Long-acting coagulation factors and methods of producing same
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions comprising the polypeptides and polynucleotides of the invention and methods of using and producing same are also disclosed.
1. A method of reducing excessive bleeding in a subject, the method comprising the step of administering a pharmaceutical composition comprising a CTP-modified activated Factor VII (FVIIa) polypeptide to the subject, wherein said CTP-modified activated Factor VII (FVIIa) polypeptide comprises a FVII polypeptide and three to five chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus of said CTP-modified FVII polypeptide, thereby reducing excessive bleeding in said subject.
2. The method of claim 1 , wherein the sequence of said modified Factor VII (FVII) polypeptide CTP-modified activated Factor VII (FVIIa) polypeptide is selected from the group consisting of SEQ ID NO: 25, 27, 29, and 46.
3. The method of claim 1 , wherein the sequence of at least one CTP is SEQ ID NO: 1 or SEQ ID NO: 2.
4. The method of claim 1 , wherein at least one CTP is glycosylated.
5. The method of claim 1 , wherein at least one CTP is truncated.
6. The method of claim 1 , wherein at least one CTP is attached to said activated Factor VII (FVIIa) polypeptide via a linker.
7. The method of claim 6 , wherein said linker is a peptide bond.
8. The method of claim 1 , wherein the subject is a human child.
9. The method of claim 1 , wherein said administering is via the subcutaneous route.
10. The method of claim 1 , wherein said administering is via the intravenous route.
11. The method of claim 1 , wherein said subject is afflicted with hemophilia.
12. The method of claim 1 , wherein said subject is afflicted with vitamin K deficiency.
13. The method of claim 1 , wherein said polypeptide further comprises a signal peptide.
14. The method of claim 13 , wherein said signal peptide is set forth in SEQ ID NO: 47.
15. A method of reducing excessive bleeding in a subject, the method comprising the step of administering to the subject a pharmaceutical composition comprising a CTP-modified Factor IX (FIX) polypeptide, wherein said CTP-modified Factor IX (FIX) polypeptide comprises a FIX polypeptide and three to five chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus of said CTP-modified Factor IX (FIX) polypeptide, thereby reducing excessive bleeding in said subject.
16. The method of claim 15 , wherein the sequence of said CTP-modified coagulation factor polypeptide is SEQ ID NO: 31.
17. The method of claim 15 , wherein the sequence of at least one CTP is ID NO: 1 or SEQ ID NO: 2.
18. The method of claim 15 , wherein at least one CTP is glycosylated.
19. The method of claim 15 , wherein at least one CTP is truncated.
20. The method of claim 15 , wherein at least one CTP is attached to said Factor IX (FIX) polypeptide via a linker.
21. The method of claim 15 , wherein said linker is a peptide bond.
22. The method of claim 15 , wherein the subject is a human child.
23. The method of claim 15 , wherein said administering is via the subcutaneous route.
24. The method of claim 15 , wherein said administering is via the intravenous route.
25. The method of claim 15 , wherein said subject is afflicted with hemophilia B.