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 chimeric protein comprising a first polypeptide chain and a second polypeptide chain,
wherein said first chain comprises (i) a clotting factor, which is Factor VII or Factor VIIa, and (ii) an immunoglobulin constant region or portion thereof fused to the clotting factor, which is a neonatal Fc Receptor (FcRn) binding partner, and
said second chain comprises an immunoglobulin constant region or portion thereof, which is a FcRn binding partner, without the clotting factor of said first chain and without an immunoglobulin variable domain, and
wherein said first chain and said second chain are linked.
2. The chimeric protein of claim 1 , wherein said clotting factor is fused to the immunoglobulin constant region or portion thereof by a linker.
3. The chimeric protein of claim 2 , wherein the linker comprises about 1 to about 20 amino acids.
4. The chimeric protein of claim 2 , wherein the linker comprises the sequence (GlyGlySer)n or SEQ ID NO: 31, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
5. The chimeric protein of claim 1 , wherein the portion of an immunoglobulin constant region of the first chain is an Fc fragment.
6. The chimeric protein of claim 5 , wherein the portion of an immunoglobulin constant region of the second chain is an Fc fragment.
7. The chimeric protein of claim 5 , wherein the Fc fragment comprises an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO: 3, wherein said amino acid sequence binds to FcRn.
8. The chimeric protein of claim 6 , wherein the Fc fragment comprises an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO: 3, wherein said amino acid sequence hinds to FcRn.
9. The chimeric protein of claim 1 , wherein the immunoglobulin constant region or portion thereof of the first chain and the immunoglobulin constant region or portion thereof of the second chain are identical.
10. The chimeric protein of claim 1 , wherein said first chain and said second chain are linked covalently or non-covalently.
11. The chimeric protein of claim 1 , Wherein said first chain and second chain are linked via a disulfide bond.
12. The chimeric protein of claim 1 , wherein said second chain consists of the immunoglobulin constant region or portion thereof comprising a FcRn biding partner.
13. A pharmaceutical composition comprising the chimeric protein of claim 1 and a pharmaceutically acceptable carrier.
14. The composition of claim 13 , which promotes hemostasis.
15. The composition of claim 14 , which is formulated for oral administration, buccal administration, sublingual administration, intravenous injection, subcutaneous injection, intramuscular injection, nasal administration, rectal administration, vaginal administration, pulmonary administration, or inhalation.
16. The composition of claim 13 , further comprising at least one agent, which is capable of treating a disease or condition.
17. The composition of claim 16 , Wherein said at least one agent is a protein comprising a clotting factor.
18. The composition of claim 17 , wherein said clotting factor is selected from the group consisting of Factor V, Factor VII, Factor VIIa, Factor VIII, Factor VIIIa, Factor IX, Factor IXa, Factor X, Factor Xa, Factor XI, Factor XII, Factor XIII, fibrinogen, prothrombin, von Willebrand factor, and a combination thereof.
19. A chimeric protein having the formula:
X-L-F:F or F:F-L-X
wherein F is an immunoglobulin constant region or portion thereof comprising an FcRn binding partner, L is a linker or a direct bond, X is Factor VII or Factor VIIa, and: is a covalent or non-covalent bond.
20. The chimeric protein of claim 19 , wherein said F is an Fc fragment.
21. The chimeric protein of claim 19 , wherein said F in X-L-F and said F in F are identical.
22. The chimeric protein of claim 19 , wherein the linker comprises about 1 to about 20 amino acids.
23. The chimeric protein of claim 22 , wherein the linker comprises the sequence (GlyGlySer)n or SEQ ID NO: 31, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
24. The chimeric protein of claim 19 , wherein said (:) is a disulfide bond.