Claims for Patent: 7,951,356

Summary for Patent: 7,951,356

Title:	Tissue factor compositions and kits for coagulation and tumor treatment
Abstract:	The invention embodies the surprising discovery that Tissue Factor (TF) compositions and variants thereof specifically localize to the blood vessels within a vascularized tumor following systemic administration. The invention therefore provides methods and compositions comprising coagulant-deficient Tissue Factor for use in effecting specific coagulation and for use in tumor treatment. The TF compositions and methods of present invention may be used alone, as TF conjugates with improved half-life, or in combination with other agents, such as conventional chemotherapeutic drugs, targeted immunotoxins, targeted coaguligands, and/or in combination with Factor VIIa (FVIIa) or FVIIa activators.
Inventor(s):	Thorpe; Philip E. (Dallas, TX), King; Steven W. (Foothill Ranch, CA), Gao; Boning (Dallas, TX)
Assignee:	Board of Regents, The University of Texas System (Austin, TX)
Application Number:	09/573,835
Patent Claims:	1. A therapeutic kit comprising, in distinct container means, a combined biologically effective amount of at least a first anti-cancer agent and at least a first coagulation-deficient Tissue Factor compound, wherein said coagulation-deficient Tissue Factor compound is not attached to a targeting moiety, is between about 100-fold and about 1,000,000-fold less active in the coagulation cascade than full length, native Tissue Factor, specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor. 2. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound is deficient in binding to a phospholipid surface. 3. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound is a truncated Tissue Factor. 4. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound is a dimeric Tissue Factor. 5. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound is a polymeric Tissue Factor. 6. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound is at least a first mutant Tissue Factor compound deficient in the ability to activate Factor VII. 7. The kit of claim 6, wherein said kit further comprises said at least a first mutant Tissue Factor compound in combination with at least one of Factor VIIa or an activator of Factor VII. 8. The kit of claim 7, wherein said at least a first mutant Tissue Factor compound and said at least one of Factor VIIa or an activator of Factor VII are comprised within distinct compositions. 9. The kit of claim 7, wherein said at least a first mutant Tissue Factor compound and said at least one of Factor VIIa or an activator of Factor VII are comprised within a single composition. 10. The kit of claim 7, wherein said kit comprises said at least a first mutant Tissue Factor compound in combination with Factor VIIa. 11. The kit of claim 10, wherein said at least a first mutant Tissue Factor compound and said Factor VIIa are in a pre-formed Tissue Factor-Factor VIIa complex. 12. The kit of claim 1, wherein said at least a first anti-cancer agent is a chemotherapeutic agent. 13. The kit of claim 12, wherein said at least a first anti-cancer agent is a chemotherapeutic agent selected from the group consisting of an alkylating agent, an antimetabolite, an antibiotic, an enzyme, a platinum coordination complex, an anthracenedione, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, a hormone and a hormone antagonist. 14. The kit of claim 13, wherein said at least a first anti-cancer agent is a nitrogen mustard, an ethylenimene, a methylmelamine, an alkyl sulfonate, a nitrosourea, a triazine, a folic acid analog, a pyrimidine analog, a purine analog, a vinca alkaloid, an epipodophyllotoxin, an adrenocorticosteroid, a progestin, an estrogen, an antiestrogen, an androgen, an antiandrogen or a gonadotropin-releasing hormone analog. 15. The kit of claim 14, wherein said at least a first anti-cancer agent is mechlorethamine (HN.sub.2), cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, 5-fluouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, 2-deoxycoformycin, vinblastine, vincristine, etoposide, tertiposide, actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin C, L-asparaginase, interferon-alfa, cisplatin, carboplatin, mitoxantrone, hydroxyurea, procarbazine, mitotane, aminoglutethimide, prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide or leuprolide. 16. The kit of claim 1, 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. 17. The kit of claim 16, wherein said antibody construct comprises an antibody or antigen binding region that specifically binds to a component of tumor vasculature. 18. The kit of claim 16, wherein said antibody construct comprises an antibody or antigen binding region that specifically binds to a component of tumor stroma. 19. The kit of claim 16, wherein said antibody construct comprises an antibody or antigen binding region operatively attached to Tissue Factor or a Tissue Factor derivative. 20. The kit of claim 1, wherein said at least a first anti-cancer agent is a radiotherapeutic agent. 21. The kit of claim 1, wherein said at least a first anti-cancer agent is an agent that induces apoptosis. 22. The kit of claim 1, wherein said at least a first anti-cancer agent is a cytokine. 23. The kit of claim 1, wherein said kit comprises at least a first coagulation-deficient Tissue Factor compound in combination with at least a first and second anti-cancer agent. 24. The kit of claim 1, wherein at least one of said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent is formulated in a pharmaceutically acceptable composition. 25. The kit of claim 24, wherein at least one of said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent is formulated in a pharmaceutically acceptable liposomal formulation. 26. The kit of claim 24, wherein at least one of said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent is formulated for intravenous injection. 27. The kit of claim 1, wherein said at least a first coagulation-deficient Tissue Factor compound has been modified to increase its biological half life, other than wherein the modification consists of linking the coagulation-deficient Tissue Factor compound to a targeting moiety. 28. The kit of claim 27, wherein said at least a first coagulation-deficient Tissue Factor compound is operatively linked to a carrier molecule that increases the biological half life of said coagulation-deficient Tissue Factor compound, other than wherein said carrier molecule a targeting moiety. 29. The kit of claim 28, wherein said carrier molecule is a protein carrier molecule. 30. The kit of claim 29, wherein said carrier molecule is an antibody or portion thereof, wherein said antibody or portion thereof does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma. 31. The kit of claim 30, wherein said carrier molecule is an IgG molecule that does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma. 32. The kit of claim 30, wherein said carrier molecule is an Fc portion of an antibody. 33. The kit of claim 1, wherein said kit further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound. 34. A therapeutic kit comprising, in at least a first container, a combined biologically effective amount of at least a first anti-cancer agent and at least a first coagulation-deficient Tissue Factor compound, wherein said coagulation-deficient Tissue Factor compound is not attached to a targeting moiety, is between about 100-fold and about 1,000,000-fold less active in the coagulation cascade than full length, native Tissue Factor specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor. 35. The kit of claim 34, wherein said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent are comprised within distinct containers. 36. The kit of claim 34, wherein said at least a first anti-cancer agent is a chemotherapeutic agent. 37. A therapeutic kit comprising, in at least a first container, a combined biologically effective amount of at least a first coagulation-deficient Tissue Factor compound, wherein said coagulation-deficient Tissue Factor compound is not attached to a targeting moiety, is between about 100-fold and about 1,000,000-fold less active in the coagulation cascade than full length, native Tissue Factor, specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor; and at least a first anti-cancer agent selected from the group consisting of a chemotherapeutic agent, an anti-cancer antibody or immunoconjugate, a radiotherapeutic agent, an agent that induces apoptosis and a cytokine. 38. The kit of claim 37, wherein said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent are comprised within distinct compositions. 39. The kit of claim 37, wherein said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent are comprised within a single composition. 40. The kit of claim 37, wherein said at least a first coagulation-deficient Tissue Factor compound is a truncated Tissue Factor. 41. The kit of claim 37, wherein said at least a first coagulation-deficient Tissue Factor compound has been modified to increase its biological half life, other than wherein the modification consists of linking the coagulation-deficient Tissue Factor compound to a targeting moiety. 42. The kit of claim 37, wherein said at least a first anti-cancer agent is a chemotherapeutic agent. 43. The kit of claim 42, wherein said anti-cancer agent is a chemotherapeutic agent selected from the group consisting of an alkylating agent, an antimetabolite, an antibiotic, an enzyme, a platinum coordination complex, an anthracenedione, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, a hormone and a hormone antagonist. 44. The kit of claim 37, wherein said 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. 45. The kit of claim 37, wherein said kit further comprises at least one of Factor VIIa or an activator of Factor VII. 46. The kit of claim 37, wherein said kit further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound. 47. A composition comprising at least a first coagulation-deficient Tissue Factor compound which is between about 100-fold and about 1,000,000-fold less active in the coagulation cascade than full length, native Tissue Factor, specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor; wherein said coagulation-deficient Tissue Factor compound has been introduced into an IgG molecule in place of the C.sub.H3 domain to create an IgG carrier molecule that comprises said coagulation-deficient Tissue Factor compound, other than wherein said IgG molecule exhibits significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma. 48. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is a truncated Tissue Factor. 49. The composition of claim 48, wherein said coagulation-deficient Tissue Factor compound is about 219 amino acids in length. 50. The composition of claim 48, wherein said coagulation-deficient Tissue Factor compound consists essentially of the amino acid sequence of SEQ ID NO:1. 51. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is at least about 1,000-fold less active in coagulation than full length, native Tissue Factor. 52. The composition of claim 51, wherein said coagulation-deficient Tissue Factor compound is at least about 10,000-fold less active in coagulation than full length, native Tissue Factor. 53. The composition of claim 52, wherein said coagulation-deficient Tissue Factor compound is at least about 100,000-fold less active in coagulation than full length, native Tissue Factor. 54. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is a human Tissue Factor compound. 55. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is deficient in binding to a phospholipid surface. 56. The composition of claim 47, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor deficient in the ability to activate Factor VII. 57. The composition of claim 56, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor compound that includes at least a first mutation; said at least a first mutation being located in the amino acid region between about position 157 and about position 167 of SEQ ID NO:1. 58. The composition of claim 57, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor wherein Tip at position 158 is changed to Arg; wherein Ser at position 162 is changed to Ala; wherein Gly at position 164 is changed to Ala; or wherein Tip at position 158 is changed to Arg and Ser at position 162 is changed to Ala. 59. The composition of claim 58, wherein said coagulation-deficient Tissue Factor compound has the amino acid sequence of SEQ ID NO:8. 60. The composition of claim 58, wherein said coagulation-deficient Tissue Factor compound has the amino acid sequence of SEQ ID NO:9. 61. The composition of claim 47, wherein said composition further comprises at least a first anti-cancer agent. 62. The composition of claim 61, wherein said at least a first anti-cancer agent is a chemotherapeutic agent. 63. The composition of claim 62, wherein said at least a first anti-cancer agent is a chemotherapeutic agent selected from the group consisting of an alkylating agent, an antimetabolite, an antibiotic, an enzyme, a platinum coordination complex, an anthracenedione, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, a hormone and a hormone antagonist. 64. The composition of claim 62, wherein said at least a first anti-cancer agent is etoposide. 65. The composition of claim 61, 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. 66. The composition of claim 61, wherein said at least a first anti-cancer agent is a radiotherapeutic agent. 67. The composition of claim 61, wherein said at least a first anti-cancer agent is an agent that induces apoptosis. 68. The composition of claim 61, wherein said at least a first anti-cancer agent is a cytokine. 69. The composition of claim 47, wherein said composition further comprises at least one of Factor VIIa or an activator of Factor VII. 70. The composition of claim 47, wherein said composition is a pharmaceutically acceptable composition. 71. The composition of claim 70, wherein said composition is formulated for intravenous injection. 72. The composition of claim 70, wherein said composition is a pharmaceutically acceptable liposomal formulation. 73. The composition of claim 70, wherein said composition is an ophthalmic formulation. 74. The composition of claim 47, wherein said composition further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound. 75. A composition comprising at least a first coagulation-deficient Tissue Factor compound that is between about 100-fold and about 1,000,000-fold less active in the coagulation cascade than full length, native Tissue Factor, that specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor, and that has been modified to increase its biological half life, other than wherein the modification consists of linking the first coagulation-deficient Tissue Factor compound to an antibody that exhibits significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma; wherein said composition further comprises at least a second, distinct type of coagulation-deficient Tissue Factor compound. 76. The composition of claim 75, wherein said first and second coagulation-deficient Tissue Factor compounds are distinct types of coagulation-deficient Tissue Factor compounds selected from the group consisting of truncated, mutant, homodimeric, heterodimeric, and multimeric coagulation-deficient Tissue Factor compounds. 77. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is prepared by recombinant expression. 78. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is a truncated Tissue Factor. 79. The composition of claim 78, wherein said first coagulation-deficient Tissue Factor compound consists essentially of the amino acid sequence of SEQ ID NO:1. 80. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is a dimeric Tissue Factor. 81. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is a human Tissue Factor compound. 82. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is at least about 100,000-fold less active in coagulation than full length, native Tissue Factor. 83. The composition of claim 75, wherein said first coagulation-deficient Tissue Factor compound is operatively linked to a carrier molecule that increases the biological half life of said coagulation-deficient Tissue Factor compound. 84. The composition of claim 83, wherein said carrier molecule is a protein carrier molecule. 85. The composition of claim 84, wherein said carrier molecule is an albumin or a globulin. 86. The composition of claim 84, wherein said carrier molecule is an antibody or portion thereof, wherein said antibody or portion thereof does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma. 87. The composition of claim 86, wherein said carrier molecule is an IgG molecule that does not exhibit significant specific binding to a component of a tumor cell, tumor vasculature or tumor stroma. 88. The composition of claim 86, wherein said carrier molecule is an Fc portion of an antibody. 89. The composition of claim 83, wherein said carrier molecule is a non-protein carrier molecule. 90. The composition of claim 89, wherein said carrier molecule is a polysaccharide carrier molecule. 91. The composition of claim 89, wherein said carrier molecule is a synthetic polymer carrier molecule. 92. The composition of claim 83, wherein said first coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule. 93. The composition of claim 92, wherein said first coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule by a biochemical cross-linker. 94. The composition of claim 92, wherein said first coagulation-deficient Tissue Factor compound is covalently linked to said carrier molecule by preparing a fusion protein by expressing a recombinant vector in a host cell, wherein said vector comprises a DNA sequence encoding said coagulation-deficient Tissue Factor operatively linked, in frame, to a DNA sequence encoding said carrier molecule. 95. The composition of claim 75, wherein said composition further comprises at least a first anti-cancer agent. 96. The composition of claim 75, wherein said composition is a pharmaceutically acceptable composition. 97. The kit of claim 2, wherein said at least a first coagulation-deficient Tissue Factor compound that is deficient in binding to a phospholipid surface substantially fails to convert Factor VII to Factor VIIa in a Tissue Factor assay and retains the catalytic activity of activating Factor X in the presence of Factor VIIa. 98. The kit of claim 3, wherein said coagulation-deficient Tissue Factor compound is about 219 amino acids in length. 99. The kit of claim 3, wherein said coagulation-deficient Tissue Factor compound has the amino acid sequence of SEQ ID NO:1. 100. The kit of claim 6, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor compound that includes at least a first mutation; said at least a first mutation being located in the amino acid region between about position 157 and about position 167 of SEQ ID NO:1. 101. The kit of claim 100, wherein said coagulation-deficient Tissue Factor compound is a mutant Tissue Factor wherein Trp at position 158 is changed to Arg; wherein Ser at position 162 is changed to Ala; wherein Gly at position 164 is changed to Ala; or wherein Trp at position 158 is changed to Arg and Ser at position 162 is changed to Ala. 102. The kit of claim 100, wherein said coagulation-deficient Tissue Factor compound has the amino acid sequence of SEQ ID NO:8. 103. The kit of claim 100, wherein said coagulation-deficient Tissue Factor compound has the amino acid sequence of SEQ ID NO:9. 104. The kit of claim 1, wherein said coagulation-deficient Tissue Factor compound is at least about 1,000-fold less active in coagulation than full length, native Tissue Factor. 105. The kit of claim 1, wherein said coagulation-deficient Tissue Factor compound is at least about 10,000-fold less active in coagulation than full length, native Tissue Factor. 106. The kit of claim 1, wherein said coagulation-deficient Tissue Factor compound is at least about 100,000-fold less active in coagulation than full length, native Tissue Factor. 107. The kit of claim 1, wherein said coagulation-deficient Tissue Factor compound is a human Tissue Factor compound. 108. The kit of claim 24, wherein at least one of said at least a first coagulation-deficient Tissue Factor compound and said at least a first anti-cancer agent is formulated in a pharmaceutically acceptable ophthalmic formulation. 109. A therapeutic kit comprising, in distinct container means, a combined biologically effective amount of at least a first anti-cancer agent and at least a first coagulation-deficient Tissue Factor compound, wherein said coagulation-deficient Tissue Factor compound is not attached to a targeting moiety, has between about 100-fold and about 1,000,000-fold reduced procoagulation cofactor activity than full length, native Tissue Factor, specifically localizes to tumor vasculature and promotes coagulation in tumor vasculature following administration to an animal having a vascularized tumor.

Details for Patent 7,951,356

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2017-01-22