Modified factor VIIa

• US 7,173,000 B2
• Filed: 11/09/2001
• Issued: 02/06/2007
• Est. Priority Date: 11/09/2000
• Status: Active Grant

• Current Assignee: The Scripps Research Institute
• Original Assignee: The Scripps Research Institute
• Inventors: Ruf, Wolfram, Petrovan, Ramona J.
• Primary Examiner(s): Kerr; Kathleen M.
• Assistant Examiner(s): SCHNIZER, HOLLY G
• Application Number:
  US10/415,963
• Publication Number:
  US 20040033566A1
• Time in Patent Office: 1,915 Days
• Field of Search: None
• US Class Current: 514/14.3
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 16/36 against blood coagulation factors
• CPC Class Codes: C12N 9/6437 Coagulation factor VIIa (3.4.21.21)
• CPC Class Codes: C12Y 304/21021 Coagulation factor VIIa (3.4.21.21)

Abstract

A modified factor VIIa is provided. The modified factor has increased amidolytic activity in the absence of T.F. and a higher affinity for T.F. when compared to the native factor VIIa but does not have substantially altered proteolytic activity when bound to T.F. Nucleic acid molecules that encode the factor, expression vectors that contain the nucleic acid molecules, cells that contain the nucleic acid molecules, and cells transformed with the expression vector are also provided. In a preferred embodiment, the modified factor is a human factor VIIa.

Claims

1. A wild-type Factor VII modified by a single substitution at position Met298 relative to wild-type human Factor VII, wherein said substitution is selected from the group consisting of Gln(Q), Glu(E), Asn(N), and Ser(S), wherein the wild-type Factor VII has amidolytic activity.

2. A Factor VII as defined in claim 1, wherein said substitution is M298Q.

3. A pharmaceutical formulation comprising a modified Factor VII as defined in claim 2 and a pharmaceutically acceptable carrier.

4. A method for treating a bleeding disorder, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical formulation as defined in claim 3.

5. An isolated nucleic acid encoding a modified Factor VII as defined in claim 1.

6. A vector comprising an isolated nucleic acid as defined in claim 5.

7. An isolated host cell comprising a nucleic acid as defined in claim 5.

8. A method for producing a modified Factor VII, the method comprising (i) culturing a cell as defined in claim 7 under conditions suitable for expression of the modified Factor VII, and (ii) recovering the modified Factor VII from the culture medium.

9. A wild-type Factor VII as defined in claim 1, wherein said wild-type Factor VII exhibits increased amidolytic activity relative to wild-type human Factor VII.

10. A pharmaceutical formulation comprising a modified Factor VII as defined in claim 1 and a pharmaceutically acceptable carrier.

11. A method for treating a bleeding disorder, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical formulation as defined in claim 10.

12. An isolated nucleic acid encoding a modified Factor VII as defined in claim 1.

13. A vector comprising an isolated nucleic acid as defined in claim 12.

14. An isolated host cell comprising a nucleic acid as defined in claim 12.

15. A method for producing a modified Factor VII, the method comprising (i) culturing a cell as defined in claim 14 under conditions suitable for expression of the modified Factor VII, and (ii) recovering the modified Factor VII from the culture medium.