Polymer-factor VIII moiety conjugates
View Patent ↗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.
1. A conjugate comprising one, two or 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 from 6,000 Daltons to 150,000 Daltons and further wherein the cojugate is a 1-mer, 2-mer or 3-mer.
2. The conjugate of claim 1 , wherein each 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 conjugate of claim 2 , wherein each water-soluble polymer is a poly(alkylene oxide).
4. The conjugate of claim 3 , wherein each poly(alkylenc oxide) is a poly(ethylene glycol).
5. The conjugate 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 conjugate of claim 4 , wherein the poly(ethylene glycol) is terminally capped with methoxy.
7. The conjugate of claim 4 , wherein the poly(ethylene glycol) is terminally capped wit hydroxy.
8. The conjugate of claim 4 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from 6,000 Daltons to 100,000 Daltons.
9. The conjugate of claim 8 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from 10,000 Daltons to 85,000 Daltons.
10. The conjugate of claim 9 , wherein the poly(ethylene glycol) has a nominal avenge molecular weight in the range of from 20,000 Daltons to 85,000 Daltons.
11. The conjugate of claim 10 , wherein the poly(ethylenc glycol) has a nominal average molecular weight in the range of from 53,000 Daltons to 75,000 Daltons.
12. The conjugate of claim 3 , wherein each water-soluble polymer is linear.
13. The conjugate of claim 3 , wherein each water-soluble polymer is branched.
14. The conjugate 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, and B-domain deleted Factor VIII.
15. The conjugate 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 conjugate of claim 14 , wherein the Factor VIII moiety is B-domain deleted Factor VIII.
17. The conjugate of claim 3 , wherein the Factor VIII moiety is recombinently derived.
18. The conjugate of claim 3 , wherein the Factor VIII moiety is blood-derived.
19. The conjugate of claim 1 , wherein the one, two or three water-soluble polymers are covalently attached by an amide linkage.
20. The conjugate of claim 1 , wherein the one, two or three water-soluble polymers are covalently attached by a secondary amine linkage.
21. The conjugate of claim 1 , wherein the one, two or three water-soluble polymers are covalently attached by a carbarnate linkage.
22. The conjugate of claim 1 , wherein the one, two or three water-soluble polymers are covalently attached by a thioether linkage.
23. The conjugate of claim 1 , wherein the one, two or three water-soluble polymers are covalently attached by a disulfide linkage.
24. A composition comprising the conjugate of claim 3 .
25. The composition of claim 24 , wherein the composition is substantially free of albumin.
26. The composition of claim 24 , wherein the composition is substantially free of proteins that do not have Factor VIII activity.
27. The composition of claim 24 , wherein the composition is substantially free of noncovalently attached water-soluble polymers.
28. The composition of claim 24 , wherein at least one water-soluble polymer is covalently attached to a site in the active form of the moiety having Factor VIII activity.
29. The composition of claim 24 , in lyophilized form.
30. The composition of claim 24 , in the form of a liquid.
31. The composition of claim 24 , further comprising a pharmaceutically acceptable excipient.