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 a Factor VIII polypeptide covalently attached to one, two, three or four water-soluble polymers via a degradable 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, and
(ii) the water-soluble polymer is selected from the group consisting of poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(acryloylmorpholine).
2. The conjugate of claim 1 , wherein the water-soluble polymer is a poly(alkylene oxide).
3. The conjugate of claim 2 , wherein the poly(alkylene oxide) is a poly(ethylene glycol).
4. The conjugate of claim 3 , 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.
5. The conjugate of claim 3 , wherein the poly(ethylene glycol) is terminally capped with methoxy.
6. The conjugate of claim 3 , wherein the poly(ethylene glycol) is terminally capped with hydroxy.
7. The conjugate of claim 3 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of greater than 5,000 Daltons to 150,000 Daltons.
8. The conjugate of claim 7 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from 10,000 Daltons to 85,000 Daltons.
9. The conjugate of claim 8 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from 20,000 Daltons to 85,000 Daltons.
10. The conjugate of claim 9 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from 53,000 Daltons to 75,000 Daltons.
11. The conjugate of claim 2 , wherein the water-soluble polymer is linear.
12. The conjugate of claim 2 , wherein the water-soluble polymer is branched.
13. The conjugate of claim 1 , wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, and Factor VIII:vWF.
14. The conjugate of claim 1 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII.
15. The conjugate of claim 1 , wherein the Factor VIII polypeptide is Factor VIII:vWF.
16. The conjugate of claim 1 , wherein hydrolysis of the degradable linkage is effective to release the parent Factor VIII polypeptide.
17. The conjugate of claim 1 , wherein the Factor VIII polypeptide is recombinantly derived.
18. The conjugate of claim 1 , wherein the Factor VIII polypeptide is blood-derived.
19. A composition comprising the conjugate of claim 1 .