Polymer-factor VIII conjugate compositions
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 composition that is at least 85% free from albumin, the composition comprising a conjugate comprising a water-soluble polymer covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue that has been added to or substituted in the Factor VIII polypeptide, wherein the water-soluble polymer is selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and combinations thereof.
2. The composition of claim 1 , wherein the composition is at least 95% free from albumin.
3. The composition of claim 1 , wherein the composition is at least 99% free from albumin.
4. The composition of claim 1 , wherein the composition is free from albumin.
5. The composition of claim 1 , 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.
6. The composition of claim 5 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII.
7. The composition of claim 1 , wherein the water-soluble polymer is a poly(saccharide).
8. The composition of claim 7 , wherein the water-soluble polymer is selected from the group consisting of maltodextrin, dextran, and starch.
9. The conjugate of claim 8 , wherein the water-soluble polymer is a dextran or a starch.
10. The composition of claim 1 , wherein the water-soluble polymer is a poly(ethylene glycol).
11. The composition of claim 10 , wherein the conjugate is monoPEGylated.
12. The composition of claim 10 , 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.
13. The composition of claim 12 , 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.
14. The composition of claim 13 , 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.
15. The composition of claim 14 , 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.
16. The composition of claim 12 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 90,000 Daltons.
17. The composition of claim 1 , wherein the added or substituted cysteine residue to which the water-soluble polymer is covalently attached is located within the A1 subunit of the Factor VIII polypeptide.
18. The composition of claim 1 , wherein the added or substituted cysteine residue to which the water-soluble polymer is covalently attached is located within the A2 subunit of the Factor VIII polypeptide.
19. The composition of claim 1 , wherein the added or substituted cysteine residue to which the water-soluble polymer is covalently attached is located within the A3 subunit of the Factor VIII polypeptide.
20. The composition of claim 1 , wherein the added or substituted cysteine residue to which the water-soluble polymer is covalently attached is located within the C1 subunit of the Factor VIII polypeptide.
21. The composition of claim 1 , wherein the added or substituted cysteine residue to which the water-soluble polymer is covalently attached is located within the C2 subunit of the Factor VIII polypeptide.
22. The composition of claim 10 , wherein the conjugate is diPEGylated and comprises two poly(ethylene glycols), each covalently attached to the Factor VIII polypeptide via a thiol group of a cysteine residue that has been added to or substituted in the Factor VIII polypeptide.
23. The composition of claim 10 , 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.
24. The composition of claim 23 , wherein the poly(ethylene glycol) is terminally capped with methoxy.
25. The composition of claim 23 , wherein the poly(ethylene glycol) is terminally capped with hydroxy.
26. The composition of claim 10 , wherein the poly(ethylene glycol) is linear.
27. The composition of claim 10 , wherein the poly(ethylene glycol) is branched.
28. The composition of claim 1 , wherein the Factor VIII polypeptide is recombinant.
29. The composition of claim 1 , wherein the Factor VIII polypeptide is obtained from blood.
30. The composition of claim 1 , wherein the composition is in a lyophilized form.
31. The composition of claim 1 , wherein the composition is in a liquid form.
32. The composition of claim 1 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a thioether linkage.
33. The composition of claim 1 , wherein the water-soluble polymer is covalently attached to the Factor VIII polypeptide via a disulfide linkage.