Claims
- 1. A method for promoting coagulation in prothrombotic blood vessels of an animal, comprising administering to said animal a composition comprising at least a first coagulation-deficient Tissue Factor compound in an amount sufficient to promote coagulation preferentially in said prothrombotic blood vessels.
- 2. The method of claim 1, wherein said prothrombotic blood vessels are associated with a vascularized tumor.
- 3. A method for promoting coagulation in the tumor vasculature of an animal having a vascularized tumor, comprising administering to said animal a composition comprising at least a first coagulation-deficient Tissue Factor compound in an amount effective to preferentially promote coagulation in said tumor vasculature.
- 4. The method of claim 3, wherein said composition is administered to said animal systemically and wherein said coagulation-deficient Tissue Factor compound preferentially localizes to said tumor vasculature.
- 5. A method for treating an animal having a vascularized tumor, comprising administering to said animal a biologically effective amount of a coagulating composition that comprises an amount of a first coagulation-deficient Tissue Factor compound sufficient to specifically promote coagulation in the vasculature of said tumor.
- 6. The method of claim 5, wherein said composition is administered to said animal via intravenous injection.
- 7. A method for treating an animal having a vascularized tumor, comprising systemically administering to said animal a biologically effective amount of a composition comprising at least a first coagulation-deficient Tissue Factor compound in an amount effective to promote coagulation specifically in the tumor vasculature and to cause tumor necrosis.
- 8. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is between about 100-fold and about 1,000,000-fold less active than full length, native Tissue Factor.
- 9. The method of claim 8, wherein said coagulation-deficient Tissue Factor compound is at least about 1,000-fold less active than full length, native Tissue Factor.
- 10. The method of claim 9, wherein said coagulation-deficient Tissue Factor compound is at least about 10,000-fold less active than full length, native Tissue Factor.
- 11. The method of claim 10, wherein said coagulation-deficient Tissue Factor compound is at least about 100,000-fold less active than full length, native Tissue Factor.
- 12. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is a human Tissue Factor compound.
- 13. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is prepared by recombinant expression.
- 14. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is deficient in binding to a phospholipid surface.
- 15. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is a truncated Tissue Factor.
- 16. The method of claim 15, wherein said coagulation-deficient Tissue Factor compound is about 219 amino acids in length.
- 17. The method of claim 15, wherein said coagulation-deficient Tissue Factor compound consists essentially of the amino acid sequence of SEQ ID NO:1.
- 18. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is a dimeric Tissue Factor.
- 19. The method of claim 18, wherein said coagulation-deficient Tissue Factor compound is a polymeric Tissue Factor.
- 20. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor deficient in the ability to activate Factor VII.
- 21. The method of claim 20, further comprising administering to said animal an amount of Factor VIIa sufficient to increase tumor vasculature coagulation and tumor necrosis.
- 22. The method of claim 7, wherein said coagulation-deficient Tissue Factor compound has been modified to increase its biological half life.
- 23. The method of claim 22, wherein said coagulation-deficient Tissue Factor compound is operatively linked to a carrier molecule.
- 24. The method of claim 23, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an albumin or a globulin.
- 25. The method of claim 23, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an antibody or portion thereof, wherein the antibody does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma.
- 26. The method of claim 25, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an IgG molecule.
- 27. The method of claim 25, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an Fc portion of an antibody.
- 28. The method of claim 25, wherein said coagulation-deficient Tissue Factor compound has been introduced into an IgG molecule in place of the CH3 domain.
- 29. The method of claim 7, further comprising administering to said animal a biologically effective amount of at least a second therapeutic compound selected from the group consisting of Factor VIIa, an activator of Factor VIIa and an anti-cancer agent.
- 30. The method of claim 29, further comprising administering to said animal a biologically effective amount of at least a first anti-cancer agent.
- 31. The method of claim 30, wherein said at least a first anti-cancer agent is a chemotherapeutic agent.
- 32. The method of claim 30, wherein said at least a first anti-cancer agent is an antibody construct comprising an antibody or antigen binding region that specifically binds to a component of a tumor cell, tumor vasculature or tumor stroma, the antibody operatively linked to a cytotoxic agent or to a coagulation factor.
- 33. The method of claim 29, further comprising administering to said animal a biologically effective amount of at least one of Factor VIIa or an activator of Factor VIIa.
- 34. The method of claim 7, wherein said composition is administered to said animal via intravenous injection.
- 35. The method of claim 7, wherein said composition further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound.
- 36. The method of claim 7, wherein said animal has a vascularized tumor of at least about medium size.
- 37. The method of claim 36, wherein said animal has a large vascularized tumor.
- 38. The method of claim 7, wherein said animal is a human subject.
- 39. A method for treating an animal having a vascularized tumor, comprising administering to said animal at least a first coagulation-deficient Tissue Factor compound and at least a first anti-cancer agent in a combined amount effective to coagulate the tumor vasculature and induce tumor necrosis.
- 40. A method for treating an animal having a vascularized tumor, comprising administering to said animal at least a first coagulation-deficient Tissue Factor compound in combination with at least one of Factor VIIa or an activator of Factor VIIa in a combined amount effective to promote coagulation in the tumor vasculature and to cause necrosis in the tumor.
- 41. The method of claim 40, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor deficient in the ability to activate Factor VII.
- 42. The method of claim 40, wherein said coagulation-deficient Tissue Factor compound is administered in combination with Factor VIIa.
- 43. A composition comprising at least a first coagulation-deficient Tissue Factor compound that has been modified to increase its biological half life, other than wherein the modification consists of linking the coagulation-deficient Tissue Factor compound to an antibody or antigen binding region thereof that binds to a component of a tumor cell, tumor vasculature or tumor stroma.
- 44. The composition of claim 43, wherein said coagulation-deficient Tissue Factor compound is a truncated Tissue Factor.
- 45. The composition of claim 43, wherein said coagulation-deficient Tissue Factor compound is operatively linked to a carrier molecule.
- 46. The composition of claim 45, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an albumin or a globulin.
- 47. The composition of claim 45, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an antibody or portion thereof.
- 48. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an IgG molecule.
- 49. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is operatively linked to an Fc portion of an antibody.
- 50. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound has been introduced into an IgG molecule in place of the CH3 domain.
- 51. A therapeutic kit comprising, in suitable container means:
(a) a biologically effective amount of at least a first coagulation-deficient Tissue Factor compound in combination with a biologically effective amount of at least a first anti-cancer agent; or (b) a biologically effective amount of at least a first mutant Tissue Factor compound deficient in the ability to activate Factor VII in combination with a biologically effective amount of at least one of Factor VIIa or an activator of Factor VIIa.
- 52. The kit of claim 51, comprising at least a first coagulation-deficient Tissue Factor compound in combination with at least a first anti-cancer agent.
- 53. The kit of claim 52, wherein said at least a first anti-cancer agent is a chemotherapeutic agent.
- 54. The kit of claim 52, wherein said at least a first anti-cancer agent is an antibody construct comprising an antibody or antigen binding region that specifically binds to a component of a tumor cell, tumor vasculature or tumor stroma, the antibody operatively linked to a cytotoxic agent or to a coagulation factor.
- 55. The kit of claim 51, comprising at least a first mutant Tissue Factor compound deficient in the ability to activate Factor VII in combination with at least one of Factor VIIa or an activator of Factor VIIa.
- 56. The kit of claim 55, comprising at least a first mutant Tissue Factor compound deficient in the ability to activate Factor VII in combination with Factor VIIa.
Parent Case Info
[0001] The present application is a non-provisional application directed to the subject matter of provisional application Serial No. 60/042,427 (Attorney Docket No. UTSD:517PZ3), filed Mar. 27, 1997; provisional application Serial No. 60/036,205 (Attorney Docket No. UTSD:517PZ2), filed Jan. 27, 1997; and provisional application Serial No. 60/035,920 (Attorney Docket No. UTSD:517PZ1), filed Jan. 22, 1997; the entire disclosures of each of which provisional applications are incorporated herein by reference without disclaimer.
Government Interests
[0002] The U.S. Government owns rights in the present invention pursuant to grant numbers ROI-CA59569, ROI-CA54168 and POI-HL16411 from the National Institutes of Health.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60042427 |
Mar 1997 |
US |
|
60036205 |
Jan 1997 |
US |
|
60035920 |
Jan 1997 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09009822 |
Jan 1998 |
US |
Child |
09573835 |
May 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09573835 |
May 2000 |
US |
Child |
10375741 |
Feb 2003 |
US |