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

• US 20070010449A1
• Filed: 09/12/2006
• Published: 01/11/2007
• Est. Priority Date: 05/06/2003
• Status: Active Grant

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Inventors: Vlasuk, George
• Granted Patent: US 7,329,640 B2
• Time in Patent Office: Days
• US Class Current: 514/14.300
• 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 hemorrhagic fever which comprises administering to said mammal an amount of a selective Factor VIIa/tissue factor inhibitor effective to ameliorate symptoms of said fever.

2. A method according to claim 1 wherein said hemorrhagic fever is caused by a virus.

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

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

5. A method according to claim 1 wherein said inhibitor is selected from the group consisting of an Nematode-Extracted Anticoagulant Protein (“

NAP”

) having Factor VIIa/tissue factor inhibitory activity (“

fVIIa/TF”

) and tissue factor pathway inhibitor (“

TFPI”

) or a TFPI analog.

6. A method according to claim 5 wherein said NAP is an isolated protein having fVIIa/TF inhibitory activity and having 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;

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

(d) A4 is an amino acid sequence;

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

(f) A6 is an amino acid sequence;

(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;

wherein each of A2, A4, A6 and A10 has an independently selected number of independently selected amino acid residues and each sequence is selected such that each NAP domain has in total less than about 120 amino acid residues.

7. A method according to claim 6 wherein said NAP is AcaNAPc2 (SEQ. ID. NO. 3).

8. A method according to claim 6 wherein said NAP is AcaNAPc2/proline (SEQ. ID. NO. 4).

9. A method according to claim 5 wherein said inhibitor is TFPI or a TFPI analog.

10. A method of treating a mammal having a hemorrhagic fever which comprises administering to said mammal a therapeutically effective amount of a compound which specifically inhibits the catalytic activity of the fVIIa/TF complex in the presence of Factor Xa (“

fXa”

) or catalytically inactive fXa derivative and does not specifically inhibit the catalytic activity of the fVIIa/TF complex in the absence of fXa or catalytically inactive fXa derivative and does not specifically inhibit the activity of fVIIa in the absence of the TF and does not specifically inhibit prothrombinase.

11. A method according to claim 10 wherein said hemorrhagic fever is caused by a virus.

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 10 wherein said compound is selected from the group consisting of a NAP having fVIIa/TF inhibitory activity and a TFPI or a TFPI analog.

15. A method according to claim 14 wherein said NAP is an isolated protein having fVIIa/TF inhibitory activity and having 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;

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

(d) A4 is an amino acid sequence;

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

(f) A6 is an amino acid sequence;

(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;

wherein each of A2, A4, A6 and A10 has an independently selected number of independently selected amino acid residues and each sequence is selected such that each NAP domain has in total less than about 120 amino acid residues.

16. A method according to claim 15 wherein said NAP is AcaNAPc2 (SEQ. ID. NO. 3).

17. A method according to claim 15 wherein said NAP is AcaNAPc2/proline (SEQ. ID. NO. 4).

18. A method according to claim 14 wherein said compound is TFPI or a TFPI analog.

19. A method of treating coagulopathy and/or an inflammatory response due to a hemorrhagic fever in a mammal which comprises administering to said mammal an amount of a selective fVIIa/TF inhibitor effective to decrease or prevent said coagulopathy and/or inflammatory response in said mammal.

20. A method according to claim 19 wherein said hemorrhagic fever is caused by a virus.

21. A method according to claim 20 wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.

22. A method according to claim 21 wherein said virus is from the family Filoviridae.

23. A method according to claim 19 wherein said inhibitor is selected from the group consisting of a NAP having fVIIa/TF inhibitory activity and a TFPI or a TFPI analog.

24. A method according to claim 23 wherein said NAP is an isolated protein having fVIIa/TF inhibitory activity and having 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;

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

(d) A4 is an amino acid sequence;

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

(f) A6 is an amino acid sequence;

(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;

wherein each of A2, A4, A6 and A10 has an independently selected number of independently selected amino acid residues and each sequence is selected such that each NAP domain has in total less than about 120 amino acid residues.

25. A method according to claim 24 wherein said NAP is AcaNAPc2 (SEQ. ID. NO. 3).

26. A method according to claim 24 wherein said NAP is AcaNAPc2/proline (SEQ. ID. NO. 4).

27. A method according to claim 23 wherein said compound is TFPI or a TFPI analog.