Abstract: The present invention provides conjugates between erythropoietin and PEG moieties. The conjugates are linked via an intact glycosyl linking group interposed between and covalently attached to the peptide and the modifying group. The conjugates are formed from glycosylated peptides by the action of a glycosyltransferase. The glycosyltransferase ligates a modified sugar moiety onto a glycosyl residue on the peptide. Also provided are methods for preparing the conjugates, methods for treating various disease conditions with the conjugates, and pharmaceutical formulations including the conjugates.

Abstract: The present invention relates to a method of carbamylating an erythropoietin such that the resulting carbamylated erythropoietin has less that about 10% free primary amines on the lysines and the N-terminal amino acids, is not digested when exposed to Lys-C proteolysis, exhibits no erythropoietic activity in a TF-1 or UT-7/EPOR cell viability assay at a concentration of 1 ?g/ml, and demonstrates a static sciatic index of less than about 0.65 within a Sciatic Nerve Assay. Additionally, the invention is related to pharmaceutical compositions containing carbamylated erythropoietins of the invention and the use of the pharmaceutical compositions for the treatment of conditions and diseases of excitable tissues.

Abstract: The present invention provides conjugates between erythropoietin and PEG moieties. The conjugates are linked via an intact glycosyl linking group interposed between and covalently attached to the peptide and the modifying group. The conjugates are formed from glycosylated peptides by the action of a glycosyltransferase. The glycosyltransferase ligates a modified sugar moiety onto a glycosyl residue on the peptide. Also provided are methods for preparing the conjugates, methods for treating various disease conditions with the conjugates, and pharmaceutical formulations including the conjugates.

Abstract: The present invention provides polypeptides that include an O-linked glycoconjugate in which a species such as a water-soluble polymer, a therapeutic agent of a biomolecule is covalently linked through an intact O-linked glycosyl residue to the polypeptide. The polypeptides of the invention include wild-type peptides and mutant peptides that include an O-linked glycosylation site that is not present in the wild-type peptide. Also provided are methods of making the peptides of the invention and methods, pharmaceutical compositions containing the peptides and methods of treating, ameliorating or preventing diseased in mammals by administering an amount of a peptide of the invention sufficient to achieve the desired response.

Abstract: Modified human four helical bundle (4HB) polypeptides and uses thereof are provided.

Abstract: Physiologically active PEG-GCSF conjugates having a formula as follows: are described, as well as compositions containing a mixture of each conjugates in which m and n can be different integers for the conjugates in the composition.

Abstract: The present invention provides sequon polypeptides with an amino acid sequence including one or more exogenous O-linked glycosylation sequence of the invention. In addition, the present invention provides methods of making polypeptide conjugates as well as methods of using such conjugates and their pharmaceutical compositions. The invention further provides libraries of sequon polypeptides, wherein each member of such library includes at least one exogenous O-linked glycosylation sequence of the invention. Also provided are methods of making and using such libraries.

Abstract: The present invention relates to conjugates of hydroxyalkyl starch and a granulocyte colony stimulating factor protein (G-CSF) wherein these conjugates are formed by a covalent linkage between the hydroxyalkyl starch or a derivative of the hydroxyalkyl starch and the protein. The present invention also relates to the methods of producing these conjugates and the use of these conjugates.

Abstract: This invention provides VEGF-FSH compounds having increased serum half-lives relative to either native VEGF or FSH, in which both VEGF and FSH are biologically active. This invention also provides related compositions and methods for increasing fertility, egg production and spermatogenesis in a subject, as well as methods for increasing vascularization in a tissue, particularly in ovarian tissue.

Abstract: Forms of differentially acting glycoprotein hormones are disclosed. These compositions are of the formula ?1-(linker1)m-?-(linker2)n-?2;??(1) ?1-(linker1)m-?2-(linker2)n-?;??(2) ?-(linker1)m-?1-(linker2)n-?2;??(3) ?2??-(linker)m-?1; or??(4) ?1-(linker)m-???2??(5) wherein each of ?1 and ?2 has the amino acid sequence of the ? subunit of a vertebrate glycoprotein hormone or a variant of said amino acid sequence, as variants are defined herein. “?” designates the ? subunit of a vertebrate glycoprotein hormone or a variant thereof, “linker” refers to a covalently linked moiety that spaces the ?1 and ?2 subunits at appropriate distances from the ? subunit and from each other. “?” is a noncovalent link. Each of m and n is independently 0 or 1.

Abstract: The present invention relates to EPO polypeptides and their uses, particularly for therapeutic or prophylactic treatment in human subjects. The invention also relates to nucleic acids encoding said polypeptides, vectors comprising such nucleic acids and recombinant cells containing the same. The invention further discloses methods of producing such polypeptides, as well as methods and tools for detecting or dosing these polypeptides in any sample.

Abstract: The present invention provides a method of providing acute neuroprotection by inducing the erythropoietin (EPO) signaling pathway in neuronal cells close to or subsequent to the time of excitatory insult; and inducing an insulin-like growth factor (IGF) signaling pathway in the neuronal cells close to or subsequent to the time of excitatory insult, thereby producing a synergistic acute neuroprotective effect in the neuronal cells. The invention also provides a method of preventing or reducing the severity of a neurologic condition in a subject by administering to the subject EPO or an active fragment or analog thereof at a dose of at most 2000 U/kg; and administering to the subject an IGF or an active fragment or analog thereof, thereby providing neuroprotection and preventing or reducing the severity of the neurologic condition.

Abstract: The present invention provides processes for the manufacturing of polypeptide conjugates. In particular, the invention provides methods for the purification of polypeptide conjugates, which include at least one polymeric modifying groups, such as a poly(alkylene oxide) moiety. Exemplary poly(alkylene oxide) moieties include poly(ethylene glycol) (PEG) and poly(propylene glycol). In an exemplary process, hydrophobic interaction chromatography (HIC) is used to resolve different glycoforms of glycoPEGylated polypeptides.

Abstract: In part, the present invention relates to a compound or polymer comprising a non-protein-binding moiety and at least one protein-binding group. The present invention relates to a method of screening compounds or polymers for the property of inhibiting protein aggregation in solution, a method of preparing a compound or polymer having the property of protein aggregation inhibition in solution, a method of classifying a compound or polymer as either inhibitory of protein aggregation in solution or not inhibitory of protein aggregation in solution, and to a method of determining the preferential binding coefficient, ?XP, of an additive in a protein solution. The present invention also relates to a method of suppressing or preventing aggregation of a protein in solution, a method of decreasing the toxicological risk associated with administering a protein to a mammal in need thereof, and a method of facilitating native folding of a recombinant protein in solution.

Abstract: The present invention relates to the elucidation of the role of erythropoietin and the erythropoietin receptor in the development and progression of certain solid tumors, including those found in breast, cervical, uterine, ovarian, prostate and brain cancer.

Abstract: The invention relates to a conjugate exhibiting interferon ? (IFNB) activity and comprising at least one first non-polypeptide moiety covalently attached to an IFNB polypeptide, the amino acid sequence of which differs from that of wildtype human IFNB in at least one introduced and at least one removed amino acid residue comprising an attachment group for said first non-polypeptide moiety. The first non-polypeptide moiety is e.g. a polymer molecule or a sugar moiety. The conjugate finds particular use in therapy. The invention also relates to a glycosylated variant of a parent IFNB polypeptide comprising at least one in vivo glycosylation site, wherein an amino acid residue of said parent polypeptide located close to said glycosylation site has been modified to obtain the variant polypeptide having an increased glycosylation as compared to the glycosylation of the parent polypeptide.

Abstract: Methods and kits are provided for assessing the ovarian reserve and predicting the ovarian response to fertility treatments in a female subject. The serum levels of MIS are shown to be positively correlated with the production and retrieval of mature oocytes and serve as prognostic indicators for the female response to fertility treatment. The MIS levels can be monitored prior to and during fertility treatment and are useful to adjust the timing and dosage of treatments in order to produce optimal outcome in individual patients, to avoid ovarian hyperstimulation, or to indicate cancellation of an unsuccessful treatment. MIS can also be administered to women to stimulate follicle development and to prevent depletion of ovarian reserve.

Abstract: The present invention provides an expression construct capable of producing high levels of erythropoietin in mammalian cells. More particularly, the expression construct includes an erythropoietin coding region fused to a unique 5?-UTR sequence and a truncated 3?-UTR. The present invention also provides methods of synthesizing large amounts of erythropoietin and in increasing serum erythropoietin level in individuals in need thereof.

Abstract: The present invention provides a manufacturing method for polypeptides that are produced in insect cells using a baculoviral expression system. In one example, the insect cell culture is supplemented with a lipid mixture immediately prior to infection (e.g., one hour prior to infection). The polypeptides are isolated from the insect cell culture using a method that employs anion exchange or mixed-mode chromatography early in the purification process. This process step is useful to remove insect-cell derived endoglycanases and proteases and thus reduces the loss of desired polypeptide due to enzymatic degradation. In another example, mixed-mode chromatography is combined with dye-ligand affinity chromatography in a continuous-flow manner to allow for rapid processing of the insect-cell culture liquid and capture of the polypeptide.

Abstract: The invention provides compositions and methods of identifying, modifying and producing modified target molecules, including therapeutic molecules by modification with non-natural amino acids. Certain aspects of the invention include methods of adding a chemical moiety to a target molecule, and the compositions resulting therefrom. Certain aspects of the invention also relate to kits for identifying, modifying and producing modified target molecules described herein.

Abstract: Methods and compositions are provided for protecting or enhancing excitable tissue function in mammals by systemic administration of an erythropoietin receptor activity modulator, such as erythropoietin, which signals via an EPO-activated receptor to modulate the function of excitable tissue. Excitable tissues include central neuronal tissues, such as the brain, peripheral neuronal tissues, retina, and heart tissue. Protection of excitable tissues provides treatment of hypoxia, seizure disorders, neurodegenerative diseases, hypoglycemia, and neurotoxin poisoning. Enhancement of function is useful in learning and memory. The invention is also directed to compositions and methods for facilitating the transport of molecules across endothelial cell tight junction barriers, such as the blood-brain barrier, by association of molecules with an erythropoietin receptor activity modulator, such as an erythropoietin.

Abstract: The invention includes methods and compositions for remodeling a peptide molecule, including the addition or deletion of one or more glycosyl groups to a peptide, and/or the addition of a modifying group to a peptide.

Abstract: Compositions containing an N-linked oligosaccharide having little or no terminal sialic acid residues which is attached to a therapeutic protein that is bonded to a glycol polymer.

Abstract: The present invention provides a method for manufacturing a glycoprotein having a human-type sugar chain comprising a step in which transformed plant cell is obtained by introducing to a plant cell the gene of glycosyltransfetase and the gene of an exogenous glycoprotein, and a step in which the obtained transformed plant cell is cultivated.

Abstract: Methods and materials are provided for the production of compositions of erythropoietin protein, wherein said compositions comprise a pre-selected N-linked glycosylation pattern as the predominant N-glycoform.

Abstract: Use of human erythropoietin or a derivative thereof having the biological activity of human erythropoietin of increasing the expression of frataxin for the production of a pharmaceutical preparation for the treatment of Friedreich's ataxia or for the treatment or prevention of a disease associated therewith.

Abstract: The present invention relates to granulocyte colony-stimulating factor (“G-CSF”) hybrid molecules which retain the internal core helices of G-CSF. Also provided are pharmaceutical compositions containing hybrid molecules.

Abstract: Purified cartilage and/or bone inductive proteins and processes for producing them are disclosed. The proteins may be used in the treatment of bone and/or cartilage defects and in wound healing and related tissue repair.

Abstract: Novel ?10 polypeptides and heterodimers thereof, and nucleic acid molecules encoding the same are disclosed. The invention also provides vectors, host cells, selective binding agents, and methods for producing ?10 polypeptides and heterodimeric forms thereof, specifically ?2/?10. Also provided for are methods for the treatment, diagnosis, amelioration, or prevention of diseases with ?10 polypeptides and ?2/?10 heterodimers or their respective binding agents.

Abstract: Methods and compositions are provided for protecting or enhancing excitable tissue function in mammals by systemic administration of an erythropoietin receptor activity modulator, such as erythropoietin, which signals via an EPO-activated receptor to modulate the function of excitable tissue. Excitable tissues include central neuronal tissues, such as the brain, peripheral neuronal tissues, retina, and heart tissue. Protection of excitable tissues provides treatment of hypoxia, seizure disorders, neurodegenerative diseases, hypoglycemia, and neurotoxin poisoning. Enhancement of function is useful in learning and memory. The invention is also directed to compositions and methods for facilitating the transport of molecules across endothelial cell tight junction barriers, such as the blood-brain barrier, by association of molecules with an erythropoietin receptor activity modulator, such as an erythropoietin.

Abstract: Novel ?10 polypeptides and heterodimers thereof, and nucleic acid molecules encoding the same are disclosed. The invention also provides vectors, host cells, selective binding agents, and methods for producing ?10 polypeptides and heterodimeric forms thereof, specifically ?2/?10. Also provided for are methods for the treatment, diagnosis, amelioration, or prevention of diseases with ?10 polypeptides and ?2/?10 heterodimers or their respective binding agents.

Abstract: The inventors have designed novel FSH mutants with increased glycosylation and longer half-lives for use in inducing folliculogenesis in human patients. The use of a FSH mutant preparation of the invention permits the use of lower cumulative doses of FSH to achieve the same or better clinical result.

Abstract: The invention provides recombinant forms of piscine follicle-stimulating hormone (FSH) with characteristic intramolecular disulfide bonds and modified glycosylation patterns in the ?-subunit that enhance the stability and metabolic activity of the hormone. Also provided are recombinant materials to produce the FSH ? and glycoprotein ?-subunits singly or in combination to obtain complete heterodimeric hormone of regulated glycosylation pattern. The piscine FSH agonists of the invention are therapeutically useful to expedite the onset of puberty in captive fish and to alleviate reproductive dysfunctions in fish.

Abstract: Described are methods for identifying, selecting, and obtaining mammalian cells capable of producing proteinaceous molecules having predetermined post-translational modifications, wherein the post-translational modifications are brought about by the mammalian cell in which the proteinaceous molecule is expressed. Preferably, the predetermined post-translational modifications include glycosylation. Also described are methods for obtaining and producing proteinaceous molecules, using mammalian cells obtainable by a method of the present invention. Preferably, the proteinaceous molecules includes erythropoietin (EPO), since EPO's effect depends heavily on its glycosylation pattern. Mammalian cells that have been obtained on the basis of their ability to produce proteins and/or post-translational modifications that are indicative for a predetermined post-translational modification that is desired are also provided.

Abstract: Methods for increasing and maintaining hematocrit in a mammal comprising administering a hyperglycosylated analog of erythropoietin are disclosed. An analog may be administered less frequently than an equivalent molar amount of recombinant human erythropoietin to obtain a comparable target hematocrit and treat anemia. Alternatively, a lower molar amount of a hyperglycosylated analog may be administered to obtain a comparable target hematocrit and treat anemia. Also disclosed are new hyperglycosylated erythopoietin analogs, methods of production of the analogs, and compositions comprising the analogs.

Abstract: Erythropoietin (Epo), a member of the cytokine superfamily, is a pluripotent molecule that is involved in a number of signal transduction pathways that include the stimulation of the production of red blood cells and the protection of the central nervous system from acute injury and ischemia. The invention is the discovery of Epo and the Epo receptor in the peripheral nervous system where it can act as a neuroprotective agent. The invention is also a method of use for the treatment of neuropathic pain and to increase the rate of healing from nerve injury comprising administration of Epo.

Abstract: Method of increasing blood platelet formation by administering a parathyroid hormone (PTH) or at least one PTH derivative as an active ingredient.

Abstract: A conjugate of formula A-L-P, in which: A represents a glycosylated/galactosylated peptide that binds to a cell-surface receptor, L represents a bifunctional linker, which does not comprise a naturally occurring amino acid and is covalently bonded to A and P in a regiospecific manner, and P represents a monomer, homopolymer or heteropolymer comprising at least one nucleotide or an analogue thereof, which inhibits the intracellular biosynthesis of nucleotides or nucleic acids in a sequence-independent manner, wherein either or both of the covalent bond between A and L and the covalent bond between L and P can be cleaved intracellularly; a composition comprising such a conjugate; and a method of inhibiting abnormal cellular proliferation in a mammal; and a method of inhibiting replication of a virus in a mammal.

Abstract: The present invention broadly relates to the field of protein modification, and, more specifically, the attachment of water soluble polymers to novel erythropoietin stimulating protein (NESP).

Abstract: A polypeptide and polynucleotides encoding same comprising at least two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to an EPO peptide are disclosed. Pharmaceutical compositions comprising the polypeptide and polynucleotides of the invention and methods of using same are also disclosed.

Abstract: A polypeptide and polynucleotides encoding same comprising at least two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to a peptide-of-interest are disclosed. Pharmaceutical compositions comprising the polypeptide and polynucleotides of the invention and methods of using same are also disclosed.

Abstract: The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Abstract: Fc fusion proteins of human EPO with increased biological activities relative to rHuEPO on a molar basis are disclosed. The HuEPO-L-vFc fusion protein comprises HuEPO, a flexible peptide linker of about 20 or fewer amino acids, and a human IgG Fc variant. The Fc variant is of a non-lytic nature and shows minimal undesirable Fc-mediated side effects. A method is also disclosed to make or produce such fusion proteins at high expression levels. Such HuEPO-L-vFc fusion proteins exhibit extended serum half-life and increased biological activities, leading to improved pharmacokinetics and pharmacodynamics, thus fewer injections will be needed within a period of time.

Abstract: The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Abstract: Methods and kits are provided for assessing the ovarian reserve and predicting the ovarian response to fertility treatments in a female subject. The serum levels of MIS are shown to be positively correlated with the production and retrieval of mature oocytes and serve as prognostic indicators for the female response to fertility treatment. The MIS levels can be monitored prior to and during fertility treatment and are useful to adjust the timing and dosage of treatments in order to produce optimal outcome in individual patients, to avoid ovarian hyperstimulation, or to indicate cancellation of an unsuccessful treatment. MIS can also be administered to women to stimulate follicle development and to prevent depletion of ovarian reserve.

Abstract: The present invention provides new interferon ? conjugates, methods of preparing such conjugates and the use of such conjugates in therapy, in particular for the treatment of multiple sclerosis.

Abstract: Erythropoietin analogs having at least one additional site for glycosylation, or a rearrangement of at least one site for glycosylation are disclosed. The invention also relates to DNA sequences encoding said erythropoietin analogs, and recombinant plasmids and host cells for analog expression.

Abstract: The invention relates to novel modified erythropoietin (EPO) forms such as fusion proteins comprising a Fc portion of an Ig molecule and a target molecule having the biological activity of EPO. By selective altering of the amino acid sequences of the erythropoietin moiety as well as of the immunoglobulin moiety and the glycosylation pattern of erythropoietin fusion proteins with enhanced biological activity can be obtained. The invention relates also to novel nun-fused EPO molecules which have a pattern of cysteines or disulfide bonding which is distinct from human or animal EPO.

Abstract: The present invention relates to a liquid pharmaceutical composition consisting essentially of an erythropoietin protein, a multiple charged inorganic anion in a pharmaceutically acceptable buffer suitable to keep the solution pH in the range from about 5.5 to about 7.0, and optionally one or more pharmaceutically acceptable excipients. This composition is especially useful for the prophylaxis and treatment of diseases related to erythropoiesis.

Abstract: The present invention relates generally to the fields of immunology and molecular biology, and particularly to a method for treating hematopoietic disorders. The invention provides a method to treat a deficiency of one or more types of blood cells in a mammal, which includes administering an effective amount of TISF or of a compound that stimulates CD4+ cells like TISF does. In one embodiment, TISF that originates from a mammalian species is administered to a mammalian subject diagnosed as having a deficiency in one or more types of blood cells.