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: The present invention relates to a liquid pharmaceutical composition comprising 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 invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

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: 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: The present invention refers to conjugates of erythropoietin with poly(ethylene glycol) comprising an erythropoietin glycoprotein having an N-terminal ?-amino group and having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and selected from the group consisting of human erythropoietin and analogs thereof which have the sequence of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites or a rearrangement of at least one glycosylation site; said glycoprotein being covalently linked to one poly(ethylene glycol) group of the formula —CO—(CH2)x—(OCH2CH2)m—OR wherein the —CO of the poly(ethylene glycol) group forms an amide bond with said N-terminal ?-amino group; and wherein R is lower alkyl; x is 2 or 3; and m is from about 450 to about 1350.

Abstract: The present invention relates to a fusion protein having enhanced in vivo activity of erythropoietin wherein a carboxy terminal peptide fragment of thrombopoietin is fused with the carboxy terminal of human erythropoietin. This fusion protein has highly enhanced in vivo half-life due to increased carbohydrate content without loss of the inherent activity of erythropoietin, and does not cause any antigenicity when applied to the human body.

Abstract: Aspects of the present invention relate to nucleotide and amino acid sequences of oocyte factors for altering ovarian follicular growth in vivo or in vitro. The present invention also concerns novel homodimeric and heterodimeric polypeptides and their use for altering mammalian ovarian follicular growth in vivo or in vitro.

Abstract: Provided is a fusion protein comprising, at its carboxy terminal of human erythropoietin (EPO), a mutant having one to four amino acid substitutions in the carboxy terminal peptide (CTP) fragment of a human chorionic gonadotropin (HCG) ? subunit, for increasing an in vivo half-life activity of EPO. The in vivo half-life can be greatly elongated while retaining the intrinsic activity of the EPO, without increasing the sugar chain content.

Abstract: The invention discloses several novel therapeutic properties and methods of treatment using the recombinant erythropoietin prepared by expression from the Apa I restriction fragment of human genomic erythropoietin DNA transformed into baby hamster kidney cells (BHK) according to U.S. Pat. No. 5,688,697 to Powell. This recombinant erythropoietin designated herein as Epoetin Omega is shown to possesses several unexpected and superior qualities over other recombinant erythropoietins such as those designated Epoetin Alfa and Beta which are prepared from genomic or cDNA expressed in Chinese Hamster Ovary (CHO) according to U.S. Pat. Nos. 4,703,008 and 5,955,422 to Lin. The superior properties of Epoetin Omega include, but are not limited to, a much higher potency, a much more rapid response (i.e.

Abstract: One aspect of the present invention is an isolated nucleic acid molecule encoding canine erythropoietin. The present invention also relates to an isolated canine erythropoietin protein or polypeptide. Another aspect of the present invention is a method for providing erythropoietin therapy to a dog or a cat including administering recombinant canine erythropoietin to a dog or a cat in need of erythropoietin therapy in an amount sufficient to increase production of reticulocytes and red blood cells in the dog or cat.

Abstract: A novel hemopoietin receptor gene (NR12) was successfully isolated by extracting motifs conserved among the amino acid sequences of known hemopoietin receptors and by using the predicted sequence. The NR12 gene encodes two forms of proteins, a transmembrane type and a soluble type. The expression of the NR12 gene was detected in tissues containing hematopoietic cells. NR12 is a novel hemopoietin receptor molecule involved in the regulation of immune system and hematopoiesis in vivo. Thus, NR12 is useful in the search for novel hematopoietic factors that functionally bind to the NR12 receptor, and in the development of therapeutic drugs for diseases associated with immunity or hematopoiesis.

Abstract: The present invention provides specific peptides identified as having cell adhesion, growth, expression or secretion-enhancing activities. Many of the peptides of the invention may be produced in large quantity by such means as chemical synthesis or recombinant DNA methodology. They may be non-specifically adsorbed, or chemically attached to a surface or, alternatively, formulated in a culture medium to produce the desired effect on cultured cells.

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: Purification process of humanPurification process of human urinary gonadotropins of high biological activity and chemical purity absolutely free of foreign contaminating materials derived from the use of biological reagents or chromatography dyes, from crude of gonadotropins. The high biological activity and chemically pure composition of human gonadotropins obtained by this process, are used for the treatment of infertility and are selected from the group of follitropin or menotropins, having a bioactivity greater than 2500 IU/mg protein as tested by biological assay in rats, for both FSH and LH hormones for menotropins and greater than 5000 IU/mg protein for follitropin having an FSH:LH ratio about 75:1. Pharmaceutical preparations of said gonadotropins free of these contaminating materials are also comprised within the present invention.

Abstract: Glycosylated or nonglycosylated molecules of the formula ?1-(linker1)n1-?2-(linker2)n2-?3-(linker3)n3-?;??(1) ?1-(linker1)n1-?2-(linker2)n2-?-(linker3)n3-?3 ;??(2) ?1-(linker1)n1-?-(linker2)n2-?2-(linker3)n3-?3 ;??(3) and ?-(linker1)n1-?1-(linker2)n2-?2-(linker3)n3-?3 ??(4) wherein ? is the ? subunit of a vertebrate glycoprotein hormone or a variant thereof; each ? is independently a glycoprotein ? subunit or a variant thereof, each “linker” is a hydrophilic, flexible spacer equivalent to a peptide containing 1–100 amino acid residues; and each n is a 0 or 1; said compound optionally comprising one or more additional ?x(linkerx)nx and/or one or more additional ? subunits are useful in protocols to enhance fertility in humans and in animals.

Abstract: A process for the preparation of biologically active somatotropin from inclusion bodies of a recombinant host cell containing an inactive form of said somatotropin protein comprises the steps of: (a) contacting the inclusion bodies with an aqueous alcohol solution at an alkaline pH to solubilize said protein; and (b) bringing the solubilized protein into contact with a mild oxidizing agent to refold and form intramolecular disulfide bonds between cysteine residues of said protein.

Abstract: In accordance with the present invention, there are provided novel Schwannomin-Binding-Proteins (SBPs). Nucleic acid sequences encoding such proteins and assays employing same are also disclosed. The invention SBPs can be employed in a variety of ways, for example, for the production of anti-SBP antibodies thereto, in therapeutic compositions and methods employing such proteins and/or antibodies. Also provided are transgenic non-human mammals that express the invention protein.

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

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: Compositions and methods based on mutant Cystine Knot Growth Factors (CKGFs) comprising amino acid substitutions relative to the wild type hormone/growth factor. Mutated glycoprotein hormones, including thyroid stimulating hormone (TSH) and chorionic gonadotropin (CG) are disclosed as exemplary mutant CKGFs. Mutant TSH heterodimers and hCH heterodimers possessed modified bioactivities, including superagonist activity. Accordingly, the present invention provides methods for using mutant CKGFs, CKGF analogs, fragments, and derivatives thereof for treating or preventing diseases. Pharmaceutical and diagnostic compositions, methods of using mutant TSH heterodimers and TSH analogs with utility for treatment and prevention of metabolic and reproductive diseases are also provided.

Abstract: A cDNA clone having a base sequence for human tissue factor inhibitor (TFI) has been developed and characterized and the amino acid sequence of the TFI has been determined.

Abstract: Polypeptide conjugates with G-CSF activity comprising a polypeptide having at least one introduced lysine residue and at least one removed lysine residue compared to the sequence of human G-CSF, and which are conjugated to 2-6 polyethylene glycol moieties. The conjugates have a low in vitro bioactivity, a long in vivo half-life, a reduced receptor-mediated clearance, and provide a more rapid stimulation of production of white blood cells and neutrophils than non-conjugated recombinant human G-CSF.

Abstract: The present invention is directed to novel chimpanzee erythropoietin 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, and antibodies which bind to the polypeptides of the present invention.

Abstract: A novel lyophilizate and method of preparation as well as the use of the lyophilizate to treat female infertility and for gonad protection. Cetrorelix is dissolved in acetic acid 30% v/v, the solution is transferred to water and freeze dried.

Abstract: Disclosed are compositions with tethered growth effector molecules, and methods of using these compositions for growing cells and tissues. Growth effector molecules, including growth factors and extracellular matrix molecules, are flexibly tethered to a solid substrate. The compositions can be used either in vitro or in vivo to grow cells and tissues. By tethering the growth factors, they will not diffuse away from the desired location. By making the attachment flexible, the growth effector molecules can more naturally bind to cell surface receptors. A significant feature of these compositions and methods is that they enhance the biological response to the growth factors. The new method also offers other advantages over the traditional methods, in which growth factors are delivered in soluble form: (1) the growth factor is localized to a desired target cell population; (2) significantly less growth factor is needed to exert a biologic response.

Abstract: The present invention provides methods of discovering and mapping secondary binding sites on biological molecules (e.g., proteins), the effects, if any, of site occupancy on the primary function of the molecule, and the screening of small molecules against the secondary binding sites. The invention further provides novel complexes for modification of secondary binding sites and the resulting modified biological molecules.

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: Specially designed non-mammalian GnRH analogs resistant to degradation by the tumor tissue enzymes, post-proline peptidases as well as endopeptidases, are disclosed. The GnRH analogs are further defined as analogs of chicken II GnRH, salmon GnRH, or herring GnRH, but can include any non-mammalian GnRH analog with similar amino acid structure. These non-mammalian analogs incorporate D-arginine, D-leucine, D-tBu-Serine or D-Trp or other similar amino acids at position 6 and ethylamide or aza-Gly-amide or similar amides at position 10. These analogs demonstrate preferential binding to tumor cell GnRH receptors that is greater relative to the binding of the mammalian analogs to the tumor cell GnRH receptor. These non-mammalian GnRH analogs may be used in pharmaceutical preparations, and specifically in various treatments as an anti-tumor, anti-proliferation, anti-metastatic and/or an apoptotic agent.

Abstract: The invention provides recombinant native and mutein forms of human follicle stimulating hormone beta subunit (FSH beta) with characteristic glycosylation patterns which are influential in the metabolic activity of the protein. The invention also provides recombinant mutant forms of the human alpha subunit common to FSH, LH, CG, and TSH, to obtain hormones which also have unique glycosylation patterns. Also provided are recombinant materials to produce these subunits separately or together to obtain complete heterodimeric hormones of regulated glycosylation pattern.

Abstract: The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain, and preferably two peptide chains branched from a dipeptide branch moiety composed of two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a linker, which may be a hydrophobic linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Abstract: The present invention relates to a method for the preparation of a Neutrophil Inhibitory Factor (NIF) comprising the cultivation of mammalian cells expressing NIF in an animal component-free growth medium. The present invention may be employed in large-scale preparation of NIF. The invention also relates to a method for the preparation of recombinant proteins comprising the cultivation of mammalian cells expressing an exogenous recombinant protein in an animal component-free growth medium.

Abstract: The current invention concerns novel antiangiogenic peptides which correspond to about 10 to about 150 consecutive amino acids of N-terminal sequences of human growth hormone, human placental lactogen, human growth hormone variant hGH-V, and prolactin, and their use in inhibiting angiogenesis and in the diagnosis of diseases of human pregnancy involving abnormalities of placental vascularization.

Abstract: Compositions of proteins with tendon/ligament-like tissue inducing activity are disclosed. The compositions are useful in the treatment of tendinitis and tendon or ligament defects and in related tissue repair.

Abstract: The present invention provides compositions which allow for the extended release and enhanced bioavailability of biologically-active polypeptides following parenteral delivery to an animal. More particularly, it concerns compositions comprising biologically-active somatotropin formulated for extended release, methods of preparing these compositions, and methods of using the same. These compositions comprise somatotropin, a bioavailability-enhancing constituent (BEC), and a substantially non-aqueous, hydrophobic excipient. The BEC may comprise (i) amino acids or amino acid derivatives, such as histidine-HCl; (ii) hydroxamate derivatives, such as histidine hydroxamate or suberohydroxamic acid; (iii) non-reducing carbohydrates, such as trehalose or trehalose octaacetate; (iv) oxo-acid salts, such as a mixture of monobasic and dibasic sodium phosphate; or (v) a mixture of two or more compounds from within the foregoing classes (i)-(iv).

Abstract: The present invention provides compositions comprising biologically-active somatotropin formulated for extended release and methods of preparing and methods of using the same. These compositions comprise somatotropin, at least a first bioavailability-enhancing constituent (BEC), and a substantially non-aqueous, hydrophobic excipient, and optionally a second BEC. The first BEC is typically a surfactant (preferably a non-ionic surfactant) or a cyclodextrin compound. The optional second BEC may comprise (i) amino acids or amino acid derivatives; (ii) hydroxamate derivatives; (iii) non-reducing carbohydrates; (iv) oxo-acid salts; or (v) a mixture of two or more compounds from within the foregoing classes (i)-(iv).

Abstract: The present invention relates to polypeptides to be administered especially to humans and in particular for therapeutic use. The polypeptides are modified polypeptides whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The inention in particular relates to the modification of erythropoietin (EPO) to result in erythropoietin proteins that are substantially non-immunogenic or less immunogenic than any non-modified counterpart when used in vivo.

Abstract: The invention refers to liquid pharmaceutical compositions containing hCG stabilised with a polyalcohol or a non-reducing sugar. Preferably, the compositions are stabilised with mannitol. In the preferred embodiments such compositions are aqueous solutions in a phosphate buffer at pH 7. Such compositions are ready to be injected and, therefore, the step of reconstitution of the lyophilised powder is avoided, thus simplifying the way of use.

Abstract: One aspect of the present invention is an isolated nucleic acid molecule encoding canine erythropoietin. The present invention also relates to an isolated canine erythropoietin protein or polypeptide. Another aspect of the present invention is a method for providing erythropoietin therapy to a dog or a cat including administering recombinant canine erythropoietin to a dog or a cat in need of erythropoietin therapy in an amount sufficient to increase production or reticulocytes and red blood cells in the dog or cat.

Abstract: Single-chain forms of the glycoprotein hormones LH, FSH, TSH or CG which are lacking at least one disulfide bridge in the sequence representing the &agr; and/or &bgr; subunit are useful as agonists or antagonists of the native glycoprotein hormones.

Abstract: Glycosylated or nonglycosylated proteins of the formula FSH&bgr;-(linker1)n1-LH&bgr;(1-X)-(linker2)n2-&agr; wherein FSH&bgr; is a vertebrate follicle stimulating hormone &bgr; subunit or a variant thereof; LH&bgr;(1-X) refer's to a &bgr; subunit of a vertebrate luteinizing hormone containing positions 1-X where X is an integer of 114-121 or a variant thereof; each “linker” is a hydrophilic, flexible amino acid sequence containing 1-100 amino acid residues; each n is a 0 or 1; and &agr; is the &agr; subunit of a vertebrate glycoprotein hormone or a variant thereof are useful in protocols to enhance fertility in humans and in animals.

Abstract: The present invention relates to a rapid and readily reproducible process for stabilizing biologically active substances by combining the biologically active substance witha a stabilizingmixture and drying the resulting mixture into a dry, amorphous product by means of convection drying. The invention also relates to the amorphous, microscopically homogeneous products which are obtained by this process, are in the form of powders and have a uniform geometric, in particular spherical, shape. The invention furthermore relates to the use of substance mixtures for stabilizing biologically active material, in particular proteins by means of spray drying.

Abstract: The present invention is directed to compositions comprising 1-(&bgr;-D-ribofuranosyl)-1H-1,2,4-triazole compounds and either endogenous or exogenous neurotrophic factors. Methods of using such compounds and compositions are also provided. In one aspect, the invention provides methods of using invention compositions and compounds to enhance neurite outgrowth, neuronal survival and neuronal proliferation in mammalian cells. In a preferred embodiment, a 1-(&bgr;-D-ribofuranosyl)1H-1,2,4-triazole compound is infused directly to a desired situs. In a more preferred embodiment the 1-(&bgr;-D-ribofuranosyl)-1,2,4-triazole compound is administered orally. In another aspect, the invention provides methods of treating a neurological disease in a mammal subject. In a further aspect, the invention provides methods of treating neuronal trauma in a mammal subject.

Abstract: Targeted therapeutics that localize to a specific subcellular compartment such as the lysosome are provided. The targeted therapeutics include a therapeutic agent and a targeting moiety that binds a receptor on an exterior surface of the cell, permitting proper subcellular localization of the targeted therapeutic upon internalization of the receptor. Nucleic acids, cells, and methods relating to the practice of the invention are also provided.

Abstract: The present invention relates to novel human thrombopoietin (; hTPO) derivatives, and to process of preparation thereof. Particularly, sugar chains are introduced into native hTPO by substituting amino acids such as asparagine for amino acids at specific positions in native hTPO, preparing novel hTPO derivatives with high activities enhancing the platelet production in vivo. Therefore, the novel hTPO derivatives of this invention may be useful for the treatment of thrombocytopenia associated with anticancer therapy or the transplantation of bone marrow.

Abstract: The present invention relates to the use of GDF-9 in assisted reproduction and to kits comprising GDF-9. A method is provided to stimulate follicle and oocyte development and maturation. The method comprises administering GDF-9 in combination with gonadotropins.

Abstract: The invention relates to polypeptide conjugates comprising a polypeptide exhibiting G-CSF activity and having an amino acid sequence that differs from the amino acid sequence of human G-CSF in at least one specified introduced and/or removed amino acid residue comprising an attachment group for a non-polypeptide moiety, and having at least one non-polypeptide moiety attached to an attachment group of the polypeptide. The attachment group may e.g., be a lysine, cysteine, aspartic acid or glutamic acid residue or a glycosylation site, and the non-polypeptide moiety may e.g., be a polymer such as polyethylene glycol or an oligosaccharide. The conjugate has one or more improved properties such as increased biological half-life and reduced side effects.

Abstract: Novel &bgr;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 &bgr;10 polypeptides and heterodimeric forms thereof, specifically &agr;2/&bgr;10. Also provided for are methods for the treatment, diagnosis, amelioration, or prevention of diseases with &bgr;10 polypeptides and &agr;2/&bgr;10 heterodimers or their respective binding agents.

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

Abstract: Synthetic erythropoiesis stimulating proteins are provided. Also provided are methods for synthesizing the proteins. The invention further relates to derivatives of such synthetic erythropoiesis stimulating proteins that are polymer-modified in a defined manner. Methods and uses for such proteins and derivatized proteins are also provided.