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US 5,766,897 AGranted
Cysteine-pegylated proteins
AssigneeIncyte Pharmaceuticals, Inc.
InventorScott M. Braxton
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AssigneeIncyte Pharmaceuticals, Inc.
InventorScott M. Braxton
Estimating the term…
Methods and compositions are provided for the production of PEGylated proteins having polyethylene glycol covalently bound to a cysteine residue present in either the naturally-occurring protein or introduced by site-specific mutation. Where the cysteine residue is introduced by mutation, the site for mutation is selected on the basis of the presence of an N-linked glycosylation site or the position of the residue which is normally solvent-accessible in the naturally-occurring protein. The modified proteins produced by the method of the invention are referred to as cysteine-PEGylated proteins. Proteins PEGylated according to the invention have increased half-lives following administration to a subject and decreased immunogenicity and antigenicity, while retaining substantially the same level of biological activity as that of the naturally-occurring, unmodified protein. Modification of proteins according to methods of the invention thus provide improved pharmaceutical compositions.
A chemically modified protease nexin-1 variant comprised of the amino acid sequence of protease nexin-1, wherein an amino acid residue at a position selected from the group consisting of P.sub.4, P.sub.3, P.sub.2, P.sub.1, P.sub.1 ', P.sub.2 ', P.sub.3 ' and P.sub.4 ' is replaced with a natural amino acid residue which is different from the amino acid residue naturally present at that position, and which sequence includes at least one cysteine residue, wherein the chemical modification comprises the coupling of polyethylene glycol to a cysteine residue of the protein.
A chemically modified protease nexin-1 variant wherein amino acid residues at the active site of protease nexin-1 are replaced with an equivalent number of active site amino acid residues of a serine protease inhibitor other than protease nexin-1, and the amino acid sequence of the variant protein includes at least one cysteine residue, wherein the chemical modification comprises the coupling of polyethylene glycol to a cysteine residue of the protein.
A chemically modified protease nexin-1 variant wherein three or more amino acid residues of the active site of protease nexin-1 are replaced with different amino acid residues which comprise a substrate sequence specific for a given protease and the amino acid sequence of the variant protein includes at least one cysteine residue wherein the chemical modification comprises the coupling of polyethylene glycol to a cysteine residue of the protein.
A method of coupling polyethylene glycol to a protease nexin-1 variant comprising the steps of:
A method of coupling polyethylene glycol to a protease nexin-1 variant comprising the steps of:
A method of coupling polyethylene glycol to a protease nexin-1 variant comprising the steps of:
Dependencies are inferred from the claim text.