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AssigneeAmylin Pharmaceuticals, Inc.
InventorsGerd Kochendoerfer, Paolo Botti, James Bradburne, Shiah -yun Chen, Sonya Cressman, Christie Hunter, Stephen Kent, Donald Low, Jill Wilken
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The present invention relates to methods and compositions for modifying peptides, polypeptides and proteins with polymers, especially glyco-mimetic polymers, so as to improve their biological activity or pharmacokinetic properties. The invention further provides methods and uses for such polymer-modified peptides, polypeptides and proteins. The invention is particularly suitable for use in the synthesis of polymer-modified, synthetic bioactive proteins, and of pharmaceutical compositions that contain such proteins.
An isolated synthetic bioactive protein having the formula Protein-Un-B-Polymer-J*, wherein Protein comprises a polypeptide chain of a ribosomally specified protein, said polypeptide chain comprising one or more non-overlapping peptide segments covalently bonded by one or more chemical ligation sites, U is a residue of a unique functional group covalently bonded to a mutually reactive unique functional group of a side chain n of one or more amino acids of one or more of said non-overlapping peptide segments, where n is a discrete integer selected from 1 to 6, B is a branching core having three or more arms that may be the same or different and may be present or absent, Polymer is a substantially non-antigenic water-soluble polymer, and J* is a pendant group having a net charge under physiological conditions selected from the group consisting of negative, neutral and positive.
A synthetic bioactive protein comprising a polypeptide chain comprising an amino acid sequence of a ribosomally specified glycoprotein, said polypeptide chain having one or more water-soluble polymers attached thereto and a monomer molecular weight of greater than 25 kDa.
A method of treating a human disease or condition that comprises administering to an individual in need of such treatment an effective amount of a pharmaceutical composition comprising one or more molecularly homogeneous pharmaceutical compositions of a polymer-modified synthetic bioactive protein having a monomer molecular weight greater than about 25 kDa and that possesses a bioactivity that mimics a bioactivity associated with a natural human protein receptor or fragment thereof, protein receptor ligand or fragment thereof, or a cytokine.
A method of producing a polymer-modified polypeptide chain of a synthetic bioactive polymer-modified protein, said method comprising chemically ligating peptide segments comprising non-overlapping amino acid sequences of a polypeptide chain of said synthetic bioactive polymer-modified protein, wherein one or more of said peptide segments has a water-soluble polymer attached thereto, whereby a polymer-modified polypeptide chain of said synthetic bioactive polymer-modified protein is produced.
A method of producing a polymer-modified polypeptide chain of a synthetic bioactive polymer-modified protein, said method comprising the steps:
A method of producing a synthetic bioactive polymer-modified protein, said method comprising the steps:
A molecularly homogeneous water-soluble polymer of the formula:
Dependencies are inferred from the claim text.