Fibrin(ogen) degradation by fibrinolytic matrix metalloproteinase

• US 5,830,468 A
• Filed: 05/17/1995
• Issued: 11/03/1998
• Est. Priority Date: 05/17/1995
• Status: Expired due to Fees

• Current Assignee: New York Blood Center Incorporated
• Original Assignee: New York Blood Center Incorporated
• Inventors: Bini, Alessandra
• Primary Examiner(s): Walsh, Stephen
• Assistant Examiner(s): KEMMERER, ELIZABETH
• Application Number:
  US08/446,887
• Time in Patent Office: 1,266 Days
• Field of Search: 424/94.67, 424/94.64, 424/94.1, 424/93.21, 206/210, 604/173, 530/389.3, 435/219
• US Class Current: 424/94.67
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention provides a method of causing the degradation of fibrin(ogen) (i.e., fibrin, fibrinogen, and related substances) by means of a fibrinolytic metalloproteinase, such as MMP-3. The method of the invention may be performed in vitro to provide diagnostic information characterizing fibrin(ogen) and the fibrinolytic physiology. The method may also be performed in vivo as a method of thrombolytic therapy in which a fibrinolytic metalloproteinase is administered to a subject to degrade thrombus in situ. The invention further provides compositions containing a fibrinolytic metalloproteinase for the performance of fibrinolytic or thrombolytic procedures. Also provided are kits which include a fibrinolytic metalloproteinase for performing fibrinolytic or thrombolytic procedures.

Claims

1. A method of degrading fibrin(ogen), comprising:

contacting said fibrin(ogen) with an effective amount of a fibrinolytic matrix metalloproteinase.

2. The method of claim 1, wherein said fibrinolytic matrix metalloproteinase is endogenous to a mammal.

3. The method of claim 1, wherein said fibrinolytic matrix metalloproteinase is a stromelysin.

4. The method of claim 1, wherein said fibrinolytic matrix metalloproteinase is matrix metalloproteinase-3 (MMP-3).

5. The method of claim 1, wherein said method further comprises:

contacting said fibrin(ogen) with an effective amount of an adjunct composition comprising at least one adjunct compound having activity in fibrinolysis.

6. The method of claim 5, wherein said adjunct composition comprises a plasminogen activator, hirudin, an enzyme inhibitor, an anticoagulant, or a combination thereof.

7. The method of claim 6, wherein said adjunct composition comprises a urokinase-plasminogen activator (u-PA), a tissue-type plasminogen activator (t-PA), a streptokinase, a staphylokinase, or a combination thereof.

8. The method of claim 1, wherein said method is performed ex vivo.

9. The method of claim 1, wherein said method is performed in vivo.

10. A method of fibrinolytic therapy, comprising:

administering to a subject in need of fibrinolytic therapy a therapeutically effective amount of a fibrinolytic matrix metalloproteinase.

11. The method of claim 10, wherein said fibrinolytic matrix metalloproteinase is endogenous to the species of the subject.

12. The method of claim 10, wherein said fibrinolytic matrix metalloproteinase is a stromelysin.

13. The method of claim 10, wherein said fibrinolytic matrix metalloproteinase is matrix metalloproteinase-3 (MMP-3).

14. The method of claim 10, wherein said method further comprises:

administering to said subject a therapeutically effective amount of an adjunct composition comprising at least one adjunct compound having activity in fibrinolysis.

15. The method of claim 14, wherein said adjunct composition comprises a plasminogen activator, hirudin, an enzyme inhibitor, an anticoagulant, or a combination thereof.

16. The method of claim 15, wherein said adjunct composition comprises a urokinase-plasminogen activator (u-PA), a tissue-type plasminogen activator (t-PA), a streptokinase, a staphylokinase, or a combination thereof.

17. A composition for thrombolytic therapy, comprising:

a fibrinolytic matrix metalloproteinase,

at least one adjunct compound having activity in fibrinolysis, and

a pharmaceutically acceptable carrier.

18. The composition of claim 17, wherein said fibrinolytic matrix metalloproteinase is endogenous to a mammal.

19. The composition of claim 17, wherein said fibrinolytic matrix metalloproteinase is a stromelysin.

20. The composition of claim 17, wherein said fibrinolytic matrix metalloproteinase is matrix metalloproteinase-3 (MMP-3).

21. The composition of claim 17, wherein said composition comprises a plasminogen activator, hirudin, an enzyme inhibitor, an anticoagulant, or a combination thereof.

22. The composition of claim 21, wherein said composition comprises a urokinase-plasminogen activator (u-PA), a tissue-type plasminogen activator (t-PA), a streptokinase, a staphylokinase, or a combination thereof.

23. A kit for performing thrombolytic therapy, comprising:

a composition comprising a fibrinolytic matrix metalloproteinase, at least one adjunct composition comprising at least one adjunct compound having activity in fibrinolysis, and a container.

24. The kit of claim 23, wherein said fibrinolytic matrix metalloproteinase is endogenous to mammal.

25. The kit of claim 23, wherein said fibrinolytic matrix metalloproteinase is a stromelysin.

26. The kit of claim 23, wherein said fibrinolytic matrix metalloproteinase is matrix metalloproteinase-3 (MMP-3).

27. The kit of claim 23, wherein said adjunct composition comprises a plasminogen activator, hirudin, an enzyme inhibitor, an anticoagulant, or a combination thereof.

28. The kit of claim 27, wherein said adjunct composition comprises a urokinase-plasminogen activator (u-PA), a tissue-type plasminogen activator (t-PA), a streptokinase, a staphylokinase, or a combination thereof.

29. The kit of claim 23, further comprising means for administering a therapeutically effective amount of said composition.

30. The kit of claim 29, wherein said administering means includes means for administering said composition parenterally.