Factor VIII-FC chimeric and hybrid polypeptides, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11266720-B2
Application number	US-201916270302-A
Country	US
Kind code	B2
Filing date	Feb 7, 2019
Priority date	Dec 6, 2009
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The present invention provides methods of administering Factor VIII; methods of administering chimeric and hybrid polypeptides comprising Factor VIII; chimeric and hybrid polypeptides comprising Factor VIII; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells.

First claim

What is claimed is:

1. A method of reducing the incidence of a bleeding episode in a human subject with hemophilia A, comprising
administering to the human subject multiple doses of a chimeric polypeptide comprising a Factor VIII portion and an Fc portion at a dosing interval of about three to about five days, wherein each of the multiple doses is about 25-100 IU/kg, wherein the chimeric polypeptide is administered intravenously.

2. The method of claim 1 , wherein said dosing interval of said chimeric polypeptide is about every five days.

3. The method of claim 1 , wherein said dosing interval of said chimeric polypeptide is about once every 4 days.

4. The method of claim 1 , wherein the Factor VIII portion of said chimeric polypeptide is at least 90% or 95% identical to a Factor VIII amino acid sequence with a signal sequence selected from the group consisting of amino acids 1 to 1457 of SEQ ID NO:2; amino acids 1 to 2351 of SEQ ID NO:6; amino acids 1 to 759 of SEQ ID NO:8; amino acids 1 to 764 of SEQ ID NO:10; and amino acids 1 to 704 of SEQ ID NO:12 or at least 90% or 95% identical to a Factor VIII amino acid sequence without a signal sequence selected from the group consisting of amino acids 20 to 1457 of SEQ ID NO:2; amino acids 20 to 2351 of SEQ ID NO:6; amino acids 20 to 759 of SEQ ID NO:8; amino acids 20 to 764 of SEQ ID NO:10; and amino acids 21 to 704 of SEQ ID NO:12, and
wherein said chimeric polypeptide is in the form of a hybrid comprising a second polypeptide in association with said chimeric polypeptide, wherein said second polypeptide consists essentially of an Fc.

5. The method of claim 4 , wherein said chimeric polypeptide comprises a sequence at least 90% or 95% identical to the Factor VIII and Fc amino acid sequence without a signal sequence set forth as amino acids 20 to 1684 of SEQ ID NO:2 or at least 90% or 95% identical to the Factor VIII and Fc amino acid sequence with a signal sequence set forth as amino acids 1 to 1684 of SEQ ID NO:2.

6. A method for prophylactic treatment of a spontaneous bleeding episode in a human subject with hemophilia A, comprising
administering to the subject multiple doses of a chimeric polypeptide comprising a Factor VIII portion and an Fc portion at a dosing interval of about three to about five days, wherein each of the multiple doses is about 25-65 IU/kg, wherein the chimeric polypeptide is administered intravenously.

7. The method of claim 6 , wherein said Factor VIII portion is at least 90% or 95% identical to a Factor VIII amino acid sequence without a signal sequence selected from the group consisting of amino acids 20 to 1457 of SEQ ID NO:2; amino acids 20 to 2351 of SEQ ID NO:6; amino acids 20 to 759 of SEQ ID NO:8; amino acids 20 to 764 of SEQ ID NO:10; and amino acids 21 to 704 of SEQ ID NO:12.

8. The method of claim 6 , wherein said Factor VIII portion is at least 90% or 95% identical to a Factor VIII amino acid sequence with a signal sequence selected from the group consisting of amino acids 1 to 1457 of SEQ ID NO:2; amino acids 1 to 2351 of SEQ ID NO:6; amino acids 1 to 759 of SEQ ID NO:8; amino acids 1 to 764 of SEQ ID NO:10; and amino acids 1 to 704 of SEQ ID NO:12, and
wherein said Fc portion is at least 90%, at least 95%, or 100% identical to an Fc amino acid sequence selected from the group consisting of amino acids 1458 to 1684 of SEQ ID NO:2;
amino acids 2352 to 2578 of SEQ ID NO:6; amino acids 760 to 986 of SEQ ID NO:8; amino acids 765 to 991 of SEQ ID NO:10; and amino acids 705 to 931 of SEQ ID NO:12.

9. The method of claim 6 , wherein said chimeric polypeptide is a Factor VIII-Fc chimeric polypeptide in the form of a hybrid comprising a second polypeptide in association with said chimeric polypeptide, wherein said second polypeptide consists essentially of an Fc, wherein said chimeric polypeptide comprises a sequence at least 95% identical to the Factor VIII and Fc amino acid sequence without a signal sequence set forth as amino acids 20 to 1684 of SEQ ID NO:2 or at least 90% or 95% identical to the Factor VIII and Fc amino acid sequence with a signal sequence set forth as amino acids 1 to 1684 of SEQ ID NO:2.

10. The method of claim 1 , wherein the chimeric polypeptide comprises a FVIII portion and two Fcs, wherein one of the Fcs is fused to the C-terminus of the light chain of the FVIII portion.

11. The method of claim 1 , wherein the chimeric polypeptide is a rFVIIIFc monomer dimer hybrid recombinant fusion protein comprising a single molecule of recombinant B-domain deleted human FVIII fused to the dimeric Fc domain of human IgG1, with no intervening linker sequence.

12. The method of claim 1 , wherein the hemophilia A is severe hemophilia A.

13. The method of claim 1 , wherein each of the multiple doses is about 70-80 IU/kg.

14. The method of claim 1 , wherein each of the multiple doses is about 80-90 IU/kg.

15. The method of claim 1 , wherein each of the multiple doses is about 90-100 IU/kg.

16. The method of claim 6 , wherein the chimeric polypeptide comprises a FVIII portion and two Fcs, wherein one of the Fcs is fused to the C-terminus of the light chain of the FVIII portion.

17. The method of claim 6 , wherein the chimeric polypeptide is a rFVIIIFc monomer dimer hybrid recombinant fusion protein comprising a single molecule of recombinant B-domain deleted human FVIII fused to the dimeric Fc domain of human IgG1, with no intervening linker sequence.

18. The method of claim 6 , wherein the hemophilia A is severe hemophilia A.

19. The method of claim 6 , wherein each of the multiple doses is about 70-80 IU/kg.

20. The method of claim 6 , wherein each of the multiple doses is about 80-90 IU/kg.

21. The method of claim 6 , wherein each of the multiple doses is about 90-100 IU/kg.

22. A method for treating a bleeding episode in a human subject with hemophilia A, comprising
administering to the subject multiple doses of a chimeric polypeptide comprising a Factor VIII portion and an Fc portion at a dosing interval of about three to about five days, wherein each of the multiple doses is about 25-80 IU/kg, wherein the chimeric polypeptide is administered intravenously.

23. The method of claim 22 , wherein said Factor VIII portion is at least 90% or 95% identical to a Factor VIII amino acid sequence without a signal sequence selected from the group consisting of amino acids 20 to 1457 of SEQ ID NO:2; amino acids 20 to 2351 of SEQ ID NO:6; amino acids 20 to 759 of SEQ ID NO:8; amino acids 20 to 764 of SEQ ID NO:10; and amino acids 21 to 704 of SEQ ID NO:12.

24. The method of claim 22 , wherein said Factor VIII portion is at least 90% or 95% identical to a Factor VIII amino acid sequence with a signal sequence selected from the group consisting of amino acids 1 to 1457 of SEQ ID NO:2; amino acids 1 to 2351 of SEQ ID NO:6; amino acids 1 to 759 of SEQ ID NO:8; amino acids 1 to 764 of SEQ ID NO:10; and amino acids 1 to 704 of SEQ ID NO:12, and
wherein said Fc portion is at least 90%, at least 95%, or 100% identical to an Fc amino acid sequence selected from the group consisting of amino acids 1458 to 1684 of SEQ ID NO:2; amino acids 2352 to 2578 of SEQ ID NO:6; amino acids 760 to 986 of SEQ ID NO:8; amino acids 765 to 991 of SEQ ID NO:10; and amino acids 705 to 931 of SEQ ID NO:12.

25. The method of claim 22 , wherein said chimeric polypeptide is a Factor VIII-Fc chimeric polypeptide in the form of a hybrid comprising a second polypeptide in association

Assignees

• Bioverativ Therapeutics Inc

Inventors

• Dumont Jennifer A
• Low Susan
• Bitonti Alan J
• Pierce Glenn
• Luk Alvin
• Jiang Haiyan
• Mckinney Byron
• Ottmer Matt
• Sommer Jurg
• Nugent Karen
• Li Lian
• Peters Robert

Classifications

• Y02A90/10

  Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation · CPC title

• A61K47/643

  Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL] · CPC title

• C07K16/46

  Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00) · CPC title

• A61K38/37 Primary

  Factors VIII · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title