IP Library › Granted Patent US 7,863,421
Granted Patent B2
US 7,863,421 · App. 12/157,072 · Granted Jan 4, 2011

Polymer-factor VIII moiety conjugates

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Quick Facts
Patent No.
US 7,863,421
App. No.
12/157,072
Granted
Jan 4, 2011
Kind
B2
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 (40)

1. A conjugate comprising a water-soluble polymer covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue contained within the Factor VIII polypeptide, wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII, and wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(N-acryloylmorpholine).

2. The conjugate of claim 1 , wherein the Factor VIII polypeptide is a Factor VIII polypeptide that has been modified to add a cysteine residue to which the water-soluble polymer is covalently attached.

3. The conjugate of claim 2 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII modified to add a cysteine residue to which the water-soluble polymer is covalently attached.

4. The conjugate of claim 1 or claim 2 , wherein the water-soluble polymer is a poly(ethylene glycol) and the conjugate is monoPEGylated.

5. The conjugate of claim 1 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.

6. The conjugate of claim 1 or claim 3 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue located within the A1 subunit of the Factor VIII polypeptide.

7. The conjugate of claim 1 or claim 3 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue located within the A2 subunit of the Factor VIII polypeptide.

8. The conjugate of claim 1 or claim 3 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue located within the A3 subunit of the Factor VIII polypeptide.

9. The conjugate of claim 1 or claim 3 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue located within the C1 subunit of the Factor VIII polypeptide.

10. The conjugate of claim 1 or claim 3 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue located within the C2 subunit of the Factor VIII polypeptide.

11. The conjugate of claim 1 or claim 3 , formed by reaction of a maleimide-terminated water-soluble polymer with the thiol group of the cysteine residue.

12. A conjugate comprising a water-soluble polymer covalently attached to a Factor VIII polypeptide via a thioether linkage, wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII, wherein the Factor VIII polypeptide has been modified to add a cysteine residue to which the water-soluble polymer is covalently attached, and wherein the water-soluble polymer is a poly(alkylene glycol).

13. The conjugate of claim 12 , wherein the poly(alkylene glycol) is a poly(ethylene glycol).

14. The conjugate of claim 13 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII.

15. The conjugate of claim 13 , wherein the conjugate is monoPEGylated.

16. The conjugate of claim 14 , wherein the conjugate is monoPEGylated.

17. A composition comprising a plurality of monoPEGylated or diPEGylated Factor VIII polypeptide conjugates, wherein polyethylene glycol is covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue contained within the Factor VIII polypeptide and wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII.

18. A composition comprising a conjugate comprising a water-soluble polymers covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue contained within the Factor VIII polypeptide, wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII, wherein the composition is free from positional isomers of the conjugate, and wherein the water-soluble polymer is a poly(ethylene glycol).

19. The composition of claim 17 or claim 18 , wherein the 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.

20. The composition of claim 17 or claim 18 , wherein the poly(ethylene glycol) is terminally capped with methoxy.

21. The composition of claim 17 or claim 18 , wherein the poly(ethylene glycol) is terminally capped with hydroxy.

22. The composition of claim 17 or claim 18 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of greater than 5,000 Daltons to about 150,000 Daltons.

23. The composition of claim 22 , 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.

24. The composition of claim 23 , 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.

25. The composition of claim 24 , 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.

26. The composition of claim 25 , 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.

27. The composition of claim 17 or claim 18 , wherein the conjugate comprises a linear poly(ethylene glycol).

28. The composition of claim 17 or claim 18 , wherein the conjugate comprises a branched poly(ethylene glycol).

29. The composition of claim 17 or claim 18 , wherein the conjugate comprises a Factor VIII polypeptide selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C and Factor VIII:vWF.

30. The composition of claim 17 or claim 18 , wherein the Factor VIII polypeptide is B domain deleted Factor VIII.

31. The composition of claim 30 , wherein the B-domain deleted Factor VIII has been modified to add a cysteine residue to which the poly(ethylene glycol) is covalently attached.

32. The composition of claim 17 or claim 18 , wherein the conjugate comprises a recombinant Factor VIII polypeptide.

33. The composition of claim 17 or claim 18 , wherein the conjugate comprises a Factor VIII polypeptide that is obtained from blood.

34. The composition of claim 17 or claim 18 , wherein the composition is free of albumin.

35. The composition of claim 17 or claim 18 , wherein the composition is free of proteins that do not have Factor VIII activity.

36. The composition of claim 17 or claim 18 , in a lyophilized form.

37. The composition of claim 17 or claim 18 , in a liquid form.

38. The composition of claim 17 or claim 18 , further comprising a pharmaceutically acceptable excipient.

39. The composition of claim 17 or claim 18 , wherein the conjugate comprises a thioether linkage.

40. The composition of claim 17 or claim 18 , wherein the conjugate comprises a disulfide linkage.

Assignments (5)
RELEASE OF SECURITY INTEREST Recorded Apr 17, 2020
From: TC LENDING, LLC, AS COLLATERAL AGENT
To: NEKTAR THERAPEUTICS
Reel/Frame 053180/0009 →
RELEASE OF SECURITY INTEREST RECORDED AT REEL 28571, FRAME 0141 Recorded Oct 14, 2015
From: WELLS FARGO BANK, NATIONAL ASSOCIATION, AS COLLATERAL AGENT
To: NEKTAR THERAPEUTICS
Reel/Frame 036866/0700 →
GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS Recorded Oct 6, 2015
From: NEKTAR THERAPEUTICS
To: TC LENDING, LLC, AS COLLATERAL AGENT
Reel/Frame 036796/0562 →
GRANT OF SECURITY INTEREST Recorded Jul 17, 2012
From: NEKTAR THERAPEUTICS
To: WELLS FARGO BANK, NATIONAL ASSOCIATION, AS COLLATERAL AGENT
Reel/Frame 028571/0141 →
MERGER Recorded Aug 31, 2009
From: NEKTAR THERAPEUTICS AL, CORPORATION
To: NEKTAR THERAPEUTICS
Reel/Frame 023196/0394 →