Factor VIII polymer conjugates
View Patent ↗The invention is a proteinaceous construct comprising a Factor VIII molecule which is conjugated to a water-soluble polymer via carbohydrate moieties of Factor VIII, and methods of preparing same.
1. A method of administering a composition in an amount effective to treat a bleeding disorder to a subject in need thereof, comprising:
i) determining a dosage amount for a subject suffering from a bleeding disorder based on type of bleeding disorder, severity of the bleeding disorder, and the subject's clinical history; and
ii) administering a composition comprising (i) a conjugate comprising a native Factor VIII modified with a water soluble polymer bound thereto, said water soluble polymer attached to the modified Factor VIII via an oxidized carbohydrate moiety, said modified Factor VIII retaining at least 50% of native FVIII activity, and (ii) a pharmaceutically acceptable excipient.
2. The method of claim 1 , wherein said composition is substantially free from albumin.
3. The method of claim 1 , wherein said water soluble polymer is attached to said oxidized carbohydrate moiety via a linker.
4. The method of claim 3 , wherein said linker is 4-[4-N-maleimidophenyl]butyric acid hydrazide (MBPH).
5. The method of claim 3 , wherein the linker is releasable or hydrolysable.
6. The method of claim 1 , wherein said oxidized carbohydrate moiety is located in a native Factor VIII B domain.
7. The method of claim 1 , wherein said water soluble polymer is selected from the group consisting of polyethylene glycol (PEG), polysialic acid (PSA) and dextran.
8. The method according to claim 1 , wherein said modified Factor VIII retains at least 60% of native FVIII activity.
9. The method according to claim 8 , wherein said modified Factor VIII retains at least 70% of native FVIII activity.
10. The method according to claim 1 , wherein said bleeding disorder is hemophilia A.
11. The method of claim 1 , wherein said water soluble polymer has a molecular weight of 2,000 to 150,000 Da.
12. The method of claim 11 , wherein said water soluble polymer has a molecular weight of 5,000 to 50,000 Da.
13. The method of claim 1 , wherein said water soluble polymer is branched.
14. The method of claim 1 , wherein said water soluble polymer is linear.
15. The method of claim 1 , wherein the Factor VIII is recombinant Factor VIII.
16. The method of claim 1 , wherein the Factor VIII is plasmatic Factor VIII.
17. The method of claim 1 , wherein the composition comprises a plurality of conjugates, each having at least one water soluble polymer bound to a native Factor VIII, said water soluble polymer attached to the modified Factor VIII via one or more oxidized carbohydrate moieties, said modified Factor VIII retaining at least 50% of native FVIII activity, and (ii) a pharmaceutically acceptable excipient.
18. The method of claim 1 , wherein the composition further comprises an unconjugated Factor VIII moiety.
19. A kit comprising a pharmaceutical composition comprising (i) a conjugate comprising a native Factor VIII modified with a water soluble polymer bound thereto, said water soluble polymer attached to the modified Factor VIII via an oxidized carbohydrate moiety, said modified Factor VIII retaining at least 50% of native FVIII activity, and (ii) a pharmaceutically acceptable excipient; packaged in a container with a label that describes use of the pharmaceutical composition in the method of claim 1 .
20. A kit according to claim 19 , wherein the pharmaceutical composition is packaged in a unit dose form.
21. A kit comprising a first container comprising a conjugate comprising a native Factor VIII modified with a water soluble polymer bound thereto, said water soluble polymer attached to the modified Factor VIII via an oxidized carbohydrate moiety, said modified Factor VIII retaining at least 50% of native FVIII activity, and a second container comprising a physiologically acceptable reconstitution solution for said conjugate in the first container, wherein said kit is packaged with a label that describes use of the pharmaceutical composition in the method of claim 1 .
22. A kit according to claim 21 , wherein the pharmaceutical composition is packaged in a unit dose form.