US2010249033A1PendingUtilityA1

Polymer factor ix moiety conjugates

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Assignee: NEKTAR THERAPEUTICSPriority: Jun 30, 2004Filed: Jun 7, 2010Published: Sep 30, 2010
Est. expiryJun 30, 2024(expired)· nominal 20-yr term from priority
Inventors:Mary J. BossardGayle Stephenson
A61P 7/04A61K 38/4846C12Y 304/21022C12N 9/644C12N 9/96A61K 47/60A61K 47/50C07K 14/755
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Claims

Abstract

Conjugates of a Factor IX moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided (among other things) are compositions comprising the conjugates, methods of making the conjugates, and methods of administering to a patient compositions comprising the conjugates.

Claims

exact text as granted — not AI-modified
1 . A conjugate comprising a water-soluble polymer covalently attached to a Factor IX polypeptide via a thiol group of a cysteine residue contained within the Factor IX polypeptide, where the Factor IX polypeptide is selected from Factor IX and Factor IXa and the Factor IX polypeptide has optionally been modified to include the cysteine residue to which the water-soluble polymer is covalently attached. 
     
     
         2 . The conjugate of  claim 1 , wherein the Factor IX polypeptide is Factor IX modified to include the cysteine residue to which the water-soluble polymer is covalently attached. 
     
     
         3 . The conjugate of  claim 1 , wherein the Factor IX polypeptide is Factor IXa modified to include the cysteine residue to which the water-soluble polymer is covalently attached. 
     
     
         4 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer is a poly(ethylene glycol) and the conjugate is monoPEGylated. 
     
     
         5 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer is a poly(ethylene glycol) and the conjugate is diPEGylated. 
     
     
         6 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer has a nominal average molecular weight in the range of from about 6,000 Daltons to about 90,000 Daltons. 
     
     
         7 . The conjugate of  claim 1 , wherein the Factor IX polypeptide is glycosylated. 
     
     
         8 . The conjugate of  claim 1 , wherein the Factor IX polypeptide is unglycosylated. 
     
     
         9 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer is covalently attached to the Factor IX polypeptide at a position within the gamma carboxyglutamate-rich (GLA) domain. 
     
     
         10 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer is covalently attached to the Factor IX polypeptide at a position within the EGF-like region. 
     
     
         11 . The conjugate of  claim 2  or  claim 3 , wherein the water-soluble polymer is covalently attached to the Factor IX polypeptide at a position within the activation peptide region. 
     
     
         12 . The conjugate of  claim 2  or  claim 3 , wherein the Factor IX polypeptide is a recombinant Factor IX polypeptide. 
     
     
         13 . The conjugate of  claim 2  or  claim 3  formed by reaction of a maleimide-terminated water-soluble polymer with the thiol group of the cysteine residue. 
     
     
         14 . A conjugate comprising a water-soluble polymer covalently attached to a Factor IX polypeptide via a thioether linkage, where the Factor IX polypeptide is selected from Factor IX and Factor IXa and the Factor IX polypeptide has optionally been modified to include a cysteine residue to which the water-soluble polymer is covalently attached via the thioether linkage. 
     
     
         15 . The conjugate of  claim 14 , wherein the Factor IX polypeptide is Factor IX modified to include the cysteine residue to which the water-soluble polymer is covalently attached. 
     
     
         16 . The conjugate of  claim 14 , wherein the Factor IX polypeptide is Factor IXa modified to include the cysteine residue to which the water-soluble polymer is covalently attached. 
     
     
         17 . The conjugate of  claim 15 , wherein the water-soluble polymer is a poly(ethylene glycol) and the conjugate is monoPEGylated. 
     
     
         18 . The conjugate of  claim 16 , wherein the water-soluble polymer is a poly(ethylene glycol) and the conjugate is monoPEGylated. 
     
     
         19 . A composition comprising a plurality of monoPEGylated or diPEGylated Factor IX polypeptide conjugates, wherein the Factor IX polypeptide is selected from Factor IX and Factor IXa. 
     
     
         20 . A composition comprising conjugates having one or more of the same poly(ethylene glycol)s covalently attached to a Factor IX polypeptide selected from Factor IX and Factor IXa at one or more particular attachment sites, wherein the composition is free from positional isomers of the conjugates. 
     
     
         21 . The composition of  claim 19  or  claim 20 , wherein each poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 
     
     
         22 . The composition of claim.  21 , wherein each poly(ethylene glycol) is terminally capped with methoxy. 
     
     
         23 . The composition of  claim 21 , wherein each poly(ethylene glycol) is terminally capped with hydroxy. 
     
     
         24 . The composition of  claim 19  or  claim 20 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of greater than 5,000 Daltons to about 150,000 Daltons. 
     
     
         25 . The composition of  claim 24 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons. 
     
     
         26 . The composition of  claim 24 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons. 
     
     
         27 . The composition of  claim 26 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 20,000 Daltons to about 85,000 Daltons. 
     
     
         28 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises the same linear poly(ethylene glycol). 
     
     
         29 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises the same branched poly(ethylene glycol). 
     
     
         30 . The composition of  claim 19  or  20 , wherein the Factor IX polypeptide has been modified to include a cysteine residue to which the poly(ethylene glycol) is covalently attached. 
     
     
         31 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises a recombinant Factor IX polypeptide. 
     
     
         32 . The composition of  claim 19  or  claim 20 , wherein the composition is substantially free of albumin. 
     
     
         33 . The composition of  claim 19  or  claim 20 , wherein the composition is substantially free of proteins that do not have Factor IX activity. 
     
     
         34 . The composition of  claim 19  or  claim 20 , wherein the composition is substantially free of non-covalently attached water-soluble polymers. 
     
     
         35 . The composition of  claim 19  or  claim 20 , in lyophilized form. 
     
     
         36 . The composition of  claim 19  or  claim 20 , in the form of a liquid. 
     
     
         37 . The composition of  claim 19  or  claim 20 , further comprising a pharmaceutically acceptable excipient. 
     
     
         38 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises an amide linkage between the Factor IX polypeptide and the poly(ethylene glycol). 
     
     
         39 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises a secondary amine linkage between the Factor IX polypeptide and the poly(ethylene glycol). 
     
     
         40 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises a carbamate linkage between the Factor IX polypeptide and the poly(ethylene glycol). 
     
     
         41 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises a thioether linkage between the Factor IX polypeptide and the poly(ethylene glycol). 
     
     
         42 . The composition of  claim 19  or  claim 20 , wherein each conjugate comprises a disulfide linkage between the Factor IX polypeptide and the poly(ethylene glycol).

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