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

Patent metadata

Field	Value
Publication number	US-10010622-B2
Application number	US-201214131600-A
Country	US
Kind code	B2
Filing date	Jul 6, 2012
Priority date	Jul 8, 2011
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present invention provides methods of administering Factor VIII (processed FVIII, single chain FVIII, or a combination thereof); 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 pharmaceutical composition comprising (i) a chimeric polypeptide, which comprises Factor VIII (FVIII) and a second portion, and (ii) at least one pharmaceutically acceptable excipient, wherein 15% to 25% of the FVIII of the chimeric polypeptide is single chain FVIII and 75% to 85% of the FVIII of the chimeric polypeptide is processed FVIII, wherein the single chain FVIII comprises a FVIII heavy chain and a FVIII light chain on a single polypeptide chain and the processed FVIII comprises a FVIII heavy chain and a FVIII light chain on two polypeptide chains.

2. The pharmaceutical composition of claim 1 , wherein (a) 25% of the FVIII of the chimeric polypeptide is single chain FVIII and 75% of the FVIII of the chimeric polypeptide is processed FVIII, (b) 20% of the FVIII of the chimeric polypeptide is single chain FVIII and 80% of the FVIII of the chimeric polypeptide is processed FVIII, or (c) 15% of the FVIII of the chimeric polypeptide is single chain FVIII and 85% of the FVIII of the chimeric polypeptide is processed FVIII.

3. The pharmaceutical composition of claim 1 , wherein the single chain FVIII in the chimeric polypeptide has FVIII activity comparable to processed FVIII.

4. The pharmaceutical composition of claim 1 , wherein the chimeric polypeptide is a long-acting FVIII polypeptide.

5. The pharmaceutical composition of claim 1 , wherein the second portion is selected from the group consisting of an Fc region, albumin, a PAS sequence, transferrin, CTP (28 amino acid C-terminal peptide (CTP) of hCG with its 4 O-glycans), polyethylene glycol (PEG), hydroxyethyl starch (HES), albumin binding polypeptide, albumin-binding small molecules, and two or more combinations thereof.

6. The pharmaceutical composition of claim 5 , wherein the chimeric polypeptide is a FVIIIFc monomer dimer hybrid.

7. The pharmaceutical composition of claim 1 , wherein the FVIII comprises B-domain deleted FVIII.

8. The pharmaceutical composition of claim 7 , wherein residue 1645 corresponding to full-length, mature FVIII, residue 1648 corresponding to full-length, mature FVIII, or both residues in the single chain FVIII is arginine.

9. The pharmaceutical composition of claim 4 , wherein the chimeric polypeptide has a half-life longer than a polypeptide consisting of the FVIII.

10. The pharmaceutical composition of claim 1 , which is suitable for subcutaneous, intradermal, intravascular, intravenous, intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial or intraperitoneal injection to a human.

11. The pharmaceutical composition of claim 1 , which is lyophilized.

12. The pharmaceutical composition of claim 2 , which is lyophilized.

13. The pharmaceutical composition of claim 3 , which is lyophilized.

14. The pharmaceutical composition of claim 4 , which is lyophilized.

15. The pharmaceutical composition of claim 5 , which is lyophilized.

16. The pharmaceutical composition of claim 6 , which is lyophilized.

17. The pharmaceutical composition of claim 7 , which is lyophilized.

18. The pharmaceutical composition of claim 8 , which is lyophilized.

19. The pharmaceutical composition of claim 10 , which is lyophilized.

20. The pharmaceutical composition of claim 11 , wherein 25% of the FVIII of the chimeric polypeptide is single chain FVIII and 75% of the FVIII of the chimeric polypeptide is processed FVIII.

21. The pharmaceutical composition of claim 11 , wherein 20% of the FVIII of the chimeric polypeptide is single chain FVIII and 80% of the FVIII of the chimeric polypeptide is processed FVIII.

22. The pharmaceutical composition of claim 11 , wherein 15% of the FVIII of the chimeric polypeptide is single chain FVIII and 85% of the FVIII of the chimeric polypeptide is processed FVIII.

Assignees

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

Inventors

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

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title