Polymer factor VIII moiety conjugates

• US 8,143,378 B2
• Filed: 12/11/2009
• Issued: 03/27/2012
• Est. Priority Date: 02/26/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Bossard, Mary J., Bentley, Michael D., Zhang, Ping
• Primary Examiner(s): ROBINSON, HOPE A
• Application Number:
  US12/636,635
• Publication Number:
  US 20100125049A1
• Time in Patent Office: 837 Days
• Field of Search: None
• US Class Current: 530/383
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics

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

1. A composition comprising a plurality of conjugates, each conjugate comprising one, two or three water-soluble polymers each covalently attached to a Factor VIII moiety polypeptide via a hydrolytically stable linkage, wherein:

(i) 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;

(ii) the water-soluble polymer is selected from the group consisting of a poly(alkylene glycol), a poly(oxyethylated polyol), a poly(olefinic alcohol), a poly(vinylpyrrolidone), a poly(hydroxyalkylmethacrylamide), a poly(hydroxyalkylmethacrylate), a poly(saccharide), a poly(α

-hydroxy acid), a poly(vinyl alcohol), a polyphosphazene, a polyoxazoline, a poly(N-acryloylmorpholine), and combinations thereof; and

(iii) the composition is bioactive, comprising an in-vitro activity of at least 15% compared to that of a Factor VIII polypeptide composition in unconjugated form.

2. The composition of claim 1, having an in-vitro activity of at least 25% compared to the same Factor VIII polypeptide composition in unconjugated form.

3. The composition of claim 1, having an in-vitro activity of at least 40% compared to the same Factor VIII polypeptide composition in unconjugated form.

4. The composition of claim 1, wherein each conjugate is comprised of the same Factor VIII polypeptide.

5. The composition of claim 1, comprising a plurality of conjugates wherein the conjugates each have one or two water-soluble polymers covalently attached to the Factor VIII polypeptide.

6. The composition of claim 1, wherein the conjugates each have one water-soluble polymer covalently attached to the Factor VIII polypeptide.

7. The composition of claim 1, wherein the conjugates each have two water-soluble polymers covalently attached to the Factor VIII polypeptide.

8. The composition of claim 1, wherein the conjugates each have three water-soluble polymers covalently attached to the Factor VIII polypeptide.

9. The composition of claim 4, wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a linkage selected from amide, secondary amine, carbamate, thioether, and disulfide.

10. The composition of claim 9, wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide in each conjugate via an amide linkage.

11. The composition of claim 1, wherein each water-soluble polymer in the composition has a nominal average molecular weight in a range of from greater than 5,000 Daltons to 150,000 Daltons.

12. The composition of claim 11, wherein each conjugate in the composition comprises the same water-soluble polymer.

13. The composition of claim 11, wherein the water-soluble polymer is a poly(alkylene glycol) or a polysaccharide selected from dextran and starch.

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

15. The composition of claim 14, 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.

16. The composition of claim 14, wherein the poly(ethylene glycol) is terminally capped with methoxy or hydroxy.

17. The composition of claim 14, 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.

18. The composition of claim 14, 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.

19. The composition of claim 18, 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.

20. The composition of claim 14, wherein the poly(ethylene glycol) has a nominal average molecular weight selected from the group consisting of about 6,000 Daltons, about 7,500 Daltons, about 10,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 40,000 Daltons, about 50,000 Daltons, and about 60,000 Daltons.

21. The composition of claim 14, wherein each poly(ethylene glycol) is linear.

22. The composition of claim 14, wherein each poly(ethylene glycol) is branched.

23. The composition of claim 14, wherein the plurality of conjugates each possess the same Factor VIII polypeptide, the same water-soluble polymer, and the same covalent attachment between the water-soluble polymer and the Factor VIII polypeptide.

24. The composition of claim 14, wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:

C, and Factor VIII;

vWF.

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

26. The composition of claim 14, wherein the Factor VIII polypeptide is recombinantly-derived.

27. The composition of claim 14, wherein the Factor VIII polypeptide is blood-derived.