Claims
- 1. A method for treating an animal having a vascularized tumor, comprising:
(a) subjecting said animal to a sensitizing treatment in a manner effective to enhance the procoagulant status of the vasculature of said vascularized tumor; and (b) administering to said animal an amount of a tumor targeted coagulant effective to induce coagulation in the vasculature of said tumor; wherein said tumor targeted coagulant comprises a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, said first binding region being operatively linked to a coagulation factor or to an antibody, or antigen binding region thereof, that binds to a coagulation factor.
- 2. The method of claim 1, wherein said sensitizing treatment is performed at a biologically effective time prior to administration of said tumor targeted coagulant.
- 3. The method of claim 1, wherein said sensitizing treatment and the administration of said tumor targeted coagulant are performed essentially simultaneously.
- 4. The method of claim 1, wherein said sensitizing treatment comprises administering a sensitizing dose of a sensitizing agent to said animal.
- 5. The method of claim 4, wherein said sensitizing agent is endotoxin or a detoxified endotoxin derivative.
- 6. The method of claim 5, wherein said sensitizing agent is monophosphoryl lipid A (MPL).
- 7. The method of claim 4, wherein said sensitizing agent is an activating antibody that binds to the cell surface activating antigen CD14 and that does not bind to a tumor antigen on the cell surface of a tumor cell.
- 8. The method of claim 4, wherein said sensitizing agent is a cytokine selected from the group consisting of monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor-BB (PDGF-BB) and C-reactive protein (CRP).
- 9. The method of claim 4, wherein said sensitizing agent is tumor necrosis factor-α (TNFα) or an inducer of TNFα.
- 10. The method of claim 10, wherein said sensitizing agent is an inducer of TNFα selected from the group consisting of endotoxin, a Rac1 antagonist, DMXAA, CM101 or thalidomide.
- 11. The method of claim 4, wherein said sensitizing agent is muramyl dipeptide (MDP), threonyl-MDP or MTPPE.
- 12. The method of claim 4, wherein said sensitizing agent is a sensitizing dose of an anti-angiogenic agent.
- 13. The method of claim 12, wherein said sensitizing agent is a sensitizing dose of an anti-angiogenic agent selected from the group consisting of vasculostatin, canstatin and maspin.
- 14. The method of claim 12, wherein said sensitizing agent is a sensitizing dose of a VEGF inhibitor.
- 15. The method of claim 14, wherein said sensitizing agent is a sensitizing dose of an anti-VEGF blocking antibody.
- 16. The method of claim 14, wherein said sensitizing agent is a sensitizing dose of a soluble VEGF receptor construct (sVEGF-R), a tyrosine kinase inhibitor, an antisense VEGF construct, an anti-VEGF RNA aptamer or an anti-VEGF ribozyme.
- 17. The method of claim 4, wherein said sensitizing agent is an activating antibody that binds to the cell surface activating antigen CD40.
- 18. The method of claim 4, wherein said sensitizing agent is sCD40-Ligand (sCD153).
- 19. The method of claim 4, wherein said sensitizing agent is a sensitizing dose of a combretastatin, or a prodrug or tumor-targeted form thereof.
- 20. The method of claim 19, wherein said sensitizing agent is a sensitizing dose of combretastatin A-1, A-2, A-3, A-4, A-5, A-6, B-1, B-2, B-3, B-4, D-1 or D-2, or a prodrug or tumor-targeted form thereof.
- 21. The method of claim 4, wherein said sensitizing agent is a sensitizing dose of thalidomide.
- 22. The method of claim 4, wherein a single composition comprising said sensitizing agent and said tumor targeted coagulant is administered to said animal.
- 23. The method of claim 4, wherein distinct compositions comprising said sensitizing agent and said tumor targeted coagulant are administered to said animal.
- 24. The method of claim 1, wherein the first binding region of said tumor targeted coagulant is an antibody, or antigen-binding region thereof.
- 25. The method of claim 24, wherein the first binding region of said tumor targeted coagulant is a monoclonal, recombinant, human, humanized, part-human or chimeric antibody or antigen-binding region thereof.
- 26. The method of claim 24, wherein the first binding region of said tumor targeted coagulant is an scFv, Fv, Fab′, Fab, diabody, linear antibody or F(ab′)2 antigen-binding region of an antibody.
- 27. The method of claim 1, wherein the first binding region of said tumor targeted coagulant is a ligand, growth factor or receptor.
- 28. The method of claim 27, wherein the first binding region of said tumor targeted coagulant is VEGF.
- 29. The method of claim 1, wherein the first binding region of said tumor targeted coagulant binds to a component expressed, accessible to binding or localized on the surface of intratumoral blood vessels of a vascularized tumor.
- 30. The method of claim 29, wherein the first binding region of said tumor targeted coagulant binds to an intratumoral vasculature cell surface receptor or to a ligand or growth factor that binds to an intratumoral vasculature cell surface receptor.
- 31. The method of claim 30, wherein the first binding region of said tumor targeted coagulant binds to a VEGF receptor, an FGF receptor, a TGFβ receptor, a TIE, VCAM-1, ICAM-1, P-selectin, E-selectin, PSMA, αvβ3 integrin, pleiotropin, endosialin or endoglin.
- 32. The method of claim 30, wherein the first binding region of said tumor targeted coagulant binds to VEGF, FGF, TGFβ, a ligand that binds to a TIE, a tumor-associated fibronectin isoform, scatter factor/hepatocyte growth factor (HGF), platelet factor 4 (PF4), PDGF or TIMP.
- 33. The method of claim 1, wherein the first binding region of said tumor targeted coagulant binds to a component expressed, accessible to binding or localized on the surface of a tumor cell or to a component released from a necrotic tumor cell.
- 34. The method of claim 1, wherein the first binding region of said tumor targeted coagulant binds to a component expressed, accessible to binding, inducible or localized on tumor stroma.
- 35. The method of claim 1, wherein the first binding region of said tumor targeted coagulant is operatively linked to said coagulation factor.
- 36. The method of claim 1, wherein the first binding region of said tumor targeted coagulant is operatively linked to a second binding region that binds to said coagulation factor.
- 37. The method of claim 1, wherein the coagulant of said tumor targeted coagulant is a human coagulation factor.
- 38. The method of claim 1, wherein the coagulant of said tumor targeted coagulant is Tissue Factor or a Tissue Factor derivative.
- 39. The method of claim 38, wherein the coagulant of said tumor targeted coagulant is a truncated Tissue Factor.
- 40. The method of claim 39, wherein the coagulant of said tumor targeted coagulant is a truncated Tissue Factor of about 219 amino acids in length.
- 41. The method of claim 1, wherein the coagulant of said tumor targeted coagulant is Factor II/IIa, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, Russell's viper venom Factor X activator, thromboxane A2, thromboxane A2 synthase or α2-antiplasmin.
- 42. The method of claim 1, wherein said animal is a human patient.
- 43. A method for treating an animal having a vascularized tumor, comprising:
(a) administering to said animal a sensitizing dose of a sensitizing agent effective to enhance the procoagulant status of the vasculature of said vascularized tumor; and (b) administering to said animal an amount of a tumor targeted coagulant effective to induce coagulation in the vasculature of said tumor; wherein said tumor targeted coagulant comprises a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of a tumor cell, intratumoral vasculature or tumor-associated stroma, said first binding region being operatively linked to a coagulation factor or to an antibody, or antigen binding region thereof, that binds to a coagulation factor.
- 44. The method of claim 43, wherein said sensitizing agent is endotoxin or a detoxified endotoxin derivative.
- 45. The method of claim 43, wherein said tumor targeted coagulant comprises a first binding region that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral vasculature or tumor-associated stroma, said first binding region being directly or indirectly linked to Tissue Factor or a Tissue Factor derivative.
Parent Case Info
[0001] Applicants claim priority to U.S. provisional application Serial No. 60/325,532, filed Sep. 27, 2001, the specification, claims and drawings of which application are specifically incorporated herein by reference without disclaimer.
Provisional Applications (1)
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Number |
Date |
Country |
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60325532 |
Sep 2001 |
US |