US2021401948A1PendingUtilityA1

Polymer-factor viii moiety conjugates

81
Assignee: NEKTAR THERAPEUTICSPriority: Feb 26, 2003Filed: Sep 9, 2021Published: Dec 30, 2021
Est. expiryFeb 26, 2023(expired)· nominal 20-yr term from priority
Inventors:Mary J. BossardMichael D. BentleyPing Zhang
A61K 38/37A61K 47/10A61K 47/50A61K 38/38A61K 47/60A61P 7/04A61P 7/00A61P 7/06
81
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Claims

Abstract

Conjugates of a Factor VIII 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 are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A composition comprising a plurality of conjugates each conjugate having one to three water-soluble polymers covalently attached to a Factor VIII moiety, wherein each water-soluble polymer has a nominal average molecular weight in the range of greater than 5,000 Daltons to about 150,000 Daltons. 
     
     
         2 . The composition of  claim 1 , wherein the water-soluble polymer in each conjugate is selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(acryloylmorpholine). 
     
     
         3 . The composition of  claim 2 , wherein each water-soluble polymer is a poly(alkylene oxide). 
     
     
         4 . The composition of  claim 3 , wherein each poly(alkylene oxide) is a poly(ethylene glycol). 
     
     
         5 . The composition of  claim 4 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 
     
     
         6 . The composition of  claim 4 , wherein the poly(ethylene glycol) is terminally capped with methoxy. 
     
     
         7 . The composition of  claim 4 , wherein the poly(ethylene glycol) is terminally capped with hydroxy. 
     
     
         8 . The composition of  claim 4 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons. 
     
     
         9 . The composition of  claim 8 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons. 
     
     
         10 . The composition of  claim 9 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 20,000 Daltons to about 85,000 Daltons. 
     
     
         11 . The composition of  claim 10 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 53,000 Daltons to about 75,000 Daltons. 
     
     
         12 . The composition of  claim 3 , wherein each water-soluble polymer is linear. 
     
     
         13 . The composition of  claim 3 , wherein each water-soluble polymer is branched. 
     
     
         14 . The composition of  claim 3 , wherein the Factor VIII moiety is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF, B-domain deleted Factor VIII, and biologically active fragments, deletion variants, substitution variants or addition variants of any of the foregoing. 
     
     
         15 . The composition of  claim 14 , wherein the Factor VIII moiety is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, and Factor VIII:vWF. 
     
     
         16 . The composition of  claim 14 , wherein the Factor VIII moiety is B-domain deleted Factor VIII. 
     
     
         17 . The composition of  claim 3 , wherein the Factor VIII moiety is recombinantly derived. 
     
     
         18 . The composition of  claim 3 , wherein the Factor VIII moiety is blood-derived. 
     
     
         19 . The composition of  claim 3 , wherein the composition is substantially free of albumin. 
     
     
         20 . The composition of  claim 3 , wherein the composition is substantially free of proteins that do not have Factor VIII activity. 
     
     
         21 . The composition of  claim 3 , wherein the composition is substantially free of noncovalently attached water-soluble polymers. 
     
     
         22 . The composition of  claim 3 , wherein at least one water-soluble polymer is covalently attached to a site in the active form of the moiety having Factor VIII activity. 
     
     
         23 . The composition of  claim 1 , in lyophilized form. 
     
     
         24 . The composition of  claim 1 , in the form of a liquid. 
     
     
         25 . The composition of  claim 1 , further comprising a pharmaceutically acceptable excipient. 
     
     
         26 . The composition of  claim 1 , wherein each conjugate comprises an amide linkage. 
     
     
         27 . The composition of  claim 1 , wherein each conjugate comprises a secondary amine linkage. 
     
     
         28 . The composition of  claim 1 , wherein each conjugate comprises a carbamate linkage. 
     
     
         29 . The composition of  claim 1 , wherein each conjugate comprises a thioether linkage. 
     
     
         30 . The composition of  claim 1 , wherein each conjugate comprises a disulfide linkage. 
     
     
         31 . A composition comprising a plurality of monoPEGylated Factor VIII moiety conjugates. 
     
     
         32 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises one poly(ethylene glycol) terminally capped with an end-capping moiety selected from the group consisting hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 
     
     
         33 . The composition of  claim 31 , wherein the poly(ethylene glycol) is terminally capped with methoxy. 
     
     
         34 . The composition of  claim 31 , wherein the poly(ethylene glycol) is terminally capped with hydroxy. 
     
     
         35 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a poly(ethylene glycol) having a nominal average molecular weight in the range of greater than 5,000 Daltons to about 150,000 Daltons. 
     
     
         36 . The composition of  claim 35 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons. 
     
     
         37 . The composition of  claim 36 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons. 
     
     
         38 . The composition of  claim 37 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 20,000 Daltons to about 85,000 Daltons. 
     
     
         39 . The composition of  claim 38 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 53,000 Daltons to about 75,000 Daltons. 
     
     
         40 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a linear poly(ethylene glycol). 
     
     
         41 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety comprises a branched poly(ethylene glycol). 
     
     
         42 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a Factor VIII moiety selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF, B-domain deleted Factor VIII, and biologically active fragments, deletion variants, substitution variants or addition variants of any of the foregoing. 
     
     
         43 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a Factor VIII moiety selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, and Factor VIII:vWF. 
     
     
         44 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises B-domain deleted Factor VIII. 
     
     
         45 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a Factor VIII moiety that is recombinantly derived. 
     
     
         46 . The composition of  claim 31 , wherein each monoPEGylated Factor VIII moiety conjugate comprises a Factor VIII moiety that is blood-derived. 
     
     
         47 . The composition of  claim 31 , wherein the composition is substantially free of albumin. 
     
     
         48 . The composition of  claim 31 , wherein the composition is substantially free of proteins that do not have Factor VIII activity. 
     
     
         49 . The composition of  claim 31 , wherein the composition is substantially free of noncovalently attached water-soluble polymers. 
     
     
         50 . The composition of  claim 31 , in lyophilized form. 
     
     
         51 . The composition of  claim 31 , in the form of a liquid. 
     
     
         52 . The composition of  claim 31 , further comprising a pharmaceutically acceptable excipient. 
     
     
         53 . The composition of  claim 31 , wherein each conjugate comprises an amide linkage. 
     
     
         54 . The composition of  claim 31 , wherein each conjugate comprises a secondary amine linkage. 
     
     
         55 . The composition of  claim 31 , wherein each conjugate comprises a carbamate linkage. 
     
     
         56 . The composition of  claim 31 , wherein each conjugate comprises a thioether linkage. 
     
     
         57 . The composition of  claim 31 , wherein each conjugate comprises a disulfide linkage. 
     
     
         58 . A method for making a conjugate comprising contacting, under conjugation conditions, a Factor VIII moiety with a polymeric reagent. 
     
     
         59 . A method for treating a patient in need of Factor VIII therapy, comprising the step of administering to the patient the composition of  claim 1  or  claim 31 , wherein the composition contains a therapeutically effective amount the conjugates. 
     
     
         60 . The method of  claim 59 , wherein the patient is suffering from hemophilia A. 
     
     
         61 . The method of  claim 59 , wherein the patient is administered the composition within two days prior to undergoing surgery.

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