 MQGTQWPVT
309 4944 1248 ATGCAAGGTACACAGTGGCCTGTGACA
310 4945 1249 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCTCCTGCAAGGTTTACGGTCACACCCTCAGTGAATT
ATCCATGCACTGGGTGCGACAGGGTCCTGAAGGAGGCCTTGAGTGGA
TGGGAGCTTTTGATCATGAAGATGGTGAAGGAATCTACCCACAGAAG
TTCCAGGGCAGAATCACCATGACCGCGGACATATCGACAGACACAGC
CCACATGGAACTGAGGAGCCTCAGATCTGAGGACACGGCCGTTTATT
ACTGTGCAACACCGACCCCGGTTGGAGCAACGGACTTCTGGGGCCAG
GGAACCCTGGTCACCGTCTCCTCA
310 4946 1250 QVQLVQSGAEVKKPGASVRVSCKVYGHTLSELSMHWVRQGPEGGLEW
MGAFDHEDGEGIYPQKFQGRITMTADISTDTAHMELRSLRSEDTAVYYC
ATPTPVGATDFWGQGTLVTVSS
310 4947 1251 HTLSELSMH
310 4948 1252 CACACCCTCAGTGAATTATCCATGCAC
310 4949 1253 AFDHEDGEGIYPQKFQG
310 4950 1254 GCTTTTGATCATGAAGATGGTGAAGGAATCTACCCACAGAAGTTCCA
GGGC
310 4951 1255 ATPTPVGATDF
310 4952 1256 GCAACACCGACCCCGGTTGGAGCAACGGACTTC
310 4953 1257 GACATCCGGGTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA
CTTAAATTGGTATCAACAGAAACCAGGAAAAGCCCCTAAGCTCCTGA
TCTATGCTGCATCCACTTTGCAGAGGGGGGGCCCATCAAGATTCAGTG
GCAGTGGATCTGGGACAGATTTCACTCTCAGCATCAGCAGTCTGCAA
CCTGAAGATTTTGCAACTTACTATTGTCAACAGACTTACATTATTCCA
TACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
310 4954 1258 DIRVTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA
STLQRGGPSRFSGSGSGTDFTLSISSLQPEDFATYYCQQTYIIPYTFGQGTK
LEIK
310 4955 1259 RASQSISSYLN
310 4956 1260 CGGGCAAGTCAGAGCATTAGCAGCTACTTAAAT
310 4957 1261 AASTLQR
310 4958 1262 GCTGCATCCACTTTGCAGAGG
310 4959 1263 QQTYIIPYT
310 4960 1264 CAACAGACTTACATTATTCCATACACT
311 4961 1265 CAGGTGCAGCTGCAGGAGTCGGGCCCGGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCAGTGTCTCTGGTGGCTCCATCACCAATGT
TAATTACTACTGGGGCTGGATCCGCCAGCCCCCCGGGAAGGGCCTGG
AGTGGATTGGGAGTATCTATTATAATGGAAACACCTACTACAACCCG
TCCCTCCAGAGTCGAGTCACCATGTCCGTGGACACGTCCAAGAACCA
CTTCTCCCTGAGGCTGACGTCTGTGACCGCCGCAGACACGGCTGTATA
TTTTTGTGCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGA
TATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
311 4962 1266 QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWIRQPPGKGLEWI
GSIYYNGNTYYNPSLQSRVTMSVDTSKNHFSLRLTSVTAADTAVYFCAR
EGPNWELLNAFDIWGQGTTVTVSS
311 4963 1267 GSITNVNYYWG
311 4964 1268 GGCTCCATCACCAATGTTAATTACTACTGGGGC
311 4965 1269 SIYYNGNTYYNPSLQS
311 4966 1270 AGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGT
311 4967 1271 AREGPNWELLNAFDI
311 4968 1272 GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATC
311 4969 1273 GACATCCAGGTGACCCAGCCACCCTCGGTGTCAGTGGCCCCAGGACA
GACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAATG
TGCACTGGTACCAGCAGAAGCCAGGCCGGGCCCCTGTCTTGGTCGTCT
ATGAGGATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT
CCAACTCTGGGAACACGGCCACCCTGACCATCAGTAGGGTCGAAGCC
GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATACTAGTAGTGA
TCATGTGGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA
311 4970 1274 DIQVTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKPGRAPVLVVYE
DTHRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDTSSDHVVF
GGGTKLTVL
311 4971 1275 GGNNIGSKNVH
311 4972 1276 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC
311 4973 1277 EDTHRPS
311 4974 1278 GAGGATACCCACCGGCCCTCA
311 4975 1279 QVWDTSSDHVV
311 4976 1280 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA
312 4977 1281 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCCTGGTCAAGCCTGAGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA
TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CTGTGCGAGAGTCTCAACAGAATTGGGCTACTACTACATGGACGTCT
GGGGCAAAGGGACCACGGTCACTGTCTCCTCA
312 4978 1282 QVQLVQSGGGLVKPEGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWV
SSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR
VSTELGYYYMDVWGKGTTVTVSS
312 4979 1283 FTFSSYSMN
312 4980 1284 TTCACCTTCAGTAGCTATAGCATGAAC
312 4981 1285 SISSSSSYIYYADSVKG
312 4982 1286 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG
GGC
312 4983 1287 ARVSTELGYYYMDV
312 4984 1288 GCGAGAGTCTCAACAGAATTGGGCTACTACTACATGGACGTC
312 4985 1289 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA
CTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGCCTGAGTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA
312 4986 1290 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLI
YGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSVV
FGGGTKLTVL
312 4987 1291 TGSSSNIGAGYDVH
312 4988 1292 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC
312 4989 1293 GNSNRPS
312 4990 1294 GGTAACAGCAATCGGCCCTCA
312 4991 1295 QSYDSSLSVV
312 4992 1296 CAGTCCTATGACAGCAGCCTGAGTGTGGTA
313 4993 1297 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGATTTCCTGCAAGGCTTCGGGATACCCCTTCAGTTCCTA
TCCTATGCATTGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGA
TGGGATGGATCAACGTTGACAATGAGAACACAAAATATTCATGGAAG
TTCCGGGGCAGAGTCACCATTACCAGGGACACATCCGCGAGCACAGT
TTACATGGAGCTGAGCAGTCTGATATCTGAAGACACGGCTGTGTATTA
CTGTGGGAGAGACTGGGACGGGGCGATCCGTGTCTTGGACTACTGGG
GCCAGGGAACCCTGGTCACCGTCTCCTCA
313 4994 1298 QVQLVQSGAEVKKPGASVKISCKASGYPFSSYPMHWVRQAPGQRLEWM
GWINVDNENTKYSWKFRGRVTITRDTSASTVYMELSSLISEDTAVYYCG
RDWDGAIRVLDYWGQGTLVTVSS
313 4995 1299 YPFSSYPMH
313 4996 1300 TACCCCTTCAGTTCCTATCCTATGCAT
313 4997 1301 WINVDNENTKYSWKFRG
313 4998 1302 TGGATCAACGTTGACAATGAGAACACAAAATATTCATGGAAGTTCCG
GGGC
313 4999 1303 GRDWDGAIRVLDY
313 5000 1304 GGGAGAGACTGGGACGGGGCGATCCGTGTCTTGGACTAC
313 5001 1305 GATATTGTGATGACTCAGACTCCAGACTCCCTGGCTGTGTCTCTGGGC
GAGAGGGCCACCATCACCTGCAAGTCCAGCCAGAGTGTTTTATTCAG
CTCCGACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCGGGAC
AGCCTCCTAAATTGCTCATTTACTGGGCATCTATCCGGGAATCCGGGG
TCCCTGACCGATTCGGTGGCAGCGGGTCTGGGACACATTTCACTCTCA
CCATCACCAGCGTGCAGGCTGCAGATGTGGCAGTTTATTACTGTCAGC
AATATTATGGTAATTTCCCCACCTTCGGCCAAGGGACACGACTGGAG
ATTAAA
313 5002 1306 DIVMTQTPDSLAVSLGERATITCKSSQSVLFSSDNKNYLAWYQQKPGQPP
KLLIYWASIRESGVPDRFGGSGSGTHFTLTITSVQAADVAVYYCQQYYG
NFPTFGQGTRLEIK
313 5003 1307 KSSQSVLFSSDNKNYLA
313 5004 1308 AAGTCCAGCCAGAGTGTTTTATTCAGCTCCGACAATAAGAACTACTTA
GCT
313 5005 1309 WASIRES
313 5006 1310 TGGGCATCTATCCGGGAATCC
313 5007 1311 QQYYGNFPT
313 5008 1312 CAGCAATATTATGGTAATTTCCCCACC
314 5009 1313 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTTTCCTGTGCAGCCTCTGGATTCACCTTCAGAAACTA
TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TAGCGGCTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAGACGCC
GTGAAGGGCCGATTCAGCATCTCCAGAGACAATACCAAGAACACGCT
GTCTCTGCAAATGACCAGCCTGAGAGCTGAGGACACGGCTGTGTATT
ACTGTGCAAGAGACCCCGGAGTGGGAAGTTATTATAACGTGGTGGGT
ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
314 5010 1314 QVQLVQSGGGVVQPGRSLRLSCAASGFTFRNYGMHWVRQAPGKGLEW
VAAASYDGSSKYFADAVKGRFSISRDNTKNTLSLQMTSLRAEDTAVYYC
ARDPGVGSYYNVVGMDVWGQGTTVTVSS
314 5011 1315 FTFRNYGMH
314 5012 1316 TTCACCTTCAGAAACTATGGCATGCAC
314 5013 1317 AASYDGSSKYFADAVKG
314 5014 1318 GCTGCATCGTATGATGGGAGTAGTAAGTACTTTGCAGACGCCGTGAA
GGGC
314 5015 1319 ARDPGVGSYYNVVGMDV
314 5016 1320 GCAAGAGACCCCGGAGTGGGAAGTTATTATAACGTGGTGGGTATGGA
CGTC
314 5017 1321 GACATCCGGTTGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGT
GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGAGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGCGTTTATTACTGCATGCAA
GGTACACACTGGCCTCCTACGTTCGGCCAAGGGACCAAGGTGGAGAT
CAAA
314 5018 1322 DIRLTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRR
LIYRVSHRDSGVPDRFSGSESGTDFTLKISRVEAEDVGVYYCMQGTHWP
PTFGQGTKVEIK
314 5019 1323 RSSQSLVYSDGNTYLN
314 5020 1324 AGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAA
T
314 5021 1325 RVSHRDS
314 5022 1326 AGGGTTTCTCACCGGGACTCT
314 5023 1327 MQGTHWPPT
314 5024 1328 ATGCAAGGTACACACTGGCCTCCTACG
315 5025 1329 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCGCCTGCAAGGTTTCCGGATCCAGCCTCACTGAATT
GTCCATTCAATGGGTGCGCTTGCCTCCTGGCAAACGCCTTGAGTGGCT
GGGAGCTTTTGATGCTGAAGATGGTGCACCAATCTACTCACCGAAATT
CCAGGGCAGAGTCACCATGACCGAGGACAGATCGACAGAGACAGCC
TACATGGAGGTGACCAGCCTGAGATCTGAGGACACGGCCCTCTATTA
CTGTGCGACTCCCCTTCCCGCGGGAGCCCTTGACAAGTGGGGCCAGG
GAACCCTGGTCACCGTCTCCTCA
315 5026 1330 QVQLVQSGAEVKKPGASVKVACKVSGSSLTELSIQWVRLPPGKRLEWLG
AFDAEDGAPIYSPKFQGRVTMTEDRSTETAYMEVTSLRSEDTALYYCAT
PLPAGALDKWGQGTLVTVSS
315 5027 1331 SSLTELSIQ
315 5028 1332 TCCAGCCTCACTGAATTGTCCATTCAA
315 5029 1333 AFDAEDGAPIYSPKFQG
315 5030 1334 GCTTTTGATGCTGAAGATGGTGCACCAATCTACTCACCGAAATTCCAG
GGC
315 5031 1335 ATPLPAGALDK
315 5032 1336 GCGACTCCCCTTCCCGCGGGAGCCCTTGACAAG
315 5033 1337 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCTTCCGTAGGA
GACAGAGTCACCATCTCTTGCCGGGCAAGTCAGACTATAAGCAGATA
TTTAAATTGGTATCAGGTCAAGCCAGGGACAGCCCCTAAGCTCCTAAT
CTACGCTGCATCCAGTTTGCAAACTGGGGTCCCATCAAGATTCAGTGC
CAGTGGATCTGGGGCAGATTTCACTCTCACCATCAGCAGTCTGCAACC
TGAAGATTTTGCGACTTACCACTGTCAACAAACTTACATTATTCCGTA
CACTTTTGGCCAGGGGACCAAAGTGGATATCAAA
315 5034 1338 DIQMTQSPSSLSASVGDRVTISCRASQTISRYLNWYQVKPGTAPKLLIYA
ASSLQTGVPSRFSASGSGADFTLTISSLQPEDFATYHCQQTYIIPYTFGQGT
KVDIK
315 5035 1339 RASQTISRYLN
315 5036 1340 CGGGCAAGTCAGACTATAAGCAGATATTTAAAT
315 5037 1341 AASSLQT
315 5038 1342 GCTGCATCCAGTTTGCAAACT
315 5039 1343 QQTYIIPYT
315 5040 1344 CAACAAACTTACATTATTCCGTACACT
316 5041 1345 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGATGTCCTCATCAGCAGTGG
TGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGG
AGTGGCTTGGGTACATCTATTATACCGGGAAGACCAAATATAATCCG
TCCCTCGAGAGTCGAATTACCATGTCAGTAGACACGTCCAAGAACCA
GTTCTCCCTGAGGTTGAGCTCTGTTACTGCCGCAGACACGGCCGTATA
TTTCTGTACCAGAGATCTGGGATATAGCACCTCGTCCCCCTCCTTTTA
CTATGGGATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCT
CA
316 5042 1346 EVQLVESGPGLVKPSQTLSLTCTVSDVLISSGDYYWSWIRQSPGKGLEWL
GYIYYTGKTKYNPSLESRITMSVDTSKNQFSLRLSSVTAADTAVYFCTRD
LGYSTSSPSFYYGMDVWGQGTTVTVSS
316 5043 1347 VLISSGDYYWS
316 5044 1348 GTCCTCATCAGCAGTGGTGATTACTACTGGAGT
316 5045 1349 YIYYTGKTKYNPSLES
316 5046 1350 TACATCTATTATACCGGGAAGACCAAATATAATCCGTCCCTCGAGAGT
316 5047 1351 TRDLGYSTSSPSFYYGMDV
316 5048 1352 ACCAGAGATCTGGGATATAGCACCTCGTCCCCCTCCTTTTACTATGGG
ATGGACGTC
316 5049 1353 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGGACCTA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGATGCATCTTACAGGGTCACTGGCATCCCAGCCAGGTTCAGTGC
CAGTGGGTCTGCGACAGACTTCACTCTCACCATCAGCAGCCTAGAGC
CTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTACCAACTGGCCGA
TCACCTTCGGCCAGGGGACACGACTGGAGATTAAA
316 5050 1354 EIVLTQSPATLSLSPGERATLSCRASQSVGTYLAWYQQKPGQAPRLLIYD
ASYRVTGIPARFSASGSATDFTLTISSLEPEDFAVYFCQQRTNWPITFGQG
TRLEIK
316 5051 1355 RASQSVGTYLA
316 5052 1356 AGGGCCAGTCAGAGTGTTGGGACCTACTTAGCC
316 5053 1357 DASYRVT
316 5054 1358 GATGCATCTTACAGGGTCACT
316 5055 1359 QQRTNWPIT
316 5056 1360 CAGCAGCGTACCAACTGGCCGATCACC
317 5057 1361 CAGGTCCAGCTTGTGCAGTCTGGACCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGACGGTCTCCTGCAAGGCTTCCGGTTACACCTTTAGCCATTA
CGGTATTAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGGTGGATCAGCGCGTACCATGGTCAGACAAACTATGCACAGAAC
TTCCAGGGCAGAGTCACCATGACCACAGACACATCCTCGAACACAGC
CTACATGGAGGTCAGGAGCCTGAGATCTGACGACACGGCCGTTTATT
TCTGTGCGAGAGATGTCTTTTCGAAAACAGCAGCTCGAATCTTTGACT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
317 5058 1362 QVQLVQSGPEVKKPGASVTVSCKASGYTFSHYGISWVRQAPGQGLEWM
GWISAYHGQTNYAQNFQGRVTMTTDTSSNTAYMEVRSLRSDDTAVYFC
ARDVFSKTAARIFDYWGQGTLVTVSS
317 5059 1363 YTFSHYGIS
317 5060 1364 TACACCTTTAGCCATTACGGTATTAGT
317 5061 1365 WISAYHGQTNYAQNFQG
317 5062 1366 TGGATCAGCGCGTACCATGGTCAGACAAACTATGCACAGAACTTCCA
GGGC
317 5063 1367 ARDVFSKTAARIFDY
317 5064 1368 GCGAGAGATGTCTTTTCGAAAACAGCAGCTCGAATCTTTGACTAC
317 5065 1369 GAAATTGTATTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATATAGT
GACGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTCAGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GCTACAGACTGGCCGGTCACGTTCGGCCAAGGGACCAAGCTGGAGAT
CAAA
317 5066 1370 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLSWFQQRPGQSPRR
LIYKVSNRDSGVPDRFSGSQSGTDFTLKISRVEAEDVGVYYCMQATDWP
VTFGQGTKLEIK
317 5067 1371 RSSQSLEYSDGNTYLS
317 5068 1372 AGGTCTAGTCAAAGCCTCGAATATAGTGACGGAAACACCTACTTGAG
T
317 5069 1373 KVSNRDS
317 5070 1374 AAGGTTTCTAACCGGGACTCT
317 5071 1375 MQATDWPVT
317 5072 1376 ATGCAAGCTACAGACTGGCCGGTCACG
318 5073 1377 CAGGTGCAGCTGCAGGAGTCGGGCCCAAGACTGGTGAAGCCTTCGCA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG
TGATTATTACTGGAGTTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG
AGTGGATTGGGTACATCTATTACAGTGGGAGCACCCACTACAACCCG
TCCCTCAAGAGTCGAGTTAGCATGTCAGTAGACACGGCCAAGAACCA
GTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCAGACACGGCCGTCTA
TTACTGTGCCAGAGATATCGGCTACGGTGACCACGGGACTGGGTCTT
ATTACTACGGAATAGAAGACTGGGGCCAAGGGACCACGGTCACCGTC
TCCTCA
318 5074 1378 QVQLQESGPRLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWI
GYIYYSGSTHYNPSLKSRVSMSVDTAKNQFSLKLTSVTAADTAVYYCAR
DIGYGDHGTGSYYYGIEDWGQGTTVTVSS
318 5075 1379 GSISSGDYYWS
318 5076 1380 GGCTCCATCAGCAGTGGTGATTATTACTGGAGT
318 5077 1381 YIYYSGSTHYNPSLKS
318 5078 1382 TACATCTATTACAGTGGGAGCACCCACTACAACCCGTCCCTCAAGAGT
318 5079 1383 ARDIGYGDHGTGSYYYGIED
318 5080 1384 GCCAGAGATATCGGCTACGGTGACCACGGGACTGGGTCTTATTACTA
CGGAATAGAAGAC
318 5081 1385 GATATTGTGATGACTCAGACTCCAGCCACCCTGTCTTTGTCTCCAGGG
GACAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATATTATGAGCTA
CTTAGCCTGGTACCAACACAAACCTGGCCAGCCTCCCAGGCTCCTCAT
CTATGATGCATCCTACAGGGCCGCTGGCATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG
CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGAACCAACTGGATC
ACCTTCGGCCAAGGGACACGACTGGAGATTAAA
318 5082 1386 DIVMTQTPATLSLSPGDRATLSCRASQNIMSYLAWYQHKPGQPPRLLIYD
ASYRAAGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRTNWITFGQGT
RLEIK
318 5083 1387 RASQNIMSYLA
318 5084 1388 AGGGCCAGTCAGAATATTATGAGCTACTTAGCC
318 5085 1389 DASYRAA
318 5086 1390 GATGCATCCTACAGGGCCGCT
318 5087 1391 QQRTNWIT
318 5088 1392 CAGCAGCGAACCAACTGGATCACC
319 5089 1393 GAGGTGCAGCTGGTGGAGTCAGGGGGAGGCTTGGTGCAGCGGGGGG
GGTCCCTGAGACTCTCGTGTGCGGCCTCTGGATTCACCTTTAGTGGTA
ATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG
GTCGCATCTATTGGTGAAAGTGCTACTAGCGCATACTACGCAGACTCC
GTGAAGGGCCGGTTCACCATCTCCAGAGATGATTCGAAGAACACTCT
GTATCTCCAAATGAACAGCCTGAGACCCGAGGACACGGCCGTATATT
TCTGTGCGAAAGATCGCGTAGGATGGTTCGGGGAGTTCGACGCTTTTG
ATTTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
319 5090 1394 EVQLVESGGGLVQRGGSLRLSCAASGFTFSGNAMSWVRQAPGKGLEWV
ASIGESATSAYYADSVKGRFTISRDDSKNTLYLQMNSLRPEDTAVYFCAK
DRVGWFGEFDAFDFWGQGTMVTVSS
319 5091 1395 FTFSGNAMS
319 5092 1396 TTCACCTTTAGTGGTAATGCCATGAGC
319 5093 1397 SIGESATSAYYADSVKG
319 5094 1398 TCTATTGGTGAAAGTGCTACTAGCGCATACTACGCAGACTCCGTGAA
GGGC
319 5095 1399 AKDRVGWFGEFDAFDF
319 5096 1400 GCGAAAGATCGCGTAGGATGGTTCGGGGAGTTCGACGCTTTTGATTTC
319 5097 1401 TCCTATGAGCTGACGCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAA
GACGGCCACCATTTCCTGTGGGGGAAACAACATTGGAGGTCACAAAG
TGCACTGGTACCAGCAGAGGCCAGGCCAGGCCCCTGTCTTGGTCATCT
ATTATGATAACGTCCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT
CCAACTCTGGAAACACGGCCACCCTGACCATCAGCAGGGTCGAGGCC
GGGGATGAGGCCGACTTTTACTGTCAGGTGTGGGATAGTCGTTCTGA
ACATGTCATATTCGGCGGGGGGACCAAGGTCACCGTCCTA
319 5098 1402 SYELTQPPSVSVAPGKTATISCGGNNIGGHKVHWYQQRPGQAPVLVIYY
DNVRPSGIPERFSGSNSGNTATLTISRVEAGDEADFYCQVWDSRSEHVIF
GGGTKVTVL
319 5099 1403 GGNNIGGHKVH
319 5100 1404 GGGGGAAACAACATTGGAGGTCACAAAGTGCAC
319 5101 1405 YDNVRPS
319 5102 1406 TATGATAACGTCCGGCCCTCA
319 5103 1407 QVWDSRSEHVI
319 5104 1408 CAGGTGTGGGATAGTCGTTCTGAACATGTCATA
320 5105 1409 CAGGTCCAGCTTGTACAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCGTGCAAGACTTCTGGTTACACCTTTTCCAACTA
CGGTATCAGCTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGCATGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGG
TTTCAGGGCAGAGTCATCATGACCACAGACACATCCACGAGGACAGC
CCACATGGAGGTGAAGAGCCTGAGAACTGACGACACGGCCACATATT
ACTGTGCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
320 5106 1410 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSNYGISWLRQAPGQGLEWM
AWISPYNGNTKSAQRFQGRVIMTTDTSTRTAHMEVKSLRTDDTATYYCA
RDPAVDAIPMLDYWGQGTLVTVSS
320 5107 1411 YTFSNYGIS
320 5108 1412 TACACCTTTTCCAACTACGGTATCAGC
320 5109 1413 WISPYNGNTKSAQRFQG
320 5110 1414 TGGATCAGCCCTTATAATGGGAACACAAAGTCTGCACAGAGGTTTCA
GGGC
320 5111 1415 ARDPAVDAIPMLDY
320 5112 1416 GCGAGAGATCCAGCAGTCGATGCAATACCGATGCTTGACTAC
320 5113 1417 GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACACT
GATGGAAACACCTACTTGAGCTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAGGGTTTCTCACCGGGACTCTGGGGTCCC
AGACAGATTCACCGGCAGTGGGTCAGGCACTGATTTCACACTGATAA
TCCGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACTGGCCTCTCACTTTCGGCGGAGGGACCAAGCTGGAGAT
CAAA
320 5114 1418 DIQMTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLSWFQQRPGQSPRR
LIYRVSHRDSGVPDRFTGSGSGTDFTLIIRRVEAEDVGVYYCMQGTHWPL
TFGGGTKLEIK
320 5115 1419 RSSQSLVYTDGNTYLS
320 5116 1420 AGGTCTAGTCAAAGCCTCGTGTACACTGATGGAAACACCTACTTGAG
C
320 5117 1421 RVSHRDS
320 5118 1422 AGGGTTTCTCACCGGGACTCT
320 5119 1423 MQGTHWPLT
320 5120 1424 ATGCAAGGTACACACTGGCCTCTCACT
321 5121 1425 CAGGTCCAGCTGGTACAGTCTGGTCCTGCGCTGGTGAAACCCACACA
GACCCTCACACTGACCTGCACCTTCGGTGGATTCTCACTCAGCAGACA
TGGAATGCGTGTGACCTGGATCCGTCAGGCCCCCGGGAAGGCCCTGG
AGTGGCTTGGTCACATTGATTGGGATGATGATAAATTCTACAGGACAT
CTCTGAAGACCAGGCTCACCATCTCCAAGGACCCCTCTAACAATGAG
GTGGTCCTGAAAATGACCAACATGGACCACGTGGACACAGCCACGTA
TTACTGTGCACTGATGAGGCCCTTTTGGAGTCGTGACGACTACTACTA
TTCCATCGCCGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA
321 5122 1426 QVQLVQSGPALVKPTQTLTLTCTFGGFSLSRHGMRVTWIRQAPGKALEW
LGHIDWDDDKFYRTSLKTRLTISKDPSNNEVVLKMTNMDHVDTATYYC
ALMRPFWSRDDYYYSIAVWGKGTTVTVSS
321 5123 1427 FSLSRHGMRVT
321 5124 1428 TTCTCACTCAGCAGACATGGAATGCGTGTGACC
321 5125 1429 HIDWDDDKFYRTSLKT
321 5126 1430 CACATTGATTGGGATGATGATAAATTCTACAGGACATCTCTGAAGAC
C
321 5127 1431 ALMRPFWSRDDYYYSIAV
321 5128 1432 GCACTGATGAGGCCCTTTTGGAGTCGTGACGACTACTACTATTCCATC
GCCGTC
321 5129 1433 GATATTGTGCTGACCCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
GACAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTCGGCAGCGG
CTACGTAACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCC
TCATTTATGGTGCATCAAACAGGGCCGAAGGCATCCCAGACAGGTTC
AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCGGACT
GGAGTCTGAAGATTTTGTAATTTATTACTGTCAGCTATATCATAGGTC
ACCTGGCTCTGCGAGTCAAACCGTTTGGACGTTCGGCCAAGGGACCA
AGGTGGAAATCAAA
321 5130 1434 DIVLTQSPGTLSLSPGDRATLSCRASQSVGSGYVTWYQQKPGQAPRLLIY
GASNRAEGIPDRFSGSGSGTDFTLTISGLESEDFVIYYCQLYHRSPGSASQ
TVWTFGQGTKVEIK
321 5131 1435 RASQSVGSGYVT
321 5132 1436 AGGGCCAGTCAGAGTGTCGGCAGCGGCTACGTAACC
321 5133 1437 GASNRAE
321 5134 1438 GGTGCATCAAACAGGGCCGAA
321 5135 1439 QLYHRSPGSASQTVWT
321 5136 1440 CAGCTATATCATAGGTCACCTGGCTCTGCGAGTCAAACCGTTTGGACG
322 5137 1441 CAGGTCCAGCTTGTACAGTCTGGACCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCTCCTGCGAGGCTTCTGGTTACCCCTTTAGCAATTA
CGGCATCACCTGGGTGCGCCAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCTTACAACGGAAACAGAGACTATCTGCAGAAG
TTTCAGGGCAGACTCACCATGACCATAGACACATCCACGAGAACAGC
CCACATGGAATTGAGGCGCCTGACATCTGACGACACGGCCGTATATT
GGTGTGCGAGAGACACACCCGCCACTGCTGCCCCTCTGCTTGACTACT
GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
322 5138 1442 QVQLVQSGPEVKKPGASVRVSCEASGYPFSNYGITWVRQAPGQGLEWM
GWISAYNGNRDYLQKFQGRLTMTIDTSTRTAHMELRRLTSDDTAVYWC
ARDTPATAAPLLDYWGQGTLVTVSS
322 5139 1443 YPFSNYGIT
322 5140 1444 TACCCCTTTAGCAATTACGGCATCACC
322 5141 1445 WISAYNGNRDYLQKFQG
322 5142 1446 TGGATCAGCGCTTACAACGGAAACAGAGACTATCTGCAGAAGTTTCA
GGGC
322 5143 1447 ARDTPATAAPLLDY
322 5144 1448 GCGAGAGACACACCCGCCACTGCTGCCCCTCTGCTTGACTAC
322 5145 1449 GATATTGTGATGACTCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATTCACT
GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGGTTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTATTTTCCGGCCGGGGACGTTCGGCCAAGGGACCAAGGTGGAAAT
CAAA
322 5146 1450 DIVMTQSPLSLAVTLGQPASISCRSSQSLEFTDGNTYLNWFQQRPGQSPR
RLIYKVSNRDSGVPDRFSGSGSGTGFTLKISRVEAEDVGVYYCMQGIFRP
GTFGQGTKVEIK
322 5147 1451 RSSQSLEFTDGNTYLN
322 5148 1452 AGGTCTAGTCAAAGCCTCGAATTCACTGATGGAAACACCTACTTGAA
T
322 5149 1453 KVSNRDS
322 5150 1454 AAGGTTTCTAACCGGGACTCT
322 5151 1455 MQGIFRPGT
322 5152 1456 ATGCAAGGTATTTTCCGGCCGGGGACG
323 5153 1457 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTGTCCACTA
TGGTATCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCAGCGCATACAATGGTAATACAAACTCTGCACTGAAG
TTCCAGGACAGAGTCACCATGACCACAGACCCATCCACGAGCACAGC
CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCATTTATT
ACTGTGCGAGAGACTCAGGTTGTTGTAGTGGTTCCACCTCAGACGTCT
GGGGCAAAGGGACCACGGTCACCGTCTCCTCA
323 5154 1458 QVQLVQSGAEVKKPGASVKVSCKASGYTFVHYGISWVRQAPGQGLEW
MGWISAYNGNTNSALKFQDRVTMTTDPSTSTAYMELRSLRSDDTAIYYC
ARDSGCCSGSTSDVWGKGTTVTVSS
323 5155 1459 YTFVHYGIS
323 5156 1460 TACACCTTTGTCCACTATGGTATCAGT
323 5157 1461 WISAYNGNTNSALKFQD
323 5158 1462 TGGATCAGCGCATACAATGGTAATACAAACTCTGCACTGAAGTTCCA
GGAC
323 5159 1463 ARDSGCCSGSTSDV
323 5160 1464 GCGAGAGACTCAGGTTGTTGTAGTGGTTCCACCTCAGACGTC
323 5161 1465 GATATTGTGATGACTCAGTCTCCACTCTCTTCACCTGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGCACAGT
GATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGCC
TCCAAGACTCCTAATTTATAAGATTTCCCACCGGTTCTCTGGGGTCCC
AGACAGATTCACTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTCGGGGTTTATTACTGCATGCAA
GCTACAGAATTTCCTCCGATGTACACTTTTGGCCAGGGGACCAAGGTG
GAGATCAAA
323 5162 1466 DIVMTQSPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLHQRPGQPPRL
LIYKISHRFSGVPDRFTGSGAGTDFTLKISRVEAEDVGVYYCMQATEFPP
MYTFGQGTKVEIK
323 5163 1467 RSSQSLVHSDGNTYLS
323 5164 1468 AGGTCTAGTCAAAGCCTCGTGCACAGTGATGGAAACACCTACTTGAG
T
323 5165 1469 KISHRFS
323 5166 1470 AAGATTTCCCACCGGTTCTCT
323 5167 1471 MQATEFPPMYT
323 5168 1472 ATGCAAGCTACAGAATTTCCTCCGATGTACACT
324 5169 1473 GAGGTGCAGCTGGTGGAGACGGGCCCAGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATCAGTGGTTA
CTACTGGAGCTGGATCCGGCAGTCCCCAGGGAAGGGACTGGAGTGGA
TTGGCTATATCTATTACAGGGGGAGCACCGACTACAACCCCTCCCTCA
AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC
CTGAAACTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT
GCGAGAGATAATAAACACCATGATTCGGGAAATTATTACGCATACTT
TGACCATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
324 5170 1474 EVQLVETGPGLVKPSETLSLTCTVSGDSISGYYWSWIRQSPGKGLEWIGY
IYYRGSTDYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDNK
HHDSGNYYAYFDHWGQGTLVTVSS
324 5171 1475 DSISGYYWS
324 5172 1476 GACTCCATCAGTGGTTACTACTGGAGC
324 5173 1477 YIYYRGSTDYNPSLKS
324 5174 1478 TATATCTATTACAGGGGGAGCACCGACTACAACCCCTCCCTCAAGAG
T
324 5175 1479 ARDNKHHDSGNYYAYFDH
324 5176 1480 GCGAGAGATAATAAACACCATGATTCGGGAAATTATTACGCATACTT
TGACCAT
324 5177 1481 GATATTGTGATGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTAACACCTT
TTTAAATTGGTATCAGCACAAACCAGGGAAAGCCCCTAAACTCCTGA
TCTATGGTGCATCCCGTTTGCAGAGTGGGGTCCCATCAAGGTTCACTG
GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC
CTGAAGATTTTGCAACTTACTCCTGTCAACAGAGTTACACTACCCGGC
TCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
324 5178 1482 DIVMTQSPSSLSASVGDRVTITCRASQNINTFLNWYQHKPGKAPKLLIYG
ASRLQSGVPSRFTGSGSGTDFTLTISSLQPEDFATYSCQQSYTTRLTFGGG
TKVEIK
324 5179 1483 RASQNINTFLN
324 5180 1484 CGGGCAAGTCAGAACATTAACACCTTTTTAAAT
324 5181 1485 GASRLQS
324 5182 1486 GGTGCATCCCGTTTGCAGAGT
324 5183 1487 QQSYTTRLT
324 5184 1488 CAACAGAGTTACACTACCCGGCTCACT
325 5185 1489 CAGGTCCAGCTGGTGCAGTCTGGGACTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGATTTCCTGCAAGACTTCTGGATACACCTTCACTAATAA
TGTAATTCAATGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGA
TGGGATGGATCAGCGCTGGCAATGGTTACACAAAATATTCAGACAAG
TTCCAGGACAGAGTCACCATTACCAGGGACACATCCGCGAGCACAGC
CTACATGGAGGTGAGCAGCCTGACATCTGAAGACACGGCTATGTATT
ACTGTGCGAGACAAGTCTCGACTAGTGGCTGGCACGCAACGTCACAC
CGGTTCGCCCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
325 5186 1490 QVQLVQSGTEVKKPGASVKISCKTSGYTFTNNVIQWVRQAPGQRLEWM
GWISAGNGYTKYSDKFQDRVTITRDTSASTAYMEVSSLTSEDTAMYYCA
RQVSTSGWHATSHRFAPWGQGTLVTVSS
325 5187 1491 YTFTNNVIQ
325 5188 1492 TACACCTTCACTAATAATGTAATTCAA
325 5189 1493 WISAGNGYTKYSDKFQD
325 5190 1494 TGGATCAGCGCTGGCAATGGTTACACAAAATATTCAGACAAGTTCCA
GGAC
325 5191 1495 ARQVSTSGWHATSHRFAP
325 5192 1496 GCGAGACAAGTCTCGACTAGTGGCTGGCACGCAACGTCACACCGGTT
CGCCCCC
325 5193 1497 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGGCATTAGTAGATA
TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA
TCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT
GGAAGTGGATCTGGGACACATTTTACTTTAACCATCAGCAGCCTGCA
GCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATCTCCC
GCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA
325 5194 1498 DIQMTQSPSSLSASVGDRVTITCQASQGISRYLNWYQQKPGKAPNLLIYD
ASNLETGVPSRFSGSGSGTHFTLTISSLQPEDIATYYCQQYDNLPLTFGGG
TKVEIK
325 5195 1499 QASQGISRYLN
325 5196 1500 CAGGCGAGTCAGGGCATTAGTAGATATTTAAAT
325 5197 1501 DASNLET
325 5198 1502 GATGCATCCAATTTGGAAACA
325 5199 1503 QQYDNLPLT
325 5200 1504 CAACAGTATGATAATCTCCCGCTCACT
326 5201 1505 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGAAGCCTCTGGATTCACCTTCAGTAGTTT
TAGCATGCACTGGGTCCGCCAGGCTCCGGGCAAGGGGCTGGAGTGGG
TGGCAGTGATTTTATATGATGGGAGTAATCAATACTATGCAGACTCCG
TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTT
TATCTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTATGTATTA
CTGTGCGAAATCATCATCGTCCCATGTTAACTCTCGACAAGACAAATG
GGGCCAGGGCACCCTGGTCACCGTCTCCTCA
326 5202 1506 EVQLVESGGGVVQPGRSLRLSCEASGFTFSSFSMHWVRQAPGKGLEWV
AVILYDGSNQYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYC
AKSSSSHVNSRQDKWGQGTLVTVSS
326 5203 1507 FTFSSFSMH
326 5204 1508 TTCACCTTCAGTAGTTTTAGCATGCAC
326 5205 1509 VILYDGSNQYYADSVKG
326 5206 1510 GTGATTTTATATGATGGGAGTAATCAATACTATGCAGACTCCGTGAAG
GGC
326 5207 1511 AKSSSSHVNSRQDK
326 5208 1512 GCGAAATCATCATCGTCCCATGTTAACTCTCGACAAGACAAA
326 5209 1513 GAAATTGTATTGACACAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGGTG
GTTGGCCTGGTATCAGCAGAAACCAGGGGAAGCCCCTAAACTCCTGA
TCCACACGGCGTCTACATTAGAAAGTGGGGTCCCATCAAGGTTCAGC
GGCAGTGGCTCTGGGACAGAATTCACTCTCACCATCAACAGCCTGCA
GCCTGATGATCTTGCAACTTATTACTGCCAACAGTATTATAATTGGTG
GACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA
326 5210 1514 EIVLTQSPSTLSASVGDRVTITCRASQSISRWLAWYQQKPGEAPKLLIHTA
STLESGVPSRFSGSGSGTEFTLTINSLQPDDLATYYCQQYYNWWTFGQGT
KVEIK
326 5211 1515 RASQSISRWLA
326 5212 1516 CGGGCCAGTCAGAGTATTAGTAGGTGGTTGGCC
326 5213 1517 TASTLES
326 5214 1518 ACGGCGTCTACATTAGAAAGT
326 5215 1519 QQYYNWWT
326 5216 1520 CAACAGTATTATAATTGGTGGACG
327 5217 1521 GAGGTGCAGCTGTTGGAGTCCGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGATCTCCTGCAAGGCCTCTGGTTACATCTTTACCAGTTA
TGGTGTCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTAAGTGGA
TGGGATGGATCAGCGGTTACAATGGTAACACATACTATGACCAGAAA
TTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAACACAGC
CTACATGGAGTTGAGGAGCCTGACATCTGACGACACGGCCGTATATT
ACTGTGCGAGAGATTCCTTTTCAGAGACTGGGACTGGATTTCCTGACT
TCTGGGGCCAGGGCACCCTGGTCACCGTCTCTTCA
327 5218 1522 EVQLLESGAEVKKPGASVKISCKASGYIFTSYGVSWVRQAPGQGLKWM
GWISGYNGNTYYDQKFQGRVTMTTDTSTNTAYMELRSLTSDDTAVYYC
ARDSFSETGTGFPDFWGQGTLVTVSS
327 5219 1523 YIFTSYGVS
327 5220 1524 TACATCTTTACCAGTTATGGTGTCAGT
327 5221 1525 WISGYNGNTYYDQKFQG
327 5222 1526 TGGATCAGCGGTTACAATGGTAACACATACTATGACCAGAAATTCCA
GGGC
327 5223 1527 ARDSFSETGTGFPDF
327 5224 1528 GCGAGAGATTCCTTTTCAGAGACTGGGACTGGATTTCCTGACTTC
327 5225 1529 GAAATTGTGTTGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGT
GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
CGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAA
GCCACACACCGGCCTCGCACGTTCGGCCAAGGGACCAAAGTGGATAT
CAAA
327 5226 1530 EIVLTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNWFQQRPGQSPRR
LIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATHRP
RTFGQGTKVDIK
327 5227 1531 RSSQSLEYSDGNTYLN
327 5228 1532 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAA
T
327 5229 1533 KVSNRDS
327 5230 1534 AAGGTTTCTAACCGGGACTCT
327 5231 1535 MQATHRPRT
327 5232 1536 ATGCAAGCCACACACCGGCCTCGCACG
328 5233 1537 CAGGTCCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
AGTCTCTGAAGATCTCCTGTAAGGGTTTTGGATACAGCTTTAACAGTT
ACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGC
ATGGGCATCATCTATCCTGGCGACTCTGATACCAGATACAGCCCGTCC
TTCCAAGGGCAGGTCACCATCTCAGTCGACAAGTCCATCACTACCGCC
TACCTGCAGTGGAGCAGCCTGAAGGTCTCGGACACCGCCATGTATTA
CTGTGCGAAAAGTAATGTGGGGAATACAGGTTGGAACTACTGGGGCC
AGGGAACCCTGGTCACCGTCTCCTCA
328 5234 1538 QVQLVQSGAEVKKPGESLKISCKGFGYSFNSYWIAWVRQMPGKGLECM
GIIYPGDSDTRYSPSFQGQVTISVDKSITTAYLQWSSLKVSDTAMYYCAK
SNVGNTGWNYWGQGTLVTVSS
328 5235 1539 YSFNSYWIA
328 5236 1540 TACAGCTTTAACAGTTACTGGATCGCC
328 5237 1541 IIYPGDSDTRYSPSFQG
328 5238 1542 ATCATCTATCCTGGCGACTCTGATACCAGATACAGCCCGTCCTTCCAA
GGG
328 5239 1543 AKSNVGNTGWNY
328 5240 1544 GCGAAAAGTAATGTGGGGAATACAGGTTGGAACTAC
328 5241 1545 GAAATTGTATTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCACAGTGTTGCCACCGA
CCTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA
TCTATGATGCATCCAAGAGGGCCACTGACGTCCCAGCCAGGTTCAGT
GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGA
GCCTGAAGATGTTGCAGTTTATTACTGTCAGGAAGTTAGGAACTGGCC
TCCGTGCACTTTTGGCCAGGGGACCAAAGTGGATATCAAA
328 5242 1546 EIVLTQSPATLSLSPGERATLSCRASHSVATDLAWYQQKPGQAPRLLIYD
ASKRATDVPARFSGSGSGTDFTLTISSLEPEDVAVYYCQEVRNWPPCTFG
QGTKVDIK
328 5243 1547 RASHSVATDLA
328 5244 1548 AGGGCCAGTCACAGTGTTGCCACCGACCTAGCC
328 5245 1549 DASKRAT
328 5246 1550 GATGCATCCAAGAGGGCCACT
328 5247 1551 QEVRNWPPCT
328 5248 1552 CAGGAAGTTAGGAACTGGCCTCCGTGCACT
329 5249 1553 GAGGTGCAGCTGCAGGAGTCCGGCTCTCGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCTCTGTCTCTGGTGGCTCCCTCAACGCAGG
CGGTTACCTGTGGAGCTGGATCCGTCAGCCACCAGGGAAGGGCCTGG
AGTGGGTTGGGTACATCTATCCTAGTGGGACTACCTACTACAACCCGT
CCCTGCAGAGTCGAATCAGCATTTCACAAGACAGGTCCAGGAACCAG
TTCTCCCTGAGCGTAGCGTCTGTGACCGCCGCGGACACGGCCGTCTAT
TACTGTGCCAGATGTGGGAATGAGTACGGTGAGGTCCATCCTTTTGAT
ATTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
329 5250 1554 EVQLQESGSRLVKPSQTLSLTCSVSGGSLNAGGYLWSWIRQPPGKGLEW
VGYIYPSGTTYYNPSLQSRISISQDRSRNQFSLSVASVTAADTAVYYCARC
GNEYGEVHPFDIWGQGTTVTVSS
329 5251 1555 GSLNAGGYLWS
329 5252 1556 GGCTCCCTCAACGCAGGCGGTTACCTGTGGAGC
329 5253 1557 YIYPSGTTYYNPSLQS
329 5254 1558 TACATCTATCCTAGTGGGACTACCTACTACAACCCGTCCCTGCAGAGT
329 5255 1559 ARCGNEYGEVHPFDI
329 5256 1560 GCCAGATGTGGGAATGAGTACGGTGAGGTCCATCCTTTTGATATT
329 5257 1561 GAAATTGTATTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACCCTCTCCTGCCGGGGCAGTCCTATTGTTGGCAACAA
CTACTTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCT
CATCTATGCTGCATCCATCAGGGCCACTGGCATCCCAGACAGGTTCAG
TGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTAG
AGCCTGAAGATTTTGCAGTCTATTACTGTCAGCAATATGGCAGCTCAC
CGTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA
329 5258 1562 EIVLTQSPGTLSLSPGERATLSCRGSPIVGNNYLAWYQQKPGQAPRLLIYA
ASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQG
TKVDIK
329 5259 1563 RGSPIVGNNYLA
329 5260 1564 CGGGGCAGTCCTATTGTTGGCAACAACTACTTAGCC
329 5261 1565 AASIRAT
329 5262 1566 GCTGCATCCATCAGGGCCACT
329 5263 1567 QQYGSSPWT
329 5264 1568 CAGCAATATGGCAGCTCACCGTGGACG
330 5265 1569 CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACATCTTTACCAGTTA
TGGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTAAGTGGA
TGGGATGGATCAGCGGTTACAATGGTAACACAAACTATGACCAGAAA
CTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGC
CTACATGGAGCTGAGGAGCCTGACATCTGACGACACGGCCGTTTATT
ACTGTGCGAGAGATTCATTTTCAGAGACTGGGACTGGGTTTCCTGACT
TCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
330 5266 1570 QVQLVQSGAEVKKPGASVKVSCKASGYIFTSYGVSWVRQAPGQGLKW
MGWISGYNGNTNYDQKLQGRVTMTTDTSTSTAYMELRSLTSDDTAVYY
CARDSFSETGTGFPDFWGQGTLVTVSS
330 5267 1571 YIFTSYGVS
330 5268 1572 TACATCTTTACCAGTTATGGTGTCAGC
330 5269 1573 WISGYNGNTNYDQKLQG
330 5270 1574 TGGATCAGCGGTTACAATGGTAACACAAACTATGACCAGAAACTCCA
GGGC
330 5271 1575 ARDSFSETGTGFPDF
330 5272 1576 GCGAGAGATTCATTTTCAGAGACTGGGACTGGGTTTCCTGACTTC
330 5273 1577 GACATCCAGATGACCCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGAATACAGT
GATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAA
GCCACACACCGGCCTCGCACGTTCGGCCAAGGGACCAAGCTGGAGAT
CAAA
330 5274 1578 DIQMTQSPLSLPVTLGQPASISCRSSQSLEYSDGNTYLNWFQQRPGQSPRR
LIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQATHRP
RTFGQGTKLEIK
330 5275 1579 RSSQSLEYSDGNTYLN
330 5276 1580 AGGTCTAGTCAAAGCCTCGAATACAGTGATGGAAACACCTACTTGAA
T
330 5277 1581 KVSNRDS
330 5278 1582 AAGGTTTCTAACCGGGACTCT
330 5279 1583 MQATHRPRT
330 5280 1584 ATGCAAGCCACACACCGGCCTCGCACG
331 5281 1585 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGTTT
TTCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG
TGGCACTTATATCATCTGACGAGAGGAATTCATACTACGCAGACTCCG
TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG
TATCTGCAAATAAGCAGGCTGAAAGTCGAGGACACGGCTGTGTATTA
TTGTGCGAGAGAGGCATACGAAGAGTGGGAGCTAACGATGGGGAAC
CTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
331 5282 1586 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSFSMHWVRQAPGKGLEWV
ALISSDERNSYYADSVKGRFTISRDNSKNTLYLQISRLKVEDTAVYYCAR
EAYEEWELTMGNLDHWGQGTLVTVSS
331 5283 1587 FTFSSFSMH
331 5284 1588 TTCACCTTCAGTAGTTTTTCTATGCAC
331 5285 1589 LISSDERNSYYADSVKG
331 5286 1590 CTTATATCATCTGACGAGAGGAATTCATACTACGCAGACTCCGTGAA
GGGC
331 5287 1591 AREAYEEWELTMGNLDH
331 5288 1592 GCGAGAGAGGCATACGAAGAGTGGGAGCTAACGATGGGGAACCTTG
ACCAC
331 5289 1593 GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTGGAAATGA
TTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGA
TCTATAGTACATACAGCTTGCAAAGTGGGGTCCCATCAAGGTTCAGC
GGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCA
GCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATCGTTACCC
CTTCACTTTCGGCCCTGGGACCAAGCTGGAGATCAAA
331 5290 1594 DIQLTQSPSSLSASVGDRVTITCRASQGIGNDLGWYQQKPGKAPKRLIYS
TYSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNRYPFTFGPG
TKLEIK
331 5291 1595 RASQGIGNDLG
331 5292 1596 CGGGCAAGTCAGGGCATTGGAAATGATTTAGGC
331 5293 1597 STYSLQS
331 5294 1598 AGTACATACAGCTTGCAAAGT
331 5295 1599 LQHNRYPFT
331 5296 1600 CTACAGCATAATCGTTACCCCTTCACT
332 5297 1601 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGCCTCCGTCACCACTAA
TACTTACTACTGGACCTGGATCCGGCAGCCCCCAGGGAAGGAACTGG
AGTGGATTGGATATATCCATCACACTGGGAACACCCACTACAACCCC
TCCCTCGAGAGTCGACTCACCATGTCACTAGACACGTCCAGGAACCA
GTTCTCTCTGAACCTTAGGTCTGCCACCACTGCGGACACGGCCGTTTA
TTACTGTGCGAGAGGCGAACATTTTGCGTACTGGTGGGGAAACTGGG
GCCAGGGAGCCCTGGTCACCGTCTCCTCA
332 5298 1602 QVQLQESGPGLVKPSETLSLTCTVSGASVTTNTYYWTWIRQPPGKELEWI
GYIHHTGNTHYNPSLESRLTMSLDTSRNQFSLNLRSATTADTAVYYCAR
GEHFAYWWGNWGQGALVTVSS
332 5299 1603 ASVTTNTYYWT
332 5300 1604 GCCTCCGTCACCACTAATACTTACTACTGGACC
332 5301 1605 YIHHTGNTHYNPSLES
332 5302 1606 TATATCCATCACACTGGGAACACCCACTACAACCCCTCCCTCGAGAGT
332 5303 1607 ARGEHFAYWWGN
332 5304 1608 GCGAGAGGCGAACATTTTGCGTACTGGTGGGGAAAC
332 5305 1609 GACATCCGGGTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTGCCAGATG
GTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGA
TCTATGCTGCATCCAGTTTGCAAGGTGGGGTCCCATCAAGGTTCAGCG
GCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAG
CCTGAAGATTTTGCAACTTACTACTGTCAACAGGCTAACAGTTTTCCT
CGAACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA
332 5306 1610 DIRVTQSPSSVSASVGDRVTITCRASQGIARWLAWYQQKPGKAPKLLIYA
ASSLQGGVPSRFSGSGYGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQG
TKVEIK
332 5307 1611 RASQGIARWLA
332 5308 1612 CGGGCGAGTCAGGGTATTGCCAGATGGTTAGCC
332 5309 1613 AASSLQG
332 5310 1614 GCTGCATCCAGTTTGCAAGGT
332 5311 1615 QQANSFPRT
332 5312 1616 CAACAGGCTAACAGTTTTCCTCGAACG
333 5313 1617 CAGGTCCAGCTTGTACAGTCTGGGCCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCGAGGCTTCTGGATACACCTTCACCGACTT
CTTTGTGCACTGGGTGCGACAGGCCCCTGGTGAGGGGCTTGTGTGGTT
GGGATGGGTCAACCCTCTCAGTGGCGCCACAAAGTATGCACAGAACT
TTCAGGGCAGGGTCACCATGACCAGTGACACGTCCATCACCACAGCC
TACATGGCACTGAGCAGCCTGAGACATGACGACACGGCCGTCTATTA
CTGTACGAGCCAGACTTCACCTTATACCCCGGGCGCTATGGGCGTTTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA
333 5314 1618 QVQLVQSGPEVKKPGASVKVSCEASGYTFTDFFVHWVRQAPGEGLVWL
GWVNPLSGATKYAQNFQGRVTMTSDTSITTAYMALSSLRHDDTAVYYC
TSQTSPYTPGAMGVWGQGTTVTVSS
333 5315 1619 YTFTDFFVH
333 5316 1620 TACACCTTCACCGACTTCTTTGTGCAC
333 5317 1621 WVNPLSGATKYAQNFQG
333 5318 1622 TGGGTCAACCCTCTCAGTGGCGCCACAAAGTATGCACAGAACTTTCA
GGGC
333 5319 1623 TSQTSPYTPGAMGV
333 5320 1624 ACGAGCCAGACTTCACCTTATACCCCGGGCGCTATGGGCGTT
333 5321 1625 GACATCCGGGTGACCCAGTCTCCAGCCTCCCTGTCTGCATTTGTTGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCCGGCCATTAGCGGCTA
TTTAAGTTGGTATCAGCAGAAGGCAGGCAAAGCCCCTAAGATCCTGA
TCTATGATGCATCTAATTTGTATAGTGGGGCCCCATCACGGTTCAGTG
GCAGTAGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAAC
CTGAAGATTTTGCAACTTACTACTGTCAACAGACTTACAATGGCCTAA
TCGCTTTCGGCCCTGGGACCAAGGTGGAAATCAAA
333 5322 1626 DIRVTQSPASLSAFVGDRVTITCRASPAISGYLSWYQQKAGKAPKILIYDA
SNLYSGAPSRFSGSRSGTDFTLTITSLQPEDFATYYCQQTYNGLIAFGPGT
KVEIK
333 5323 1627 RASPAISGYLS
333 5324 1628 CGGGCAAGTCCGGCCATTAGCGGCTATTTAAGT
333 5325 1629 DASNLYS
333 5326 1630 GATGCATCTAATTTGTATAGT
333 5327 1631 QQTYNGLIA
333 5328 1632 CAACAGACTTACAATGGCCTAATCGCT
334 5329 1633 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAA
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAATACCTA
TGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGCCTGGAGTGGG
TGGCAGCTATATCATATGATGGAAGCAATGAATACTACTCAAACTCC
GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGTACACGCT
GGAGCTGCAAATGAACAGCCTGAGACCTGAGGACACGGCTGTGTATT
ACTGTGCGAGAGGCGCCTCCTACTACTATGTGAGTAGTGACCTTGGCT
ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
334 5330 1634 EVQLLESGGGVVQPGKSLRLSCAASGFTFNTYAIHWVRQAPGKGLEWV
AAISYDGSNEYYSNSVKGRFTISRDNSKYTLELQMNSLRPEDTAVYYCA
RGASYYYVSSDLGYWGQGTLVTVSS
334 5331 1635 FTFNTYAIH
334 5332 1636 TTCACCTTCAATACCTATGCTATACAC
334 5333 1637 AISYDGSNEYYSNSVKG
334 5334 1638 GCTATATCATATGATGGAAGCAATGAATACTACTCAAACTCCGTGAA
GGGC
334 5335 1639 ARGASYYYVSSDLGY
334 5336 1640 GCGAGAGGCGCCTCCTACTACTATGTGAGTAGTGACCTTGGCTAC
334 5337 1641 CAGTCTGTCGTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGTCAG
GTTATGATGTGCACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA
GTCGTCATCTATGGTAACATCAATCGGCCCTCAGGGGTCCCTGAGCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
CTGAGTGCCTCTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCT
A
334 5338 1642 QSVVTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKVVI
YGNINRPSGVPERFSGSKSGTSASLAITGLQAEDEADYYCQSYDSLSASW
VFGGGTKLTVL
334 5339 1643 TGSSSNIGSGYDVH
334 5340 1644 ACTGGGAGCAGCTCCAACATCGGGTCAGGTTATGATGTGCAC
334 5341 1645 GNINRPS
334 5342 1646 GGTAACATCAATCGGCCCTCA
334 5343 1647 QSYDSLSASWV
334 5344 1648 CAGTCCTATGACAGCCTGAGTGCCTCTTGGGTG
335 5345 1649 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGCGGCC
ACGCTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAATGG
ATGGGAGGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAA
GTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAG
TTTACATGGAGTTGAGCAGCCTGATATCTGAGGACACGGCCGTATATT
ATTGTGCGAGAGATGCTTACGAAGTGTGGACTGGTTCTTATCTCCCCC
CTTTTGACGACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
335 5346 1650 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGHAINWVRQAPGQGLEW
MGGIIHIFGTVNYAPKFQGRVTITADASTGTVYMELSSLISEDTAVYYCA
RDAYEVWTGSYLPPFDDWGQGTLVTVSS
335 5347 1651 GTFSGHAIN
335 5348 1652 GGCACCTTCAGCGGCCACGCTATCAAC
335 5349 1653 GIIHIFGTVNYAPKFQG
335 5350 1654 GGGATCATCCATATATTTGGGACAGTAAACTACGCTCCGAAGTTCCA
GGGC
335 5351 1655 ARDAYEVWTGSYLPPFDD
335 5352 1656 GCGAGAGATGCTTACGAAGTGTGGACTGGTTCTTATCTCCCCCCTTTT
GACGAC
335 5353 1657 GATATTGTGATGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCCGGG
GACAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCTATGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGGTTCA
GTGGCAGTGGGTCTGGGACAGACTTCACTCTCAGCATCAGCAGACTG
GAGCCTGAAGATTTTGCAGTATATTATTGTCAGCAGTATGGTAGCTCA
TTCCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA
335 5354 1658 DIVMTQSPGTLSLSPGDRVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIY
GAFTRATGIPDRFSGSGSGTDFTLSISRLEPEDFAVYYCQQYGSSFLTFGG
GTKVDIK
335 5355 1659 RASQTVTSSYLA
335 5356 1660 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC
335 5357 1661 GAFTRAT
335 5358 1662 GGTGCATTCACCAGGGCCACT
335 5359 1663 QQYGSSFLT
335 5360 1664 CAGCAGTATGGTAGCTCATTCCTCACT
336 5361 1665 GAGGTGCAGCTGGTGGAATCTGGGGGAGGCCTGGTCAGGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGTCTCAGTAGTTA
CGGCATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTGGG
TCTCATCCATTACTGCCGGCAGTAGTTACATAAATTACGCTGACTCAG
TGAAGGGCCGGTTCACCATCTCCAGAGACAACGCCAAGAGTTCACTG
TTCCTGCAAATGACCAGCCTGAGAGTCGAGGACACGGCTGTTTATTTC
TGTGTGAGAGAGGCGTATGCCAGCTCGTCGGCCCTTTACTGGTTCGAC
CCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
336 5362 1666 EVQLVESGGGLVRPGGSLRLSCAASGFSLSSYGMSWVRQAPGKGLEWV
SSITAGSSYINYADSVKGRFTISRDNAKSSLFLQMTSLRVEDTAVYFCVRE
AYASSSALYWFDPWGQGTLVTVSS
336 5363 1667 FSLSSYGMS
336 5364 1668 TTCAGTCTCAGTAGTTACGGCATGAGT
336 5365 1669 SITAGSSYINYADSVKG
336 5366 1670 TCCATTACTGCCGGCAGTAGTTACATAAATTACGCTGACTCAGTGAAG
GGC
336 5367 1671 VREAYASSSALYWFDP
336 5368 1672 GTGAGAGAGGCGTATGCCAGCTCGTCGGCCCTTTACTGGTTCGACCCC
336 5369 1673 CAGTCTGTCCTGACGCAGCCGCCCTCAGTCTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAATCTCGGGGCGG
GTTATGTTGTTCACTGGTACCAGCAACTTCCAGGAACATCCCCCAAAC
TCCTCATCTATGGTAACACCGATCGGCCCTCAGGGGTCCCCGACCGAT
TCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGC
TCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGTA
GCCTGAGTGGCTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
336 5370 1674 QSVLTQPPSVSGAPGQRVTISCTGSSSNLGAGYVVHWYQQLPGTSPKLLI
YGNTDRPSGVPDRFSGSKSGTSASLAISGLQAEDEADYYCQSYDSSLSGW
VFGGGTKLTVL
336 5371 1675 TGSSSNLGAGYVVH
336 5372 1676 ACTGGGAGCAGCTCCAATCTCGGGGCGGGTTATGTTGTTCAC
336 5373 1677 GNTDRPS
336 5374 1678 GGTAACACCGATCGGCCCTCA
336 5375 1679 QSYDSSLSGWV
336 5376 1680 CAGTCCTATGACAGTAGCCTGAGTGGCTGGGTG
337 5377 1681 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTACAGCCTGGGGG
GTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAATACCTA
TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGATTGGAGTGGC
TTTCATTCATTAGTAGTAGTAGTCATACCCTATACTACGCAGACTCTG
TGAAGGGCCGATTCACCGTCTTCAGAGACAATGCCAAGCACTCGCTC
TTTCTGCAAATGAACGGCCTGAGAGACGAGGACACGGCTGTTTATTTC
TGTGCGAGATCCCTTGGTTCGGGGAATTATGATAACGAAGATCAGAC
ATTTTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGG
TCACCGTCTCCTCA
337 5378 1682 EVQLVESGGGLVQPGGSLRLSCAASGFSFNTYSMNWVRQAPGKGLEWL
SFISSSSHTLYYADSVKGRFTVFRDNAKHSLFLQMNGLRDEDTAVYFCA
RSLGSGNYDNEDQTFYYYYGMDVWGQGTTVTVSS
337 5379 1683 FSFNTYSMN
337 5380 1684 TTCAGCTTCAATACCTATAGCATGAAC
337 5381 1685 FISSSSHTLYYADSVKG
337 5382 1686 TTCATTAGTAGTAGTAGTCATACCCTATACTACGCAGACTCTGTGAAG
GGC
337 5383 1687 ARSLGSGNYDNEDQTFYYYYGMDV
337 5384 1688 GCGAGATCCCTTGGTTCGGGGAATTATGATAACGAAGATCAGACATT
TTACTACTACTACGGTATGGACGTC
337 5385 1689 GAAACGACACTCACGCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
GAGCCGGCCTCCATATCCTGCCGGTCTAGTCAGAGCCTCCTGTTTCAT
AGTAATGGACACAATTATTTGGATTGGTACCTGCAGAAGCCAGGGCA
GTCTCCACAACTCCTGATCCATTTGGGTTCTAATCGGGCCTCCGGAGT
CCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGA
AAATCAGCAGAGTGGAGCCTGAGGATGTTGGGGTTTATTACTGTATG
CAAGCTCTACAAACTCCGTACACTTTTGGCCAGGGGACCAAGGTGGA
GATCAAA
337 5386 1690 ETTLTQSPLSLPVTPGEPASISCRSSQSLLFHSNGHNYLDWYLQKPGQSPQ
LLIHLGSNRASGVPDRFSGSGSGTDFTLKISRVEPEDVGVYYCMQALQTP
YTFGQGTKVEIK
337 5387 1691 RSSQSLLFHSNGHNYLD
337 5388 1692 CGGTCTAGTCAGAGCCTCCTGTTTCATAGTAATGGACACAATTATTTG
GAT
337 5389 1693 LGSNRAS
337 5390 1694 TTGGGTTCTAATCGGGCCTCC
337 5391 1695 MQALQTPYT
337 5392 1696 ATGCAAGCTCTACAAACTCCGTACACT
338 5393 1697 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACGGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCTGGTGTCTCCGTCACCATTAAT
GATTACTACTGGACTTGGCTCCGCCAGTCCCCAGGGAAAGGCCTGGA
GTGGATTGGAAACATCTATAACAGTGGGAGCACCTACCAGAACCCGT
CCCTCCAGAGTCGAGTTACCATGTCAGTGGACACGGCCAAGAACCAC
TTCTCCCTGAAGCTGACCTCTGTCACTGCCGCAGATACGGCCGTCTAT
TACTGTGCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATG
GACGTCTGGGGCCTAGGGACCACGGTCACCGTCTCCTCA
338 5394 1698 QVQLQESGPGRVKPSQTLSLTCTVSGVSVTINDYYWTWLRQSPGKGLEW
IGNIYNSGSTYQNPSLQSRVTMSVDTAKNHFSLKLTSVTAADTAVYYCA
RDLGTANNYYFGMDVWGLGTTVTVSS
338 5395 1699 VSVTINDYYWT
338 5396 1700 GTCTCCGTCACCATTAATGATTACTACTGGACT
338 5397 1701 NIYNSGSTYQNPSLQS
338 5398 1702 AACATCTATAACAGTGGGAGCACCTACCAGAACCCGTCCCTCCAGAG
T
338 5399 1703 ARDLGTANNYYFGMDV
338 5400 1704 GCCAGAGATTTAGGCACTGCCAACAACTACTACTTCGGTATGGACGT
C
338 5401 1705 GATATTGTGCTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAAGAGCCACTCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCACCTA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATAATGGATCCAACAGGGTCACTGGCACCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCGTAGAG
CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCT
CCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA
338 5402 1706 DIVLTQSPATLSLSPGERATLSCRASQSVSTYLAWYQQKPGQAPRLLIYN
GSNRVTGTPARFSGSGSGTDFTLTISSVEPEDFAVYYCQQRSNWPPYTFG
QGTKVEIK
338 5403 1707 RASQSVSTYLA
338 5404 1708 AGGGCCAGTCAGAGTGTTAGCACCTACTTAGCC
338 5405 1709 NGSNRVT
338 5406 1710 AATGGATCCAACAGGGTCACT
338 5407 1711 QQRSNWPPYT
338 5408 1712 CAGCAGCGTAGCAACTGGCCTCCGTACACT
339 5409 1713 GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGAAGCCTTCAGA
GACCCTGTCCCTCAGTTGCATTGTCTCTGGTGACTCCATCACCAGTAA
TGATTACTACTGGAGTTGGATCCGCCAGTCCCCAGGGAAGGGCCTGG
AGTGGATTGGGTACATCTATCACAGCGGGGCCACCTTCTACACTCCGT
CCCTACGGAGTCGAGTGACCATATCGACAGACAGGTCCAAGAACCAG
TTCTCCCTGAGACTGTCGTCTGTGACCGCCGCAGACACGGCCGTATAT
TATTGTGCCAGTGGACCTGTGGGGATGGCTACAAGCAACTGGTTCGA
CCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA
339 5410 1714 EVQLVESGPGLVKPSETLSLSCIVSGDSITSNDYYWSWIRQSPGKGLEWIG
YIYHSGATFYTPSLRSRVTISTDRSKNQFSLRLSSVTAADTAVYYCASGPV
GMATSNWFDPWGQGTLVTVSS
339 5411 1715 DSITSNDYYWS
339 5412 1716 GACTCCATCACCAGTAATGATTACTACTGGAGT
339 5413 1717 YIYHSGATFYTPSLRS
339 5414 1718 TACATCTATCACAGCGGGGCCACCTTCTACACTCCGTCCCTACGGAGT
339 5415 1719 ASGPVGMATSNWFDP
339 5416 1720 GCCAGTGGACCTGTGGGGATGGCTACAAGCAACTGGTTCGACCCC
339 5417 1721 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTCGCCCCGGGAAA
GACGGCCACTCTTACGTGTGGGGGAGACATCATTAGAACTAACAGTG
TGAACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTATTGATCATA
TATTATGATAGCGACCGGCCCTCAGGGATCCCTGGGCGATTCTCTGCC
TCCAACTCTGGGAGCGCGGCCACCCTGACCATCAGCAGGGTCGAAGC
CGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGACAGCAGTACTG
ATTATCACGTGGTTTTCGGCGGAGGGACCAAGCTCACCGTCCTA
339 5418 1722 QPVLTQPPSVSVAPGKTATLTCGGDIIRTNSVNWYQQKPGQAPVLIIYYD
SDRPSGIPGRFSASNSGSAATLTISRVEAGDEADYYCQVWDSSTDYHVVF
GGGTKLTVL
339 5419 1723 GGDIIRTNSVN
339 5420 1724 GGGGGAGACATCATTAGAACTAACAGTGTGAAC
339 5421 1725 YDSDRPS
339 5422 1726 TATGATAGCGACCGGCCCTCA
339 5423 1727 QVWDSSTDYHVV
339 5424 1728 CAGGTGTGGGACAGCAGTACTGATTATCACGTGGTT
340 5425 1729 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACATCTTCACCGGTTA
TTTTATACACTGGGTGCGACAGGCCCCCGGACAAGGGCTTGAGTGGA
TGGGAGTAATCAATCCCAGAGGTGGAAGCACAAGCTACGCACAAAA
GTTCCAGGGCAGAGTCGCTGTGTCCAGGGACACGTCCACGACTACAG
TCTACATGGAGCTGAACAGCCTGAGATCTGAGGACACGGCCGTATAT
TACTGTGCGAGAGCCCCGAGCCACGATGAGTGGGTCGCAATTTCCCG
AAATAACGATGTTGTGGGGTTCGACGCCTGGGGCCAGGGAACCCTGG
TCACCGTCTCCTCA
340 5426 1730 QVQLVQSGAEVKKPGASVKVSCKASGYIFTGYFIHWVRQAPGQGLEWM
GVINPRGGSTSYAQKFQGRVAVSRDTSTTTVYMELNSLRSEDTAVYYCA
RAPSHDEWVAISRNNDVVGFDAWGQGTLVTVSS
340 5427 1731 YIFTGYFIH
340 5428 1732 TACATCTTCACCGGTTATTTTATACAC
340 5429 1733 VINPRGGSTSYAQKFQG
340 5430 1734 GTAATCAATCCCAGAGGTGGAAGCACAAGCTACGCACAAAAGTTCCA
GGGC
340 5431 1735 ARAPSHDEWVAISRNNDVVGFDA
340 5432 1736 GCGAGAGCCCCGAGCCACGATGAGTGGGTCGCAATTTCCCGAAATAA
CGATGTTGTGGGGTTCGACGCC
340 5433 1737 CAGTCTGTCCTGACTCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAG
AGGGTCACCATCTCCTGCACTGGGGGCAGCTCCAACATCGGGGCAGA
TTATGACGTACACTGGTACCAGCAGCCTCCAGGAACAGCCCCCAAAC
TCCTCATATTTGCTAACAACAATCGACCCTCAGGGGTCCCTGGCCGAT
TCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGC
TCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGCCTGAGTGCTTGGGTGTTCGGCGGGGGGACCAAGCTGACCGTCCT
A
340 5434 1738 QSVLTQPPSVSGAPGQRVTISCTGGSSNIGADYDVHWYQQPPGTAPKLLI
FANNNRPSGVPGRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSAW
VFGGGTKLTVL
340 5435 1739 TGGSSNIGADYDVH
340 5436 1740 ACTGGGGGCAGCTCCAACATCGGGGCAGATTATGACGTACAC
340 5437 1741 ANNNRPS
340 5438 1742 GCTAACAACAATCGACCCTCA
340 5439 1743 QSYDSSLSAWV
340 5440 1744 CAGTCCTATGACAGCAGCCTGAGTGCTTGGGTG
341 5441 1745 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCTCAGTAGTTA
TGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGTCTGGAGTGGG
TCTCATCCATTAGTGCTGGAAGTAGTTACATCGACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCTCTG
TATCTGCAAATGAACAACCTGAGAGCCGAGGACACGGCTCTGTATTA
CTGTGCGAGAGAAGTTTTACCAGCAACCGCTATAGGAGGCGCCTGGC
TCGACCCCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
341 5442 1746 EVQLVESGGGLVKPGGSLRLSCAASGFTLSSYAMNWVRQAPGKGLEWV
SSISAGSSYIDYADSVKGRFTISRDNAKNSLYLQMNNLRAEDTALYYCAR
EVLPATAIGGAWLDPWGQGTLVTVSS
341 5443 1747 FTLSSYAMN
341 5444 1748 TTCACCCTCAGTAGTTATGCCATGAAC
341 5445 1749 SISAGSSYIDYADSVKG
341 5446 1750 TCCATTAGTGCTGGAAGTAGTTACATCGACTACGCAGACTCAGTGAA
GGGC
341 5447 1751 AREVLPATAIGGAWLDP
341 5448 1752 GCGAGAGAAGTTTTACCAGCAACCGCTATAGGAGGCGCCTGGCTCGA
CCCC
341 5449 1753 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GACGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCTG
GATATGATGTCCACTGGTACCGGCAGCTTCCAGGAACAGCCCCCAAA
CTCCTCATCTATTCTAACAACAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGACACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGGGGATGAGGCTGATTATTACTGCCAGTCCTATGACATC
AGCCTGAGTGCCTCTTATGTCTTCGGAACTGGGACCAAGGTCACCGTC
CTA
341 5450 1754 QSVLTQPPSVSGAPGQTVTISCTGSSSNIGAGYDVHWYRQLPGTAPKLLI
YSNNNRPSGVPDRFSGSKSDTSASLAITGLQAGDEADYYCQSYDISLSAS
YVFGTGTKVTVL
341 5451 1755 TGSSSNIGAGYDVH
341 5452 1756 ACTGGGAGCAGCTCCAACATCGGGGCTGGATATGATGTCCAC
341 5453 1757 SNNNRPS
341 5454 1758 TCTAACAACAATCGGCCCTCA
341 5455 1759 QSYDISLSASYV
341 5456 1760 CAGTCCTATGACATCAGCCTGAGTGCCTCTTATGTC
342 5457 1761 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAACTA
TGGTTTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA
TGGGATGGATCCTCACTCACAATGGTTACACAAACTATGCACAGAAG
TTCCAGGACAGAGTCACCATGAAGACAGACACATCCACGAGCACAGT
CTACATGGAGCTGAGGAGCCTGAGATCTGTCGACACGGCCGTGTATT
ACTGTGCGAGAATTGGCCATGTTACAGCCGTGGCTGGTGCCCCTCCTG
ACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
342 5458 1762 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGFSWVRQAPGQGLEW
MGWILTHNGYTNYAQKFQDRVTMKTDTSTSTVYMELRSLRSVDTAVYY
CARIGHVTAVAGAPPDYWGQGTLVTVSS
342 5459 1763 YTFTNYGFS
342 5460 1764 TACACCTTTACCAACTATGGTTTCAGC
342 5461 1765 WILTHNGYTNYAQKFQD
342 5462 1766 TGGATCCTCACTCACAATGGTTACACAAACTATGCACAGAAGTTCCA
GGAC
342 5463 1767 ARIGHVTAVAGAPPDY
342 5464 1768 GCGAGAATTGGCCATGTTACAGCCGTGGCTGGTGCCCCTCCTGACTAC
342 5465 1769 CAGCCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTATCAAGGACAG
TCGATCACCATCTCCTGCAGTGGAACCAGCAGTGATGTTGGGACTTAT
AACCTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCGAACT
CATGATTTATGAGGGCAGTAAGCGGCCCTCAGGGGTTTCTGATCGCTT
CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCT
CCAGGCTGAGGACGAGGCTGATTATTACTGCTGCTCATATGTAGCTGG
TAGTACTTCAGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA
342 5466 1770 QPVLTQPASVSGYQGQSITISCSGTSSDVGTYNLVSWYQQHPGKAPELMI
YEGSKRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYCCSYVAGSTSV
FGGGTKLTVL
342 5467 1771 SGTSSDVGTYNLVS
342 5468 1772 AGTGGAACCAGCAGTGATGTTGGGACTTATAACCTTGTCTCC
342 5469 1773 EGSKRPS
342 5470 1774 GAGGGCAGTAAGCGGCCCTCA
342 5471 1775 CSYVAGSTSV
342 5472 1776 TGCTCATATGTAGCTGGTAGTACTTCAGTA
343 5473 1777 GAGGTGCAGCTGGTGGAGTCGGGCCCTGGACTGGTGAAGCCTTCAGA
GACCCTGTCCCTCAGTTGCATTGTCTCTGGTGGCTCCATCACCAGTGG
TGATTACTACTGGAGTTGGCTCCGCCAGTCCCCAGGGAAGGGCCTGG
AGTGGATTGGGTACATATATCACAGCGGGGCCACCTTCTACACCCCGT
CCCTACGGAGTCGAGTGACCATTTCGACAGACACCTCCAAGAACCAA
TTCTCCCTGAGACTGTCGTCTGTGACCGCCGCAGACACGGCCGTTTAT
TATTGTGCCAGTGGACCTGTCGGGATGGCTACAAGCAACTGGTTCGA
CCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
343 5474 1778 EVQLVESGPGLVKPSETLSLSCIVSGGSITSGDYYWSWLRQSPGKGLEWI
GYIYHSGATFYTPSLRSRVTISTDTSKNQFSLRLSSVTAADTAVYYCASGP
VGMATSNWFDPWGQGTLVTVSS
343 5475 1779 GSITSGDYYWS
343 5476 1780 GGCTCCATCACCAGTGGTGATTACTACTGGAGT
343 5477 1781 YIYHSGATFYTPSLRS
343 5478 1782 TACATATATCACAGCGGGGCCACCTTCTACACCCCGTCCCTACGGAGT
343 5479 1783 ASGPVGMATSNWFDP
343 5480 1784 GCCAGTGGACCTGTCGGGATGGCTACAAGCAACTGGTTCGACCCC
343 5481 1785 TCCTATGAGCTGACACAGCCACCCTCAGTATCAGTCGCCCCGGGAAA
GACGGCCACCATTACGTGTGGGGGAGACATCATTAGAACTAACAGTG
TGAACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTCTATTGCTCATCT
ATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGCCT
CCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAGGCC
GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGACAGTGGTACTGA
TTATCACGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCAA
343 5482 1786 SYELTQPPSVSVAPGKTATITCGGDIIRTNSVNWYQQKPGQAPLLLIYYDS
DRPSGIPERFSASNSGNTATLTISRVEAGDEADYYCQVWDSGTDYHVVF
GGGTKLTVQ
343 5483 1787 GGDIIRTNSVN
343 5484 1788 GGGGGAGACATCATTAGAACTAACAGTGTGAAC
343 5485 1789 YDSDRPS
343 5486 1790 TATGATAGCGACCGGCCCTCA
343 5487 1791 QVWDSGTDYHVV
343 5488 1792 CAGGTGTGGGACAGTGGTACTGATTATCACGTGGTT
344 5489 1793 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGGC
CTCAGTGAAAGTCTCCTGCAAGGCTTCTGAATACGCCTTCACCGCCCA
CTATCTTCACTGGGTGCGACAGGCCCCTGATCAAGGACTTGAGTGGAT
GGGATGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGT
TTCACGGCAGGGTCAGCATGACCAGTGACACGTCCATCAGTACAGTC
TATATGGAACTGAGCAGCCTGACATCTGACGACACGGCCGTCTATTA
CTGTGCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTCT
GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
344 5490 1794 QVQLVQSGAEVKRPGASVKVSCKASEYAFTAHYLHWVRQAPDQGLEW
MGWISPKSGGTNYAQKFHGRVSMTSDTSISTVYMELSSLTSDDTAVYYC
ARSSLVGASPNFDFWGQGTLVTVSS
344 5491 1795 YAFTAHYLH
344 5492 1796 TACGCCTTCACCGCCCACTATCTTCAC
344 5493 1797 WISPKSGGTNYAQKFHG
344 5494 1798 TGGATCAGCCCTAAAAGTGGTGGCACCAACTATGCACAGAAGTTTCA
CGGC
344 5495 1799 ARSSLVGASPNFDF
344 5496 1800 GCGAGAAGCAGTCTGGTGGGAGCAAGCCCCAACTTTGACTTC
344 5497 1801 CAGTCTGTGGTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACA
GAGGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATA
ATTATGTATCCTGGTACCAGCAACTCCCAGGATCTACCCCCAAAGTCC
TCATTTACGACAATAATCAGCGACCCTCAGGGATTCCTGACCGTTTCT
CTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGCCATCAGCGGACTCC
AGACTGGCGACGAGGCCGTCTATTATTGCGGAACATGGGATGCCAGC
CTGAGTGCTGCAATGGTTTTCGGCGGGGGGACCAAGCTCACCGTCCT
A
344 5498 1802 QSVVTQPPSVSAAPGQRVTISCSGSSSNIGNNYVSWYQQLPGSTPKVLIY
DNNQRPSGIPDRFSGSKSGTSATLAISGLQTGDEAVYYCGTWDASLSAA
MVFGGGTKLTVL
344 5499 1803 SGSSSNIGNNYVS
344 5500 1804 TCTGGAAGCAGCTCCAACATTGGGAATAATTATGTATCC
344 5501 1805 DNNQRPS
344 5502 1806 GACAATAATCAGCGACCCTCA
344 5503 1807 GTWDASLSAAMV
344 5504 1808 GGAACATGGGATGCCAGCCTGAGTGCTGCAATGGTT
345 5505 1809 CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGA
GACCCTGTCCCTAACCTGCGCTGTCTCTGGTGGGTACTTCATTAATGA
CAACTGGAGCTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGA
TTGGAGAAATTAGTCATAGTGGAAGCACCAACTACAATCCGTCCCTC
AAGAGTCGACTCACCATATCAGTTGACACGTCCAGGCAGCAGTTTTCC
CTGAAATTGAGCTCTGTGACCGCCGCGGACAGTGGTGTTTACTACTGT
GCGCGAGTCCACCCGTCGTATGACTTTGGCTGGCGCTTCTTTGACTTC
TGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA
345 5506 1810 QVQLQQWGAGLLKPSETLSLTCAVSGGYFINDNWSWIRQSPGKGLEWIG
EISHSGSTNYNPSLKSRLTISVDTSRQQFSLKLSSVTAADSGVYYCARVHP
SYDFGWRFFDFWGQGTLVTVSS
345 5507 1811 GYFINDNWS
345 5508 1812 GGGTACTTCATTAATGACAACTGGAGC
345 5509 1813 EISHSGSTNYNPSLKS
345 5510 1814 GAAATTAGTCATAGTGGAAGCACCAACTACAATCCGTCCCTCAAGAG
T
345 5511 1815 ARVHPSYDFGWRFFDF
345 5512 1816 GCGCGAGTCCACCCGTCGTATGACTTTGGCTGGCGCTTCTTTGACTTC
345 5513 1817 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
GATACAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAGTTCCAAC
TTAGCCTGGTACCAGCAGAAACCTGGCCAGCCTCCCAGTCTCCTCATC
TATGGAGCATCCAACAGGGCCACTGGTATCCCAGACAGGTTTCGTGG
CAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGT
CTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGCATACTGGCCTC
CGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA
345 5514 1818 ETTLTQSPATLSVSPGDTATLSCRASQTISSNLAWYQQKPGQPPSLLIYGA
SNRATGIPDRFRGSGSGTEFTLTISSLQSEDFAVYYCQQYAYWPPYTFGQ
GTKVEIK
345 5515 1819 RASQTISSNLA
345 5516 1820 AGGGCCAGTCAGACTATTAGTTCCAACTTAGCC
345 5517 1821 GASNRAT
345 5518 1822 GGAGCATCCAACAGGGCCACT
345 5519 1823 QQYAYWPPYT
345 5520 1824 CAGCAGTATGCATACTGGCCTCCGTACACT
346 5521 1825 GAGGTGCAGCTGTTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACTGTCTCGGGTGGCTCCATCAACAGTAT
TGATTATTATTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG
AGTGGATTGGCTACATTTATCACAGTGGGAGCACCCACTACAGACCA
TCCCTCAAGAGTCGAGTAACGATATCATTAGACAAGGCCAAGAACGA
GTTCTCGCTGAGTCTGACCTCTGTGACTGCCGCAGACACGGCCGTGTA
TTTCTGTGCCAGTGGCCCCGTCGGGATGGCAACAAGCAACTGGTTCG
ACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
346 5522 1826 EVQLLESGPGLVKPSQTLSLTCTVSGGSINSIDYYWSWIRQPPGKGLEWIG
YIYHSGSTHYRPSLKSRVTISLDKAKNEFSLSLTSVTAADTAVYFCASGPV
GMATSNWFDPWGQGTLVTVSS
346 5523 1827 GSINSIDYYWS
346 5524 1828 GGCTCCATCAACAGTATTGATTATTATTGGAGC
346 5525 1829 YIYHSGSTHYRPSLKS
346 5526 1830 TACATTTATCACAGTGGGAGCACCCACTACAGACCATCCCTCAAGAG
T
346 5527 1831 ASGPVGMATSNWFDP
346 5528 1832 GCCAGTGGCCCCGTCGGGATGGCAACAAGCAACTGGTTCGACCCC
346 5529 1833 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCAGTGACCCCAGGAGA
GACGGCCAGGCTTCCCTGTGAGGGAGACATCGTTGTCACTAACAGTG
TCCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTTTTGGTCGTCT
ATTATGATAGCGACCGGGCCTCAGGGATCCCTGAGCGATTCTCTGGCT
CCAATTCTGGGAACACGGCCACCCTGAGCATCAGCAGGGTCGAAGCC
GGGGATGAGGCCGACTACTATTGTCAGGTGTGGGATAGTAGTACTGA
TCATCATGTGGTGTTCGGCGGTGGGACCAAGCTCACCGTCCTA
346 5530 1834 QPVLTQPPSVSVTPGETARLPCEGDIVVTNSVHWYQQKPGQAPVLVVYY
DSDRASGIPERFSGSNSGNTATLSISRVEAGDEADYYCQVWDSSTDHHV
VFGGGTKLTVL
346 5531 1835 EGDIVVTNSVH
346 5532 1836 GAGGGAGACATCGTTGTCACTAACAGTGTCCAC
346 5533 1837 YDSDRAS
346 5534 1838 TATGATAGCGACCGGGCCTCA
346 5535 1839 QVWDSSTDHHVV
346 5536 1840 CAGGTGTGGGATAGTAGTACTGATCATCATGTGGTG
347 5537 1841 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCAGATTCAGCAGCG
ACGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG
ATGGGAGGAATCATCCCTATCCGTGGGACACCAACCTACGCACAGAA
GTTCCAGGGCAGAGTCACGATTATCGCGGACGAATCCACGACTACAT
CCTACATGGAGATGAGCAGCCTGAGATCTGAGGACACGGCCGTGTAT
TACTGTGCGAGACCGAATTACGATATTTTGACTGGTTATAATGATGCT
TTTGATATTTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
347 5538 1842 QVQLVQSGAEVKKPGSSVKVSCKASGGRFSSDAISWVRQAPGQGLEWM
GGIIPIRGTPTYAQKFQGRVTIIADESTTTSYMEMSSLRSEDTAVYYCARP
NYDILTGYNDAFDIWGQGTMVTVSS
347 5539 1843 GRFSSDAIS
347 5540 1844 GGCAGATTCAGCAGCGACGCTATCAGC
347 5541 1845 GIIPIRGTPTYAQKFQG
347 5542 1846 GGAATCATCCCTATCCGTGGGACACCAACCTACGCACAGAAGTTCCA
GGGC
347 5543 1847 ARPNYDILTGYNDAFDI
347 5544 1848 GCGAGACCGAATTACGATATTTTGACTGGTTATAATGATGCTTTTGAT
ATT
347 5545 1849 CAGTCTGTGTTGACGCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTAT
AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAGACT
CATGATTTACGATGTCAGTAAGCGGCCCTCAGGGGCCCCTGATCGCTT
CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT
CCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCG
GCCTTTATGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA
347 5546 1850 QSVLTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKVPRLM
IYDVSKRPSGAPDRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGGLYV
FGTGTKLTVL
347 5547 1851 TGTSSDVGGYNYVS
347 5548 1852 ACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCC
347 5549 1853 DVSKRPS
347 5550 1854 GATGTCAGTAAGCGGCCCTCA
347 5551 1855 CSYAGGLYV
347 5552 1856 TGCTCATATGCAGGCGGCCTTTATGTC
348 5553 1857 GAGGTGCAGCTGGTGGAGTCCGGGGCTGAGGTGAAGAAGCCTGGGG
CCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCACTT
ATGATATCAACTGGGTGCGACAGGCCACTGGACGGGGGCTTGAGTGG
ATGGGATGGATGACCCCTGATAGTGGTAGCACAGGCTATCCACAGAA
CTTCCAGGGCAGAGTCACCATGACCAGGAACACCTCCATAAGCACAG
CCTACATGGAGTTGAGCAACCTGAGATCTGAGGACACGGCCGTATAT
TACTGTGTGCAAATGGACCATTGTAGAAGTACCAGCTGCTCTGAGGG
GAACTGGTTCGACACCTGGGGCCAGGGAACCCTGGTCACCGTCTCCT
CA
348 5554 1858 EVQLVESGAEVKKPGASVKVSCKASGYTFTTYDINWVRQATGRGLEWM
GWMTPDSGSTGYPQNFQGRVTMTRNTSISTAYMELSNLRSEDTAVYYC
VQMDHCRSTSCSEGNWFDTWGQGTLVTVSS
348 5555 1859 YTFTTYDIN
348 5556 1860 TACACCTTCACCACTTATGATATCAAC
348 5557 1861 WMTPDSGSTGYPQNFQG
348 5558 1862 TGGATGACCCCTGATAGTGGTAGCACAGGCTATCCACAGAACTTCCA
GGGC
348 5559 1863 VQMDHCRSTSCSEGNWFDT
348 5560 1864 GTGCAAATGGACCATTGTAGAAGTACCAGCTGCTCTGAGGGGAACTG
GTTCGACACC
348 5561 1865 CAGCCTGGGCTGACTCAGCCACCCTCGGTGTCTGCAGCCCCCAGGCA
GAGGGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAACTA
ATGCTGTAAACTGGTACCAGCAGCTCCCAGGAAAGGCTCCCAAACTC
CTCATCTATTCTGATAATCTGATGCCCTCAGGGGTCTCTGCCCGATTCT
CTGGCTCCAAGTCTGGCACCTCGGCCTCCCTGGCCATCAGTGGGCTCC
AGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGC
CTGAATGTTTGGGTGTTCGGCGGGGGGACCAAGCTCACCGTCCTA
348 5562 1866 QPGLTQPPSVSAAPRQRVTISCSGSSSNIGTNAVNWYQQLPGKAPKLLIYS
DNLMPSGVSARFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNVW
VFGGGTKLTVL
348 5563 1867 SGSSSNIGTNAVN
348 5564 1868 TCTGGAAGCAGCTCCAACATCGGAACTAATGCTGTAAAC
348 5565 1869 SDNLMPS
348 5566 1870 TCTGATAATCTGATGCCCTCA
348 5567 1871 AAWDDSLNVWV
348 5568 1872 GCAGCATGGGATGACAGCCTGAATGTTTGGGTG
349 5569 1873 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGAAGCCAGGGCG
GTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCAACTTCGGTGATTA
TGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TAGGTTTCATTAGAAGCAAAACTTATCGTGAGACAAGAGAATACGCC
GCGTCTGTGAAAGGCAGATTCACCATGTCAAGAGATGATTTCAACAG
GATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCA
TGTATTATTGTACGAGACAAGACGATTTTTGGAGTGGTCATCCCTACT
ACTTTGAGTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
349 5570 1874 EVQLVESGGGLVKPGRSLRLSCTASGFNFGDYAMSWFRQAPGKGLEWV
GFIRSKTYRETREYAASVKGRFTMSRDDFNRIAYLQMNSLKTEDTAMYY
CTRQDDFWSGHPYYFEYWGQGTLVTVSS
349 5571 1875 FNFGDYAMS
349 5572 1876 TTCAACTTCGGTGATTATGCTATGAGC
349 5573 1877 FIRSKTYRETREYAASVKG
349 5574 1878 TTCATTAGAAGCAAAACTTATCGTGAGACAAGAGAATACGCCGCGTC
TGTGAAAGGC
349 5575 1879 TRQDDFWSGHPYYFEY
349 5576 1880 ACGAGACAAGACGATTTTTGGAGTGGTCATCCCTACTACTTTGAGTAC
349 5577 1881 CAGCCTGTGCTGACTCAGCCCCCCTCCGCGTCCGGGTCTCCTGGACAG
TCAGTCACCATCTCCTGCACTGGAACCAACAGTGACGTGGGTAGTTAT
AACTATGTCTCCTGGTACCAACATCACCCAGGCAAAGCCCCCAAACT
CATCATTTATGACGTCGCTAAGCGGCCCTCAGGGGTCCCTGATCGCTT
CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT
CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA
GTAACGATTTGGGGGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA
349 5578 1882 QPVLTQPPSASGSPGQSVTISCTGTNSDVGSYNYVSWYQHHPGKAPKLII
YDVAKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNDL
GVFGTGTKLTVL
349 5579 1883 TGTNSDVGSYNYVS
349 5580 1884 ACTGGAACCAACAGTGACGTGGGTAGTTATAACTATGTCTCC
349 5581 1885 DVAKRPS
349 5582 1886 GACGTCGCTAAGCGGCCCTCA
349 5583 1887 SSYAGSNDLGV
349 5584 1888 AGCTCATATGCAGGCAGTAACGATTTGGGGGTC
350 5585 1889 GAGGTGCAGCTGGTGGAGTCCGGCCCAGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCACTGTGTCTGGTGGCTCCGTCAGTGGTCA
CTACTGGAGCTGGATTCGGCAGTTCCCAGGGAAGGAACTGGAATGGA
TTGGTCATATCTATTATATTGGGACGACCAACTACAACCCCTCCCTCA
AGAGTCGAGTCATCATATCGCTAGACACGTCCAAGAATCAGCTCTCC
CTGAAGCTGAGTTCTGTGACCGCTGCGGACACTGCCGTTTATTATTGT
GCCAGACAGTTCGGCTATGATAAAAATACTTTAAGTCGGCTTGACTTT
GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
350 5586 1890 EVQLVESGPGLVKPSETLSLTCTVSGGSVSGHYWSWIRQFPGKELEWIGH
IYYIGTTNYNPSLKSRVIISLDTSKNQLSLKLSSVTAADTAVYYCARQFGY
DKNTLSRLDFDYWGQGTLVTVSS
350 5587 1891 GSVSGHYWS
350 5588 1892 GGCTCCGTCAGTGGTCACTACTGGAGC
350 5589 1893 HIYYIGTTNYNPSLKS
350 5590 1894 CATATCTATTATATTGGGACGACCAACTACAACCCCTCCCTCAAGAGT
350 5591 1895 ARQFGYDKNTLSRLDFDY
350 5592 1896 GCCAGACAGTTCGGCTATGATAAAAATACTTTAAGTCGGCTTGACTTT
GACTAC
350 5593 1897 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAAGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA
TTTAAATTGGTATCAACAGAGACCAGGGAAAGCCCCTAAGCTCCTGA
TCTATTCTGCATTCAGTTTACATAGTGGTGTCCCATCAAGGTTCAGTG
GCAGTGGATCTGAGACAGAGTTCACTCTCACCATCAGCAGTCTGCAA
CCTGACGATTTTGCAACTTATTACTGTCAACAGAGTTACAGTATTCCC
TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
350 5594 1898 DIQMTQSPSSLSASVRDRVTITCRASQSISSYLNWYQQRPGKAPKLLIYSA
FSLHSGVPSRFSGSGSETEFTLTISSLQPDDFATYYCQQSYSIPWTFGQGTK
VEIK
350 5595 1899 RASQSISSYLN
350 5596 1900 CGGGCAAGTCAGAGCATTAGCAGCTATTTAAAT
350 5597 1901 SAFSLHS
350 5598 1902 TCTGCATTCAGTTTACATAGT
350 5599 1903 QQSYSIPWT
350 5600 1904 CAACAGAGTTACAGTATTCCCTGGACG
351 5601 1905 CAGGTGCAGCTGCAGGAGTCCGGCCCGGGACTGGTGAAGCCTTCGGA
GACCCTGTCCCTCACCTGCAGTGTCTCTGGTGGCTCCATCACCAATGT
TAATTACTACTGGGGCTGGATCCGCCAGCCCCCCGGGAAGGGCCTGG
AGTGGATTGGGAGTATCTATTATAATGGAAACACCTACTACAACCCG
TCCCTCCAGAGTCGAGTCACCATGTCCGTGGACACGTCCAAGAACCA
CTTCTCCCTGAGGCTGACGTCTGTGACCGCCGCAGACACGGCTGTATA
TTTTTGTGCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGA
TATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
351 5602 1906 QVQLQESGPGLVKPSETLSLTCSVSGGSITNVNYYWGWIRQPPGKGLEWI
GSIYYNGNTYYNPSLQSRVTMSVDTSKNHFSLRLTSVTAADTAVYFCAR
EGPNWELLNAFDIWGQGTTVTVSS
351 5603 1907 GSITNVNYYWG
351 5604 1908 GGCTCCATCACCAATGTTAATTACTACTGGGGC
351 5605 1909 SIYYNGNTYYNPSLQS
351 5606 1910 AGTATCTATTATAATGGAAACACCTACTACAACCCGTCCCTCCAGAGT
351 5607 1911 AREGPNWELLNAFDI
351 5608 1912 GCGAGAGAGGGGCCTAATTGGGAATTGTTGAATGCTTTCGATATC
351 5609 1913 TCCTATGAGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACA
GACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAATG
TGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTCTTGGTCGTCT
ATGAGGATACCCACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT
CCAACTCTGGGAACACGGCCACCCTGACCATCAGTAGGGTCGAAGCC
GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATACTAGTAGTGA
TCATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTC
351 5610 1914 SYELTQPPSVSVAPGQTARITCGGNNIGSKNVHWYQQKPGQAPVLVVYE
DTHRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDTSSDHVVF
GGGTKLTVL
351 5611 1915 GGNNIGSKNVH
351 5612 1916 GGGGGAAACAACATTGGAAGTAAAAATGTGCAC
351 5613 1917 EDTHRPS
351 5614 1918 GAGGATACCCACCGGCCCTCA
351 5615 1919 QVWDTSSDHVV
351 5616 1920 CAGGTGTGGGATACTAGTAGTGATCATGTGGTA
352 5617 1921 CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAAGGTCTCCTGCAAGACTTCTGGTTACACCTTTAGTCATTT
CGGTGTCACCTGGATACGACAGGCCCCAGGACAAGGGCTTGAGTGGC
TGGGATGGATCAGCGCTTACAATGGTAACACAGACTCTGCAGACAAA
CTGCAGGGCAGACTCACCATGACGACAGACACATCCACGAACACCGC
CTACATGGAGTTGAGGAGCCTCAGATCTGACGACACGGCCGTCTATT
ACTGTGCGAGAGATCCCCCCGCATCAGCTGCTGCCATGCTTGACTACT
GGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
352 5618 1922 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSHFGVTWIRQAPGQGLEWL
GWISAYNGNTDSADKLQGRLTMTTDTSTNTAYMELRSLRSDDTAVYYC
ARDPPASAAAMLDYWGQGTLVTVSS
352 5619 1923 YTFSHFGVT
352 5620 1924 TACACCTTTAGTCATTTCGGTGTCACC
352 5621 1925 WISAYNGNTDSADKLQG
352 5622 1926 TGGATCAGCGCTTACAATGGTAACACAGACTCTGCAGACAAACTGCA
GGGC
352 5623 1927 ARDPPASAAAMLDY
352 5624 1928 GCGAGAGATCCCCCCGCATCAGCTGCTGCCATGCTTGACTAC
352 5625 1929 GACATCCAGATGACCCAGTCTCCACTCTCCCTGGCCGTCACCCTTGGA
CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAGGCCTCGAATACACT
GATGGAAACACCTACTTGAGTTGGTTTCAGCAGAGGCCAGGCCAATC
TCCAAGGCGCCTCATTTATAAGGTTTCTAATCGGGACTCTGGGGTCCC
AGACAGATTCAGCGGCAGCGGGGCAGGCACTGATTTCACACTGAGAA
TCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA
GGTACACACGGGCGGGGAATCTCTTTCGGTCCTGGGACCAAAGTGGA
TATCAAA
352 5626 1930 DIQMTQSPLSLAVTLGQPASISCRSSQGLEYTDGNTYLSWFQQRPGQSPR
RLIYKVSNRDSGVPDRFSGSGAGTDFTLRISRVEAEDVGVYYCMQGTHG
RGISFGPGTKVDIK
352 5627 1931 RSSQGLEYTDGNTYLS
352 5628 1932 AGGTCTAGTCAAGGCCTCGAATACACTGATGGAAACACCTACTTGAG
T
352 5629 1933 KVSNRDS
352 5630 1934 AAGGTTTCTAATCGGGACTCT
352 5631 1935 MQGTHGRGIS
352 5632 1936 ATGCAAGGTACACACGGGCGGGGAATCTCT
353 5633 1937 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCTCCTGCAAGGCCTCTGGATACACCTTCACCGACTA
CTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGA
TGGGGTGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAG
TTTCAGGGCAGTGTCACCATGACCACTGACACGTCCATCACCACAGG
CTACATGGAGCTGAGGAGCCTGAGAGTTGACGACACGGCCGTCTATT
ATTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTCT
GGGGCCAAGGGACCACGGTCACCGTCTCCTCA
353 5634 1938 QVQLVQSGAEVKKPGASVRVSCKASGYTFTDYFMNWVRQAPGGGLEW
MGWINPLSGVTKYAQQFQGSVTMTTDTSITTGYMELRSLRVDDTAVYY
CASQSSPYTPGAMGVWGQGTTVTVSS
353 5635 1939 YTFTDYFMN
353 5636 1940 TACACCTTCACCGACTACTTTATGAAC
353 5637 1941 WINPLSGVTKYAQQFQG
353 5638 1942 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCA
GGGC
353 5639 1943 ASQSSPYTPGAMGV
353 5640 1944 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTC
353 5641 1945 GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGCCGGACAAGTCAGAGCGTTAGCGGCTA
TTTAAGTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA
TCTATGCGGCATCCAATTTGTACAGTGGGGTCCCATCAAGGTTCAGTG
GCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAAC
CTGAAGATTTTGCAACTTACTTCTGTCAACTGAATTCCGGTGCCCTAT
TCACTTTCGGCCCTGGGACCAAGGTGGAAATCAAA
353 5642 1946 DIRMTQSPSSLSASVGDRVTITCRTSQSVSGYLSWYQQKPGKAPKLLIYA
ASNLYSGVPSRFSGSGSGTDFTLTITSLQPEDFATYFCQLNSGALFTFGPG
TKVEIK
353 5643 1947 RTSQSVSGYLS
353 5644 1948 CGGACAAGTCAGAGCGTTAGCGGCTATTTAAGT
353 5645 1949 AASNLYS
353 5646 1950 GCGGCATCCAATTTGTACAGT
353 5647 1951 QLNSGALFT
353 5648 1952 CAACTGAATTCCGGTGCCCTATTCACT
354 5649 1953 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGA
GTCCGTGAAACTCTCCTGCGCAGCGTCTGGATTCACCATCACTGACTC
CTACATGGCCTGGATCCGCCAGTCTCCAGGGAAGGGGCTGGAGTGGC
TTGCTTACATTAGTAGTACTAGTCTTTTCACAGACTACACAGACTCTG
TGAAGGGCCGATTCATCATCACCAGAGACAATGCCGAGAACTCACTC
TATCTGCAAATGACCAGCCTGACACCGGCAGACACGGGTGTCTATTTC
TGTGCGAGGGCCAAAACATCCTACTACTTCTACGCTCTGGACGTCTGG
GGCCCAGGCACCCTGGTCACCGTCTCCTCA
354 5650 1954 EVQLVESGGGLVKPGESVKLSCAASGFTITDSYMAWIRQSPGKGLEWLA
YISSTSLFTDYTDSVKGRFIITRDNAENSLYLQMTSLTPADTGVYFCARAK
TSYYFYALDVWGPGTLVTVSS
354 5651 1955 FTITDSYMA
354 5652 1956 TTCACCATCACTGACTCCTACATGGCC
354 5653 1957 YISSTSLFTDYTDSVKG
354 5654 1958 TACATTAGTAGTACTAGTCTTTTCACAGACTACACAGACTCTGTGAAG
GGC
354 5655 1959 ARAKTSYYFYALDV
354 5656 1960 GCGAGGGCCAAAACATCCTACTACTTCTACGCTCTGGACGTC
354 5657 1961 GAAACGACACTCACGCAGTCTCCAGGCACGCTGTCTTTGTCTCCGGGG
GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACAA
CTATCTAGCCTGGTTCCAGCACAAACCTGGCCAGGCTCCCAGACTCCT
CATCTATAATGCATCCAACAGGGCCGCTGGCATCCCAGACAGGTTCA
GTGGTAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAAACTG
GAGCCTGGAGATTCTGCAGTGTATTACTGTCAGCGATATGGGAACTCT
TGGCCGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
354 5658 1962 ETTLTQSPGTLSLSPGERATLSCRASQSVNNNYLAWFQHKPGQAPRLLIY
NASNRAAGIPDRFSGSGSGTDFTLTISKLEPGDSAVYYCQRYGNSWPFGQ
GTKVEIK
354 5659 1963 RASQSVNNNYLA
354 5660 1964 AGGGCCAGTCAGAGTGTTAACAACAACTATCTAGCC
354 5661 1965 NASNRAA
354 5662 1966 AATGCATCCAACAGGGCCGCT
354 5663 1967 QRYGNSWP
354 5664 1968 CAGCGATATGGGAACTCTTGGCCG
355 5665 1969 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTCAGTC
TCCCATGAGCTGGGTCCGCCAGGCTCCTGGGAAGGGGCTGGAGTGGG
TCTCCGGTATTAGTACTGGAGGGACCAATACATACTACGCAGACTCC
GTGAAGGGCCGCTTCACCATCTCCAGAGACAATTCCAAGAACACGTT
GTATCTGCAAATGACCAGCCTGAGAGTCGGGGACACGGCCGTGTATT
ACTGTGCGAAAGAGAGTTTAGACTTTGGTTCAGGGAGCTACAACTGG
TTCGACACCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
355 5666 1970 QVQLVQSGGGLVQPGGSLRLSCAASGFTFSQSPMSWVRQAPGKGLEWV
SGISTGGTNTYYADSVKGRFTISRDNSKNTLYLQMTSLRVGDTAVYYCA
KESLDFGSGSYNWFDTWGQGTLVTVSS
355 5667 1971 FTFSQSPMS
355 5668 1972 TTCACCTTTAGTCAGTCTCCCATGAGC
355 5669 1973 GISTGGTNTYYADSVKG
355 5670 1974 GGTATTAGTACTGGAGGGACCAATACATACTACGCAGACTCCGTGAA
GGGC
355 5671 1975 AKESLDFGSGSYNWFDT
355 5672 1976 GCGAAAGAGAGTTTAGACTTTGGTTCAGGGAGCTACAACTGGTTCGA
CACC
355 5673 1977 GAAATTGTATTGACGCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAG
GTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAGACCAGGAC
AGCCTCCTAGGCTGCTCATTTCCTGGGCATCTACCCGGGAATCCGGGG
TCCCTGACCGATTCACTGGCAGCGGGTCTGGGACAGATTTCACTCTCA
CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCACC
AATATTATGATACCCACACTTTTGGCCAGGGGACCAAAGTGGATATC
AAA
355 5674 1978 EIVLTQSPDSLAVSLGERATINCKSSQSVLYRSNNKNYLAWYQQRPGQPP
RLLISWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCHQYYDT
HTFGQGTKVDIK
355 5675 1979 KSSQSVLYRSNNKNYLA
355 5676 1980 AAGTCCAGCCAGAGTGTTTTATACAGGTCCAACAATAAGAACTACTT
AGCT
355 5677 1981 WASTRES
355 5678 1982 TGGGCATCTACCCGGGAATCC
355 5679 1983 HQYYDTHT
355 5680 1984 CACCAATATTATGATACCCACACT
356 5681 1985 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
GTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCAGCTTCAGTGCCTA
TGGCATGCACTGGGTTCGCCAGGTTCCAACCAAGGGGCTGGAGTGGG
TGGCTGTTATATCATATGATGGAAGAGATATATACTATACAGACTCCG
TGAAGGGCCGATTCACCATTTCCAGAGACAATTCCAAGAACATGTTG
TATCTGCAAATGAACAGCCTGAGACCTGAGGACAGGGCTGTCTATTA
CTGTGCGAGAGATCCGTCCCTCGGTTATAATAATCACTACTTTGACTA
TTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA
356 5682 1986 EVQLVESGGGVVQPGRSLRLSCVASGFSFSAYGMHWVRQVPTKGLEWV
AVISYDGRDIYYTDSVKGRFTISRDNSKNMLYLQMNSLRPEDRAVYYCA
RDPSLGYNNHYFDYWGQGTLVTVSS
356 5683 1987 FSFSAYGMH
356 5684 1988 TTCAGCTTCAGTGCCTATGGCATGCAC
356 5685 1989 VISYDGRDIYYTDSVKG
356 5686 1990 GTTATATCATATGATGGAAGAGATATATACTATACAGACTCCGTGAA
GGGC
356 5687 1991 ARDPSLGYNNHYFDY
356 5688 1992 GCGAGAGATCCGTCCCTCGGTTATAATAATCACTACTTTGACTAT
356 5689 1993 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
GAAACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCGGCAA
CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT
CTATGCTGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG
GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG
CCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTAGCAACTGGCCT
CCTATGTACAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
356 5690 1994 EIVLTQSPATLSLSPGETATLSCRASQSVTGNLAWYQQKPGQAPRLLIYA
ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQRSNWPPMYSFG
QGTKLEIK
356 5691 1995 RASQSVTGNLA
356 5692 1996 AGGGCCAGTCAGAGTGTTACCGGCAACTTAGCC
356 5693 1997 AASNRAT
356 5694 1998 GCTGCATCCAACAGGGCCACT
356 5695 1999 QQRSNWPPMYS
356 5696 2000 CAGCAGCGTAGCAACTGGCCTCCTATGTACAGT
357 5697 2001 CAGGTCCAGCTTGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTC
CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCAGAGGCT
ACCATATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGG
ATGGGAGGGATCATCCATCTATTTGGGACAGTAAGCTACGCTCCGAA
GTTCCAGGGCAGAGTCACGATCACCGCGGACGCATCCACGGGCACAG
CCCATATGGAGTTGAGCAGCCTGACATCTGACGACACGGCCATATAC
TATTGTGCGAGAGATGCTTACGAAGTCTGGACGGGTTCTTATCTCCCC
CCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
357 5698 2002 QVQLVQSGAEVKRPGSSVKVSCKASGGTFRGYHISWVRQAPGQGLEWM
GGIIHLFGTVSYAPKFQGRVTITADASTGTAHMELSSLTSDDTAIYYCAR
DAYEVWTGSYLPPFDYWGQGTLVTVSS
357 5699 2003 GTFRGYHIS
357 5700 2004 GGCACCTTCAGAGGCTACCATATCAGC
357 5701 2005 GIIHLFGTVSYAPKFQG
357 5702 2006 GGGATCATCCATCTATTTGGGACAGTAAGCTACGCTCCGAAGTTCCAG
GGC
357 5703 2007 ARDAYEVWTGSYLPPFDY
357 5704 2008 GCGAGAGATGCTTACGAAGTCTGGACGGGTTCTTATCTCCCCCCTTTT
GACTAC
357 5705 2009 GATATTGTGATGACTCAGACTCCAGGCACCCTGTCTTTGTCTCCCGGG
GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACAAGCAG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCT
CATCTATGGTGCATTCACCAGGGCCACTGGCATCCCAGACAGGTTCA
GTGGTAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG
GAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGCTCA
TTCCTCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA
357 5706 2010 DIVMTQTPGTLSLSPGERVTLSCRASQTVTSSYLAWYQQKPGQAPRLLIY
GAFTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFLTFGG
GTKLEIK
357 5707 2011 RASQTVTSSYLA
357 5708 2012 AGGGCCAGTCAGACTGTTACAAGCAGCTACTTAGCC
357 5709 2013 GAFTRAT
357 5710 2014 GGTGCATTCACCAGGGCCACT
357 5711 2015 QQYGSSFLT
357 5712 2016 CAGCAGTATGGTAGCTCATTCCTCACT
358 5713 2017 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA
TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAG
TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CTGTGCGAGAGATGTGCAATATAGTGGCTACGATTCTGGGTACTACTT
TGACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA
358 5714 2018 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWV
SSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DVQYSGYDSGYYFDYWGQGTLVTVSS
358 5715 2019 FTFSSYSMN
358 5716 2020 TTCACCTTCAGTAGCTATAGCATGAAC
358 5717 2021 SISSSSSYIYYADSVKG
358 5718 2022 TCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAGTGAAG
GGC
358 5719 2023 ARDVQYSGYDSGYYFDY
358 5720 2024 GCGAGAGATGTGCAATATAGTGGCTACGATTCTGGGTACTACTTTGAC
TAC
358 5721 2025 CAGCCTGTGCTGACTCAGCCACCCTCAGTGTCTGGGGCCCCAGGACA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA
CTCCTCATCTATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGCCTGAGTGCCCTTTATGTCTTCGGAACTGGGACCAAGGTGACCGTC
CTA
358 5722 2026 QPVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLI
YGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSAL
YVFGTGTKVTVL
358 5723 2027 TGSSSNIGAGYDVH
358 5724 2028 ACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACAC
358 5725 2029 GNSNRPS
358 5726 2030 GGTAACAGCAATCGGCCCTCA
358 5727 2031 QSYDSSLSALYV
358 5728 2032 CAGTCCTATGACAGCAGCCTGAGTGCCCTTTATGTC
359 5729 2033 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCGGGGG
GGTCCCTGAGACTCTCCTGTGCAGGCTCTGGATTCGCCTTCGGTAGCT
TCGCGATGCACTGGGTCCGTCAGGCTCCAGGCAAGGGGCTGGAGTGG
GTGGCTGTTATTTCATTTGACGGAAAGAATACAAAATATGCTGACTCC
GTGAAGGGCCGATTCACCACCTCCAGAGACAATTCCAGGAACACGCT
CTATCTCCAAATGGACAGCCTGAGAGGTGACGACACGGCTATATATT
ACTGCGCGACAATTAGGGGAATTGTGGCTGGCCTTTGTGACAACTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCA
359 5730 2034 EVQLVESGGGVVQPGGSLRLSCAGSGFAFGSFAMHWVRQAPGKGLEWV
AVISFDGKNTKYADSVKGRFTTSRDNSRNTLYLQMDSLRGDDTAIYYCA
TIRGIVAGLCDNWGQGTLVTVSS
359 5731 2035 FAFGSFAMH
359 5732 2036 TTCGCCTTCGGTAGCTTCGCGATGCAC
359 5733 2037 VISFDGKNTKYADSVKG
359 5734 2038 GTTATTTCATTTGACGGAAAGAATACAAAATATGCTGACTCCGTGAA
GGGC
359 5735 2039 ATIRGIVAGLCDN
359 5736 2040 GCGACAATTAGGGGAATTGTGGCTGGCCTTTGTGACAAC
359 5737 2041 CAGCCTGTGCTGACTCAATCATCGTCTGACTCTGCTTCCCTGGGAGCC
TCGGTCAAGCTCACCTGTACTCTGAGCAGTGGCCACAGAAACTACAT
CATCGCATGGCATCAACAACAACCAGGGAAGGCCCCTCGGTTCCTGA
TGAAGGTTGAAGGTAGTGGAAGCTTCACCATGGGGAGCGGAGTTCCT
GATCGCTTCTCGGGCTCCAGCTCTGGGGCTGACCGCTACCTCACCATC
TCCAACCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGAGGCCTGG
GACTTTAACACGGGGGGGGTCTTCGGCGGAGGCACCCAGCTGACCGT
CCTC
359 5738 2042 QPVLTQSSSDSASLGASVKLTCTLSSGHRNYIIAWHQQQPGKAPRFLMKV
EGSGSFTMGSGVPDRFSGSSSGADRYLTISNLQSEDEADYYCEAWDFNT
GGVFGGGTQLTVL
359 5739 2043 TLSSGHRNYIIA
359 5740 2044 ACTCTGAGCAGTGGCCACAGAAACTACATCATCGCA
359 5741 2045 VEGSGSFTMGS
359 5742 2046 GTTGAAGGTAGTGGAAGCTTCACCATGGGGAGC
359 5743 2047 EAWDFNTGGV
359 5744 2048 GAGGCCTGGGACTTTAACACGGGGGGGGTC
360 5745 2049 GAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGG
GACCCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCGTCGGTAG
TGACTGGTGGAGTTGGATCCGCCAGCCCCCCGGGAAGGGGCTGGAGT
GGATTGGAGATATCTATCATGGTGGGACCACCAGCTACAACCCGTCC
CTTAAGAGTCGAGTCACCATGTCAGTAGACAAGTCCAAGAACCAATT
CTCCCTGAAGCTGACCTCTGTCACCGCCGCGGACACAGCCGTGTATTA
CTGTGCGAGACTCTCGGGAAATTGTAGTGGTGGTAGCTGTTACTCGCC
CTTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA
360 5746 2050 EVQLVESGPGLVKPSGTLSLTCAVSGDSIVGSDWWSWIRQPPGKGLEWI
GDIYHGGTTSYNPSLKSRVTMSVDKSKNQFSLKLTSVTAADTAVYYCAR
LSGNCSGGSCYSPFDHWGQGTLVTVSS
360 5747 2051 DSIVGSDWWS
360 5748 2052 GACTCCATCGTCGGTAGTGACTGGTGGAGT
360 5749 2053 DIYHGGTTSYNPSLKS
360 5750 2054 GATATCTATCATGGTGGGACCACCAGCTACAACCCGTCCCTTAAGAGT
360 5751 2055 ARLSGNCSGGSCYSPFDH
360 5752 2056 GCGAGACTCTCGGGAAATTGTAGTGGTGGTAGCTGTTACTCGCCCTTT
GACCAC
360 5753 2057 GACATCCAGATGACCCAGTCTCCATCCTCCTTGTCTGCATCTGTGGGA
GACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTAATGGTTA
TTTAAATTGGTATCAACAAAGACCAGGGAAAGCCCCTAAACTCCTGA
TCTCTGCTGCATCCAGTTTGCAGAGTGGGGTCCCATCAAGGTTCCGTG
GCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAA
CCTGAAGATTTTGCAACTTATTTCTGTCAACAGAGTTACAATACTGTG
TACACTTTTGGGCAGGGGACCAAAGTGGATATCAAA
360 5754 2058 DIQMTQSPSSLSASVGDRVTITCRASQTINGYLNWYQQRPGKAPKLLISA
ASSLQSGVPSRFRGSGYGTDFTLTISSLQPEDFATYFCQQSYNTVYTFGQG
TKVDIK
360 5755 2059 RASQTINGYLN
360 5756 2060 CGGGCAAGTCAGACCATTAATGGTTATTTAAAT
360 5757 2061 AASSLQS
360 5758 2062 GCTGCATCCAGTTTGCAGAGT
360 5759 2063 QQSYNTVYT
360 5760 2064 CAACAGAGTTACAATACTGTGTACACT
361 5761 2065 CAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGCT
ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG
ATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCG
CTCCAAGGCCAGGTCACCATCTCAGGCGACAAGTCCATCAGTACCGC
CTTCCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT
ACTGTGCGAGACCCATGACTACCCAAGAAGGTTTTGATTTGTGGGGC
CAAGGGACAATGGTCACCGTCTCTTCA
361 5762 2066 QVQLVQSGAEVKKPGESLKISCKGSGYSFSSYWIGWVRQMPGKGLEWM
GIIYPGDSDTRYSPSLQGQVTISGDKSISTAFLQWSSLKASDTAMYYCARP
MTTQEGFDLWGQGTMVTVSS
361 5763 2067 YSFSSYWIG
361 5764 2068 TACAGCTTTAGCAGCTACTGGATCGGC
361 5765 2069 IIYPGDSDTRYSPSLQG
361 5766 2070 ATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCGCTCCAA
GGC
361 5767 2071 ARPMTTQEGFDL
361 5768 2072 GCGAGACCCATGACTACCCAAGAAGGTTTTGATTTG
361 5769 2073 GACATCCGGTTGACCCAGTCTCCATCTTCTGTGTCTGCATCTGTAGGA
GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCGACTG
GTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGA
TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG
GCAGTGGATCTGGGACAGATTTCACTCTCACTATCAGCAGCCTGCAGC
CTGAAGATTTTGCAACTTACTATTGTCAACAGACTAACAGTTTCCTCC
CGCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA
361 5770 2074 DIRLTQSPSSVSASVGDRVTITCRASQGISDWLAWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTNSFLPLTFGG
GTKVDIK
361 5771 2075 RASQGISDWLA
361 5772 2076 CGGGCGAGTCAGGGTATTAGCGACTGGTTAGCC
361 5773 2077 AASSLQS
361 5774 2078 GCTGCATCCAGTTTGCAAAGT
361 5775 2079 QQTNSFLPLT
361 5776 2080 CAACAGACTAACAGTTTCCTCCCGCTCACT
362 5777 2081 GAGGTGCAGCTGGTGGAGTCGGGCCCCCGACTGGTGAAGCCTTCACA
GACCCTGTCCCTCACCTGCACCGTCTATGGTGGCTCCATCAGCGGTGG
TCAAAACTACTACAGTTGGGTCCGCCAGCCCCCAGGGAAGGGCCTGG
AGTGGATTGGGTACATCTTTTCCAGTGGGACCACCTACTACAAGCCGT
CCCTCAAGAGTCGAATTTCCATTTCATTTGACACGTCCAAGAACCAGT
TCTCCCTGAACCTGGCCTCTGTGACGGCCGCAGACACGGCCGTATATT
TCTGTGCCAGATCCGCTGACATTGATATCGTTTGGGGGAGTTCTCTCT
ACATGCCTCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
362 5778 2082 EVQLVESGPRLVKPSQTLSLTCTVYGGSISGGQNYYSWVRQPPGKGLEW
IGYIFSSGTTYYKPSLKSRISISFDTSKNQFSLNLASVTAADTAVYFCARSA
DIDIVWGSSLYMPLWGQGTLVTVSS
362 5779 2083 GSISGGQNYYS
362 5780 2084 GGCTCCATCAGCGGTGGTCAAAACTACTACAGT
362 5781 2085 YIFSSGTTYYKPSLKS
362 5782 2086 TACATCTTTTCCAGTGGGACCACCTACTACAAGCCGTCCCTCAAGAGT
362 5783 2087 ARSADIDIVWGSSLYMPL
362 5784 2088 GCCAGATCCGCTGACATTGATATCGTTTGGGGGAGTTCTCTCTACATG
CCTCTC
362 5785 2089 GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGA
CAAAGAGCCACCCTCTCCTGCAGGGCCACTCACATTGTCAGTAACAG
CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT
CATCCATGGTGTTTCCATCAGGGCCACTGGCATCCCAGACAGGTTCTC
TGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG
AGCCTGAAGATTTTGCAGTGTATTTCTGTCAGCAGTATGGTACCTCAC
CGTGGACGTTCGGCCAAGGGACCAAGCTGGAGATCAAA
362 5786 2090 EIVLTQSPGTLSLSPGQRATLSCRATHIVSNSYLAWYQQKPGQAPRLLIHG
VSIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYGTSPWTFGQG
TKLEIK
362 5787 2091 RATHIVSNSYLA
362 5788 2092 AGGGCCACTCACATTGTCAGTAACAGCTACTTAGCC
362 5789 2093 GVSIRAT
362 5790 2094 GGTGTTTCCATCAGGGCCACT
362 5791 2095 QQYGTSPWT
362 5792 2096 CAGCAGTATGGTACCTCACCGTGGACG
363 5793 2097 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGG
GTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTTACCTTCAGCAGTTA
TGCCATGAATTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGACTGGG
TCTCCTCTATCAGTGCTGGTAGCAATTTCATAGACGACGCAGACTCAG
TGAAGGGCCGCTTCACCATCTCCAGAGACAACGCCAGGAACTCACTG
TTTCTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA
CTGTGCGAGAATTGGGTACAGTAGCGCGCACCACTACCAGTACTACA
TGGACGTCTGGGGCACGGGGACCACGGTCACCGTCTCCTCA
363 5794 2098 QVQLVESGGGLVKPGGSLRLSCVASGFTFSSYAMNWVRQAPGKGLDWV
SSISAGSNFIDDADSVKGRFTISRDNARNSLFLQMNSLRAEDTAVYYCARI
GYSSAHHYQYYMDVWGTGTTVTVSS
363 5795 2099 FTFSSYAMN
363 5796 2100 TTTACCTTCAGCAGTTATGCCATGAAT
363 5797 2101 SISAGSNFIDDADSVKG
363 5798 2102 TCTATCAGTGCTGGTAGCAATTTCATAGACGACGCAGACTCAGTGAA
GGGC
363 5799 2103 ARIGYSSAHHYQYYMDV
363 5800 2104 GCGAGAATTGGGTACAGTAGCGCGCACCACTACCAGTACTACATGGA
CGTC
363 5801 2105 CAGTCTGTCCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGCAGCAGCTCCAACATCGGGGCAG
GTTATGATGTCCACTGGTACCAGGATCTTCCAGGAACTGCCCCCAAAC
TCCTCATCTATGGTAACACCAATCGGCCCTCAGGGGTCCCTGACCGAT
TCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCCCTGGTCATCACTGGGC
TCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAAG
AGCCTGAGTGGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGT
CCTA
363 5802 2106 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQDLPGTAPKLLI
YGNTNRPSGVPDRFSGSKSGASASLVITGLQAEDEADYYCQSYDKSLSG
GYVFGTGTKVTVL
363 5803 2107 TGSSSNIGAGYDVH
363 5804 2108 ACTGGCAGCAGCTCCAACATCGGGGCAGGTTATGATGTCCAC
363 5805 2109 GNTNRPS
363 5806 2110 GGTAACACCAATCGGCCCTCA
363 5807 2111 QSYDKSLSGGYV
363 5808 2112 CAGTCCTATGACAAGAGCCTGAGTGGTGGGTATGTC
364 5809 2113 CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
CTCAGTGAGGGTCACCTGCAAGGCCTCTGGATACACCTTCACCGACTA
CTTTATGAACTGGGTGCGACAGGCCCCTGGAGGGGGCCTTGAGTGGA
TGGGGTGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAG
TTTCAGGGCAGTGTCACCATGACCACTGACACGTCCATCACCACAGG
CTACATGGAGCTGAGGAGCCTGAGAGTTGACGACACGGCCGTCTATT
ATTGTGCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTCT
GGGGCCAAGGGACCACGGTCACCGTCTCTTCA
364 5810 2114 QVQLVQSGAEVKKPGASVRVTCKASGYTFTDYFMNWVRQAPGGGLEW
MGWINPLSGVTKYAQQFQGSVTMTTDTSITTGYMELRSLRVDDTAVYY
CASQSSPYTPGAMGVWGQGTTVTVSS
364 5811 2115 YTFTDYFMN
364 5812 2116 TACACCTTCACCGACTACTTTATGAAC
364 5813 2117 WINPLSGVTKYAQQFQG
364 5814 2118 TGGATCAATCCTCTCAGTGGAGTCACAAAATATGCACAGCAGTTTCA
GGGC
364 5815 2119 ASQSSPYTPGAMGV
364 5816 2120 GCGAGCCAGTCTTCCCCTTACACCCCGGGCGCCATGGGCGTC
364 5817 2121 TCCTATGAGCTGATACAGCTACCCTCGGTGTCAGTGTCCCCAGGACAG
ACGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAAGCAATATGC
TTATTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTGATAT
ATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGC
TCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGC
AGAAGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGTA
CTTATCCGGTGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA
364 5818 2122 SYELIQLPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKD
SERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTYPVVFG
GGTKLTVL
364 5819 2123 SGDALPKQYAY
364 5820 2124 TCTGGAGATGCATTGCCAAAGCAATATGCTTAT
364 5821 2125 KDSERPS
364 5822 2126 AAAGACAGTGAGAGGCCCTCA
364 5823 2127 QSADSSGTYPVV
364 5824 2128 CAATCAGCAGACAGCAGTGGTACTTATCCGGTGGTG
365 5825 2129 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31382) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5826 2130 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
5827 2131 FSFRSYSMN
5828 2132 SISSSSNYINYADSVKG
5829 2133 ARDLLPVERGPAFDI
5830 2134 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5831 2135 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIY
ANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV
FGGGTKVTVL
5832 2136 TGSSSNIGRGYDVH
5833 2137 ANSNRPS
5834 2138 QSYDSRLGGSV
366 5835 2139 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31383) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5836 2140 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
5837 2141 FSFRSYSMN
5838 2142 SISSSSNYINYADSVKG
5839 2143 ARDLLPVERGPAFDI
5840 2144 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5841 2145 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
NFGGGTKVTVL
5842 2146 TGSSSNIGAGYDVH
5843 2147 RNSNRPS
5844 2148 QSYDSRLGGSN
367 5845 2149 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31384) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5846 2150 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
5847 2151 FSFRSYSMN
5848 2152 SISASSNYINYADSVKG
5849 2153 ARDLLPVERGPAFDI
5850 2154 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5851 2155 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
VFGGGTKVTVL
5852 2156 TGSSSNIGAGYDVH
5853 2157 ANSNRPS
5854 2158 QSYDSRLGGSV
368 5855 2159 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31385) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5856 2160 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLSPVERGPAFDIWGQGTMVTVSS
5857 2161 FSFRSYSMN
5858 2162 SISSSSTYINYADSVKG
5859 2163 ARDLSPVERGPAFDI
5860 2164 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5861 2165 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
VFGGGTKVTVL
5862 2166 TGSSSNIGAGYDVH
5863 2167 ANSNRPS
5864 2168 QSYDSRLGGSV
369 5865 2169 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31345) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5866 2170 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
5867 2171 FSFRSYSMN
5868 2172 SISASSNYINYADSVKG
5869 2173 ARDLLPVERGPAFDI
5870 2174 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5871 2175 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIY
ANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV
FGGGTKVTVL
5872 2176 TGSSSNIGRGYDVH
5873 2177 ANSNRPS
5874 2178 QSYDSRLGGSV
370 5875 2179 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31346) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTGCTAGTAGTAATTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGTTACCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5876 2180 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISASSNYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLLPVERGPAFDIWGQGTMVTVSS
5877 2181 FSFRSYSMN
5878 2182 SISASSNYINYADSVKG
5879 2183 ARDLLPVERGPAFDI
5880 2184 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5881 2185 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
NFGGGTKVTVL
5882 2186 TGSSSNIGAGYDVH
5883 2187 RNSNRPS
5884 2188 QSYDSRLGGSN
371 5885 2189 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31354) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5886 2190 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLSPVERGPAFDIWGQGTMVTVSS
5887 2191 FSFRSYSMN
5888 2192 SISSSSTYINYADSVKG
5889 2193 ARDLSPVERGPAFDI
5890 2194 TCCTACGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACTATCTCCTGCACTGGGAGCAGCTCCAACATCGGGAGGG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATGCTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGGTATTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5891 2195 SYELTQPPSVSGAPGQRVTISCTGSSSNIGRGYDVHWFQQLPGAAPKLLIY
ANSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGSV
FGGGTKVTVL
5892 2196 TGSSSNIGRGYDVH
5893 2197 ANSNRPS
5894 2198 QSYDSRLGGSV
372 5895 2199 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
(ADI- GGCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTCAGGAGCTA
31362) TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG
TCTCATCCATTAGTAGTAGTAGTACTTACATAAACTACGCAGACTCAG
TGAAGGGCCGATTCAGCATCTCCAGAGACAACGCCAAGAACTCACTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA
CTGTGCGAGAGATTTGAGTCCCGTCGAGCGGGGTCCCGCTTTTGATAT
CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
5896 2200 EVQLVESGGGLVKPGGALRLSCAASGFSFRSYSMNWVRQAPGKGLEWV
SSISSSSTYINYADSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAR
DLSPVERGPAFDIWGQGTMVTVSS
5897 2201 FSFRSYSMN
5898 2202 SISSSSTYINYADSVKG
5899 2203 ARDLSPVERGPAFDI
5900 2204 TCCTATGAGCTGACACAGCCACCCTCAGTGTCTGGGGCCCCAGGGCA
GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG
GTTATGATGTACACTGGTTCCAGCAGCTTCCAGGAGCAGCCCCCAAA
CTCCTCATCTATCGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA
TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG
CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC
AGACTGGGTGGTTCGAATTTCGGCGGAGGGACCAAGGTGACCGTCCT
A
5901 2205 SYELTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWFQQLPGAAPKLLI
YRNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSRLGGS
NFGGGTKVTVL
5902 2206 TGSSSNIGAGYDVH
5903 2207 RNSNRPS
5904 2208 QSYDSRLGGSN
Additional Embodiments Embodiment 1. An isolated antibody or an antigen-binding fragment thereof that specifically binds to Respiratory Syncytial Virus (RSV) F protein (F), wherein at least one of the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and CDRL3 amino acid sequence of the antibody or the antigen-binding fragment thereof is at least 70% o identical; at least 7500 identical; 80% o identical; at least 8500 identical; at least 90% o identical; at least 9500 identical; at least 96% o identical; at least 970% identical; at least 98% o identical; at least 990%; and/or all percentages of identity in between; to at least one the CDRH1, a CDRH2, a CDRH3, a CDRL1, a CDRL2, and/or a CDRL3 amino acid sequences as disclosed in Table 6 of an antibody selected from Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and wherein said antibody or the antigen-binding fragment thereof also has one or more of the following characteristics:
a) the antibody or antigen-binding fragment thereof cross-competes with said antibody ar antigen-binding fragment thereof for binding to RSV-F;
b) the antibody or antigen-binding fragment thereof displays better binding affinity for the PreF form of RSV-F relative to the PostF form;
c) the antibody or antigen-binding fragment thereof displays a clean or low polyreactivity profile;
d) the antibody or antigen-binding fragment thereof displays neutralization activity toward RSV subtype A and RSV subtype B in vitro;
e) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F at Site Ø, Site I, Site II, Site III, Site IV, or Site V;
f) the antibody or antigen-binding fragment thereof displays antigenic site specificity for RSV-F Site Ø, Site V, or Site III relative to RSV-F Site I, Site II, or Site IV;
g) at least a portion of the epitope with which the antibody or antigen-binding fragment thereof interacts comprises the α3 helix and β3/β4 hairpin of PreF;
h) the antibody or antigen-binding fragment thereof displays an in vitro neutralization potency (IC50) of between about 0.5 microgram/milliliter (ug/ml) to about 5 ug/ml; between about 0.05 ug/ml to about 0.5 ug/ml; or less than about 0.05 mg/ml;
i) the binding affinity and/or epitopic specificity of the antibody or antigen-binding fragment thereof for any one of the RSV-F variants designated as 1, 2, 3, 4, 5, 6, 7, 8, 9, and DG in FIG. 7A is reduced or eliminated relative to the binding affinity and/or epitopic specificity of said antibody or antigen-binding fragment thereof for the RSV-F or RSV-F DS-Cav1;
j) the antibody or antigen-binding fragment thereof of displays a cross-neutralization potency (IC50) against human metapneumovirus (HMPV);
k) the antibody or antigen-binding fragment thereof does not complete with D25, MPE8, palivisumab, motavizumab, or AM-14; or
l) the antibody or antigen-binding fragment thereof displays at least about 2-fold; at least about 3-fold; at least about 4-fold; at least about 5-fold; at least about 6-fold; at least about 7-fold; at least about 8-fold; at least about 9-fold; at least about 10-fold; at least about 15-fold; at least about 20-fold; at least about 25-fold; at least about 30-fold; at least about 35-fold; at least about 40-fold; at least about 50-fold; at least about 55-fold; at least about 60-fold; at least about 70-fold; at least about 80-fold; at least about 90-fold; at least about 100-fold; greater than about 100-fold; and folds in between any of the foregoing; greater neutralization potency (IC50) than D25 and/or palivizumab.
Embodiment 2. The isolated antibody or antigen-binding fragment thereof of Embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises: at least two; at least three; at least 4; at least 5; at least 6; at least 7; at least 8; at least 9; at least 10; at least 11; or at least 12; of characteristics a) through 1).
Embodiment 3. The isolated antibody or antigen-binding fragment thereof of Embodiment 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises:
a) the CDRH3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6;
b) the CDRH2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6;
c) the CDRH1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6;
d) the CDRL3 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6;
e) the CDRL2 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6;
f) the CDRL1 amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; or
g) any combination of two or more of a), b), c), d), e), and f).
Embodiment 4. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 3, wherein the antibody or antigen-binding fragment thereof comprises:
a) a heavy chain (HC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6; and/or
b) a light chain (LC) amino acid sequence of any one of the antibodies designated Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
Embodiment 5. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 4, wherein the antibody is selected from the group consisting antibodies that are at least 70% identical; at least 75% identical; 80% identical; at least 85% identical; at least 90% identical; at least 95% identical; at least 96% identical; at least 97% identical; at least 98% identical; at least 99%; and/or all percentages of identity in between; to any one of the antibodies designated as Antibody Number 232 through Antibody Number 372 as disclosed in Table 6.
Embodiment 6. The isolated antibody or antigen-binding fragment thereof of any one of Embodiments 1 through 5, wherein the antibody is selected from the group consisting of the antibodies designated as Antibody 232 through Antibody Number 372 as disclosed in Table 6.
Embodiment 7. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment thereof according to any one of Embodiments 1 through 6.
Embodiment 8. An expression vector comprising the isolated nucleic acid sequence according to Embodiment 7.
Embodiment 9. A host cell transfected, transformed, or transduced with the nucleic acid sequence according to Embodiment 7 or the expression vector according to Embodiment 8.
Embodiment 10. A pharmaceutical composition comprising: one or more of the isolated antibodies or antigen-binding fragments thereof according to any one of Embodiments 1 through 6; and a pharmaceutically acceptable carrier and/or excipient.
Embodiment 11. A pharmaceutical composition comprising: one or more nucleic acid sequences according to Embodiment 7; or one or more the expression vectors according to Embodiment 8; and a pharmaceutically acceptable carrier and/or excipient.
Embodiment 12. A transgenic organism comprising the nucleic acid sequence according to Embodiment 7; or the expression vector according to Embodiment 8.
Embodiment 13. A method of treating or preventing a Respiratory Syncytial Virus (RSV) infection, ar at least one symptom associated with RSV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:
a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;
b) a nucleic acid sequences according to Embodiment 7;
c) an expression vector according to Embodiment 8;
d) a host cell according to Embodiment 9; or
e) a pharmaceutical composition according Embodiment 10 or Embodiment 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
Embodiment 14. A method of treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, ar at least one symptom associated with said RSV infection or said HMPV infection, comprising administering to a patient in need thereof or suspected of being in need thereof:
a) one or more antibodies or antigen-binding fragments thereof according to any of Embodiments 1 through 6;
b) a nucleic acid sequences according to Embodiment 7;
c) an expression vector according to Embodiment 8;
d) a host cell according to Embodiment 9; or
e) a pharmaceutical composition according Embodiment 10 or Embodiment 11; such that the RSV infection is treated or prevented, or the at least on symptom associated with RSV infection is treated, alleviated, or reduced in severity.
Embodiment 15. The method according to Embodiment 14, wherein the one or more antibodies or antigen-binding fragments thereof comprises Antibody Number 340.
Embodiment 16. The method according to any one of Embodiments 13 through 15, wherein the method further comprises administering to the patient a second therapeutic agent.
Embodiment 17. The method according to Embodiment 16, wherein the second therapeutic agent is selected group consisting of: an antiviral agent; a vaccine specific for RSV, a vaccine specific for
influenza virus, or a vaccine specific for metapneumovirus (MPV); an siRNA specific for an RSV antigen or a metapneumovirus (MPV) antigen; a second antibody specific for an RSV antigen or a metapneumovirus (MPV) antigen; an anti-IL4R antibody, an antibody specific for an influenza virus antigen, an anti-RSV-G antibody and a NSAID.
Embodiment 18. A pharmaceutical composition comprising any one or more of the isolated antibodies or antigen-binding fragments thereof of any one of Embodiments 1 through 7 and a pharmaceutically acceptable carrier and/or excipient.
Embodiment 19. The pharmaceutical composition according to Embodiment 18 for use in preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof or suspected of being in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
Embodiment 20. The pharmaceutical composition according to Embodiment 18 for us in treating or preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
Embodiment 21. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing a respiratory syncytial virus (RSV) infection in a patient in need thereof, or for treating a patient suffering from an RSV infection, or for ameliorating at least one symptom or complication associated with the infection, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration.
Embodiment 22. Use of the pharmaceutical composition of Embodiment 18 in the manufacture of a medicament for preventing either a Respiratory Syncytial Virus (RSV) infection or a human metapneumovirus (HMPV) infection, or at least one symptom associated with said RSV infection or said HMPV infection, in a patient in need thereof or suspected of being in need thereof, wherein the infection is either prevented, or at least one symptom or complication associated with the infection is prevented, ameliorated, or lessened in severity and/or duration as a result of such use.
