Factor VIII compositions and methods

• US 7,211,559 B2
• Filed: 10/20/2004
• Issued: 05/01/2007
• Est. Priority Date: 10/31/2003
• Status: Expired due to Fees

• Current Assignee: University of Maryland Baltimore County (University of Maryland)
• Original Assignee: University of Maryland Baltimore County (University of Maryland)
• Inventors: Saenko, Evgueni L., Ananyeva, Natalya M., Sarafanov, Andrey G.
• Primary Examiner(s): Nashed; Nashaat T.
• Assistant Examiner(s): Schnizer; Holly
• Application Number:
  US10/968,286
• Publication Number:
  US 20050100990A1
• Time in Patent Office: 923 Days
• Field of Search: None
• US Class Current: 514/13.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/755 Factors VIII , e.g. factor VIII C (AHF), factor VIII Ag (VWF)

Abstract

The present invention provides methods of increasing the half-life and/or specific activity of factor VIII. More specifically, the invention provides methods of increasing the half-life and/or specific activity of factor VIII by substituting one or more amino acids in the A2 domain. It further provides methods for producing such factor VIII mutants. The invention also provides polynucleotides encoding the mutant factor VIII, and methods of treating hemophilia using the polypeptides and polynucleotides of the invention.

Claims

1. A mutant factor VIII comprising an amino acid substitution at one or more positions selected from the group consisting of a position corresponding to Lys(377) and Lys(466) of SEQ ID NO:

5, and optionally at one or more positions selected from the group consisting of a substitution at a position corresponding to Lys(380), Ser(488), Arg(489), Arg(490), Leu(491), Lys(493), Lys(496), His(497), Lys(499), Lys(512), Lys(523), and Lys(556) of SEQ ID NO;

5, wherein the mutant factor VIII has procoagulant activity.

2. A pharmaceutically acceptable composition comprising the mutant factor VIII of claim 1.

3. A method of treating hemophilia comprising administering to a patient in need thereof an effective amount of the composition of claim 2.

4. The mutant factor VIII of claim 1, further comprising an amino acid substitution at one or more additional positions in the A2 domain.

5. A pharmaceutically acceptable composition comprising the mutant factor VIII of claim 4.

6. A method of treating hemophilia comprising administering to a patient in need thereof an effective amount of the composition of claim 5.

7. A mutant factor VIII comprising an amino acid substitution at one or more positions selected from the group consisting of a position corresponding to Lys(377) and Lys(466) of SEQ ID NO:

2, and optionally at one or more substitutions selected from the group consisting of a substitution at a position corresponding to Lys(380), Ser(488), Arg(489), Arg(490), Leu(491), Lys(493), Lys(496), His(497), Lys(499), Lys(512), Lys(523), and Lys(556) of SEQ ID NO;

2, wherein the mutant factor VIII has procoagulant activity.

8. A pharmaceutically acceptable composition comprising the mutant factor VIII of claim 7.

9. A method of treating hemophilia comprising administering to a patient in need thereof an effective amount of the composition of claim 8.

10. The mutant factor VIII of claim 7, further comprising an amino acid substitution at one or more additional positions in the A2 domain.

11. A pharmaceutically acceptable composition comprising the mutant factor VIII of claim 10.

12. A method of treating hemophilia comprising administering to a patient in need thereof an effective amount of the composition of claim 11.