Clotting factor-Fc chimeric proteins to treat hemophilia
View Patent ↗The invention relates to a chimeric protein comprising at least one clotting factor and at least a portion of an immunoglobulin constant region. The invention relates to a method of treating a hemostatic disorder comprising administering a therapeutically effective amount of a chimeric protein wherein the chimeric protein comprises at least one clotting factor and at least a portion of an immunoglobulin constant region.
1. A method of treating a hemostatic disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a chimeric protein, which comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises (i) a clotting factor, which is Factor VII or Factor VIIa, and (ii) at least a portion of an immunoglobulin constant region fused to the clotting factor, which is a FcRn binding partner, and the second polypeptide comprises at least a portion of an immunoglobulin constant region, which is a FcRn binding partner, without the clotting factor of said first polypeptide and without an immunoglobulin variable domain, and wherein said first polypeptide and said second polypeptide are linked.
2. The method of claim 1 , wherein the portion of an immunoglobulin constant region of the first polypeptide is an Fc fragment.
3. The method of claim 1 , wherein the portion of an immunoglobulin constant region of the second polypeptide is an Fc fragment.
4. The method of claim 1 , wherein the first polypeptide and the second polypeptide are linked via a disulfide bond.
5. The method of claim 1 , wherein the chimeric protein treats an acute bleeding episode in the subject.
6. The method of claim 1 , wherein the chimeric protein is administered intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route.
7. The method of claim 1 , wherein the chimeric protein is administered in combination with at least one other clotting factor that promotes hemostasis.
8. The method of claim 7 , wherein the at least one other clotting factor is selected from Factor V, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, prothrombin, fibrinogen, von Willebrand factor, or a combination thereof.
9. The method of claim 1 , wherein the clotting factor is fused to the portion of an immunoglobulin constant region in the first polypeptide by a linker.
10. The method of claim 1 , wherein the treatment is a reduction in the severity of a hemostatic disorder.
11. The method of claim 1 , wherein the treatment is prophylactic.
12. A method of treating a subject in need of a general hemostatic agent comprising administering to the subject a therapeutically effective amount of a chimeric protein, which comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises (i) a clotting factor, which is Factor VII or Factor VIIa, and (ii) at least a portion of an immunoglobulin constant region fused to the clotting factor, which is a FcRn binding partner, and the second polypeptide comprises at least a portion of an immunoglobulin constant region, which is a FcRn binding partner, without the clotting factor of said first polypeptide and without an immunoglobulin variable domain, and wherein said first polypeptide and said second polypeptide are linked.
13. The method of claim 12 , wherein the chimeric protein is administered intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route.
14. The method of claim 12 , wherein the chimeric protein is administered prior to, during, or after surgery.
15. The method of claim 12 , wherein the chimeric protein treats an acute bleeding episode in the subject.
16. A method of ameliorating one or more symptoms associated with a hemostatic disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a chimeric protein, which comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises (i) a clotting factor, which is Factor VII or Factor VIIa, and (ii) at least a portion of an immunoglobulin constant region fused to the clotting factor, which is a FcRn binding partner, and the second polypeptide comprises at least a portion of an immunoglobulin constant region, which is a FcRn binding partner, without the clotting factor of said first polypeptide and without an immunoglobulin variable domain, and wherein said first polypeptide and said second polypeptide are linked.
17. The method of claim 16 , wherein the chimeric protein is administered intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route.
18. The method of claim 16 , wherein the portion of an immunoglobulin constant region of the first polypeptide is an Fc fragment.
19. The method of claim 16 , wherein the portion of an immunoglobulin constant region of the second polypeptide is an Fc fragment.
20. The method of claim 16 , wherein the first polypeptide and the second polypeptide are linked via a disulfide bond.
21. The method of claim 1 , wherein the hemostatic disorder is hemophilia A or hemophilia B.
22. The method of claim 12 , wherein the clotting factor is fused to the portion of an immunoglobulin constant region in the first polypeptide chain by a linker.
23. The method of claim 22 , wherein the linker comprises 1-10 amino acids, 10-50 amino acids, 50-100 amino acids, or 100-200 amino acids.
24. The method of claim 9 , wherein the linker comprises 1-10 amino acids, 10-50 amino acids, 50-100 amino acids, or 100-200 amino acids.