Method of treatment of hemorrhagic disease using a factor VIIa/tissue factor inhibitor

• US 7,329,640 B2
• Filed: 09/12/2006
• Issued: 02/12/2008
• Est. Priority Date: 05/06/2003
• Status: Expired due to Fees

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Inventors: Vlasuk, George P.
• Primary Examiner(s): CARLSON, KAREN C
• Application Number:
  US11/520,079
• Publication Number:
  US 20070010449A1
• Time in Patent Office: 518 Days
• Field of Search: 514/2, 530/350, 530/380, 530/300
• US Class Current: 514/14.3
• CPC Class Codes: A61K 38/1767 from invertebrates
• CPC Class Codes: A61K 38/55 Protease inhibitors

Abstract

The present invention provides methods of treating hemorrhagic fevers where selective inhibitors of fVIIa/TF are used as a treatment for hemorrhagic fevers and have therapeutic effects which include ameliorating and/or preventing coagulopathy and inflammatory responses. These inhibitors include certain proteins which are part of a family termed Nematode-Extracted Anticoagulant Proteins (“NAPs”). Other inhibitors include Tissue Factor Pathway Inhibitor (“TFPI”) and TFPI analogs.

Claims

1. A method of treating a mammal having a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“

NAP”

) having Factor VIIa/tissue factor inhibitory activity (“

fVIIa/TF”

), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence;

Cys-A1-Cys-A2-Cys-A3-Cys-A4-Cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-Cys-A10, wherein

(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;

(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;

(c) A3 is an amino acid sequence of 3 amino acid residues;

(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;

(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;

(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;

(g) A7 is an amino acid;

(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;

(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and

(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.

2. A method according to claim 1 wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.

3. A method according to claim 2 wherein said virus is from the family Filoviridae.

4. A method according to claim 3 wherein said NAP is AcaNAPc2 (SEQ ID NO:

3) and said virus is Marburg virus.

5. A method according to claim 3 wherein said NAP is AcaNAPc2/proline (SEQ ID NO:

4) and said virus is Marburg virus.

6. A method of treating a coagulopathy in a mammal with a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“

NAP”

) having Factor VIIa/tissue factor inhibitory activity (“

fVIIa/TF”

), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence;

Cys-A1-Cys-A2-Cys-A3-Cys-A4-Cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-Cys-A10, wherein

(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;

(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;

(c) A3 is an amino acid sequence of 3 amino acid residues;

(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;

(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;

(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;

(g) A7 is an amino acid;

(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;

(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and

(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.

7. A method according to claim 6 wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.

8. A method according to claim 7 wherein said virus is from the family Filoviridae.

9. A method according to claim 8 wherein said NAP is AcaNAPc2 (SEQ ID NO:

3) and said virus is Marburg virus.

10. A method according to claim 8 wherein said NAP is AcaNAPc2/proline (SEQ ID NO:

4) and said virus is Marburg virus.

11. A method of treating an inflammatory response in a mammal with a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“

NAP”

) having Factor VIIa/tissue factor inhibitory activity (“

fVIIa/TF”

), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence;

Cys-A1-Cys-A2-Cys-A3-Cys-A4-cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-cys-A10, wherein

(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;

(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;

(c) A3 is an amino acid sequence of 3 amino acid residues;

(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;

(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;

(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;

(g) A7 is an amino acid;

(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;

(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and

(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.

12. A method according to claim 11, wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.

13. A method according to claim 12 wherein said virus is from the family Filoviridae.

14. A method according to claim 13 wherein said NAP is AcaNAPc2 (SEQ ID NO:

3) and said virus is Marburg virus.

15. A method according to claim 13 wherein said NAP is AcaNAPc2/proline (SEQ ID NO:

4) and said virus is Marburg virus.