US6036955A — Kits and methods for the specific coagulation of …

Claim 1

Independent Claim 83 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a biological agent capable of inducing the expression of an inducible marker in the intratumoral vasculature or stroma of a vascularized tumor; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature or stroma; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 2

Dependent Claim 83 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a biological agent capable of inducing the expression of an inducible marker in the intratumoral vasculature or stroma of a vascularized tumor; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature or stroma; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 3

Dependent Claim 33 words

The kit of claim 1, wherein said first pharmaceutical composition comprises a biological agent capable of inducing the expression of a cytokine-inducible marker in the intratumoral vasculature or stroma of a vascularized tumor.

Claim 4

Dependent Claim 33 words

The kit of claim 1, wherein said first pharmaceutical composition comprises a biological agent capable of inducing the expression of a coagulant-inducible marker in the intratumoral vasculature or stroma of a vascularized tumor.

Claim 5

Dependent Claim 31 words

The kit of claim 1, wherein said first pharmaceutical composition comprises a biological agent capable of inducing the expression of an inducible marker in the intratumoral stroma of a vascularized tumor.

Claim 6

Dependent Claim 31 words

The kit of claim 1, wherein said first pharmaceutical composition comprises a biological agent capable of inducing the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor.

Claim 7

Dependent Claim 61 words

The kit of claim 5, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to an activating antigen on the cell surface of a leukocyte cell and to a tumor antigen on the cell surface of a tumor cell, the bispecific antibody being effective to induce the expression of a cytokine by a leukocyte cell in a vascularized tumor.

Claim 8

Dependent Claim 80 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the tumor cell antigen p185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor-associated antigen that binds to an antibody selected from the group consisting of B3 (ATCC HB 10573), 260F9 (ATCC HB 8488), D612 (ATCC HB 9796) and KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 9

Dependent Claim 39 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to an activating antigen on the cell surface of a monocyte, macrophage, mast cell, helper T cell, CD8-positive T cell or NK cell.

Claim 10

Dependent Claim 34 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD2, CD3, CD14, CD16 (FcR for IgE), CD28 or the T cell receptor antigen.

Claim 11

Dependent Claim 31 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that induces the expression of the cytokine IL-1, TNF-α, IFN-γ, IL-4 or TNF-β by said leukocyte cell.

Claim 12

Dependent Claim 36 words

The kit of claim 6, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker VCAM-1, E-selectin, endoglin, ICAM-1 or an MHC Class II antigen.

Claim 13

Dependent Claim 30 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD14 and induces the expression of IL-1 by monocyte/macrophage cells.

Claim 14

Dependent Claim 49 words

The kit of claim 12, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD14 and to the tumor-associated antigen that binds to the antibody KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 15

Dependent Claim 27 words

The kit of claim 12, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker VCAM-1.

Claim 16

Dependent Claim 27 words

The kit of claim 12, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker E-selectin.

Claim 17

Dependent Claim 27 words

The kit of claim 12, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker endoglin.

Claim 18

Dependent Claim 27 words

The kit of claim 6, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to CD28 and induces the expression of IFN-γ by T cells.

Claim 19

Dependent Claim 31 words

The kit of claim 17, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker, an MHC Class II antigen.

Claim 20

Dependent Claim 30 words

The kit of claim 18, further comprising a third pharmaceutical composition comprising an agent capable of suppressing MHC Class II antigen expression in the vascular endothelial cells of normal tissues.

Claim 21

Dependent Claim 13 words

The kit of claim 19, wherein said third pharmaceutical composition comprises a cyclosporin.

Claim 22

Dependent Claim 67 words

The kit of claim 5, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor cell, a component of tumor vasculature or a component of tumor stroma, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; said antibody being effective to induce thrombin deposition within a tumor.

Claim 23

Dependent Claim 24 words

The kit of claim 21, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor cell.

Claim 24

Dependent Claim 84 words

The kit of claim 22, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to the tumor cell antigen p185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor-associated antigen that binds to an antibody selected from the group consisting of B3 (ATCC HB 10573), 260F9 (ATCC HB 8488), D612 (ATCC HB 9796) and KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 25

Dependent Claim 26 words

The kit of claim 21, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component of tumor stroma.

Claim 26

Dependent Claim 26 words

The kit of claim 24, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor-associated basement membrane component.

Claim 27

Dependent Claim 26 words

The kit of claim 24, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VEGF within the tumor stroma.

Claim 28

Dependent Claim 26 words

The kit of claim 21, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component of tumor vasculature.

Claim 29

Dependent Claim 30 words

The kit of claim 27, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component expressed by a tumor vascular endothelial cell.

Claim 30

Dependent Claim 29 words

The kit of claim 28, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VCAM-1, E-selectin, P-selectin, a VEGF receptor or endoglin.

Claim 31

Dependent Claim 35 words

The kit of claim 27, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a ligand or growth factor that binds to a tumor vasculature cell surface receptor.

Claim 32

Dependent Claim 24 words

The kit of claim 30, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VEGF or FGF.

Claim 33

Dependent Claim 62 words

The kit of claim 27, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a ligand:receptor complex or a growth factor:receptor complex, but does not bind to the ligand or growth factor or to the receptor when the ligand or growth factor or the receptor is not in the ligand:receptor or the growth factor:receptor complex.

Claim 34

Dependent Claim 24 words

The kit of claim 21, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region operatively linked to a coagulation factor.

Claim 35

Dependent Claim 31 words

The kit of claim 21, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region operatively linked to a second binding region that binds to a coagulation factor.

Claim 36

Dependent Claim 37 words

The kit of claim 21, wherein the coagulation factor in said first pharmaceutical composition is Tissue Factor, a Tissue Factor derivative, prothrombin, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, Factor XI/XIa or Russell's viper venom Factor X activator.

Claim 37

Dependent Claim 31 words

The kit of claim 21, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker E-selectin, P-selectin, PDGF or ICAM-1.

Claim 38

Dependent Claim 27 words

The kit of claim 36, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker E-selectin.

Claim 39

Dependent Claim 27 words

The kit of claim 36, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker P-selectin.

Claim 40

Dependent Claim 26 words

The kit of claim 1, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region operatively linked to a coagulation factor.

Claim 41

Dependent Claim 33 words

The kit of claim 1, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region operatively linked to a second binding region that binds to a coagulation factor.

Claim 42

Dependent Claim 58 words

The kit of claim 1, wherein the coagulation factor in said second pharmaceutical composition is Factor II/IIa, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, a vitamin K-dependent coagulation factor that lacks the Gla modification, Tissue Factor, a truncated Tissue Factor, a mutant Tissue Factor, a dimeric Tissue Factor, Russell's viper venom Factor X activator, thromboxane A 2 or α2-antiplasmin.

Claim 43

Dependent Claim 38 words

The kit of claim 41, wherein the coagulation factor in said second pharmaceutical composition is Tissue Factor, a truncated Tissue Factor, a mutant Tissue Factor deficient in the ability to activate Factor VII or a dimeric Tissue Factor.

Claim 44

Dependent Claim 12 words

The kit of claim 1, further comprising an anti-tumor cell antibody-therapeuticagent conjugate.

Claim 45

Dependent Claim 79 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a biological agent capable of inducing the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 46

Dependent Claim 79 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a biological agent capable of inducing the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 47

Dependent Claim 107 words

The kit of claim 44, comprising: (a) a first pharmaceutical composition comprising a bispecific antibody capable of inducing the expression of a cytokine-inducible marker in the intratumoral vasculature of a vascularized tumor, the bispecific antibody binding to a tumor cell surface antigen and to a leukocyte cell surface activation antigen and being effective to induce cytokine expression by a leukocyte cell; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said cytokine-inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 48

Dependent Claim 105 words

The kit of claim 44, comprising: (a) a first pharmaceutical composition comprising an antibody capable of inducing the expression of a coagulant-inducible marker in the intratumoral vasculature of a vascularized tumor, the antibody binding to a tumor cell, tumor stroma or tumor vascular antigen and to a coagulation factor and being effective to induce thrombin deposition within a tumor; and (b) a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said coagulant-inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 49

Dependent Claim 112 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a first antibody that comprises a first binding region that binds to a component of the intratumoral vasculature or stroma of a vascularized tumor, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; and (b) a second pharmaceutical composition comprising a second antibody comprising a distinct first binding region that binds to a distinct component of the intratumoral vasculature or stroma of a vascularized tumor, the distinct first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 50

Dependent Claim 112 words

A kit comprising, in suitable container means: (a) a first pharmaceutical composition comprising a first antibody that comprises a first binding region that binds to a component of the intratumoral vasculature or stroma of a vascularized tumor, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; and (b) a second pharmaceutical composition comprising a second antibody comprising a distinct first binding region that binds to a distinct component of the intratumoral vasculature or stroma of a vascularized tumor, the distinct first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 51

Dependent Claim 35 words

The kit of claim 47, wherein said first or second pharmaceutical compositions comprise an antibody comprising a first binding region that binds to VCAM-1, E-selectin, endoglin, ICAM-1, an MHC Class II antigen, VEGF or FGF.

Claim 52

Dependent Claim 31 words

The kit of claim 47, wherein said first pharmaceutical composition comprises an anti-VEGF-Tissue Factor antibody; and wherein said second pharmaceutical composition comprises an anti-VCAM-1-Tissue Factor antibody or an anti-E-selectin-Tissue Factor antibody.

Claim 53

Independent Claim 111 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first pharmaceutical composition comprising a biological agent effective to induce the expression of an inducible marker in the intratumoral vasculature or stroma of a vascularized tumor; and (b) introducing into the bloodstream of the animal a biologically effective amount of a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature or stroma; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 54

Independent Claim 111 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first pharmaceutical composition comprising a biological agent effective to induce the expression of an inducible marker in the intratumoral vasculature or stroma of a vascularized tumor; and (b) introducing into the bloodstream of the animal a biologically effective amount of a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature or stroma; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 55

Dependent Claim 33 words

The method of claim 50, wherein said first pharmaceutical composition comprises a biological agent effective to induce the expression of a cytokine-inducible marker in the intratumoral vasculature or stroma of a vascularized tumor.

Claim 56

Dependent Claim 33 words

The method of claim 50, wherein said first pharmaceutical composition comprises a biological agent effective to induce the expression of a coagulant-inducible marker in the intratumoral vasculature or stroma of a vascularized tumor.

Claim 57

Dependent Claim 31 words

The method of claim 50, wherein said first pharmaceutical composition comprises a biological agent effective to induce the expression of an inducible marker in the intratumoral stroma of a vascularized tumor.

Claim 58

Dependent Claim 31 words

The method of claim 50, wherein said first pharmaceutical composition comprises a biological agent effective to induce the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor.

Claim 59

Dependent Claim 61 words

The method of claim 54, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to an activating antigen on the cell surface of a leukocyte cell and to a tumor antigen on the cell surface of a tumor cell, the bispecific antibody being effective to induce the expression of a cytokine by a leukocyte cell in said vascularized tumor.

Claim 60

Dependent Claim 80 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the tumor cell antigen p185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor-associated antigen that binds to an antibody selected from the group consisting of B3 (ATCC HB 10573), 260F9 (ATCC HB 8488), D612 (ATCC HB 9796) and KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 61

Dependent Claim 39 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to an activating antigen on the cell surface of a monocyte, macrophage, mast cell, helper T cell, CD8-positive T cell or NK cell.

Claim 62

Dependent Claim 34 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD2, CD3, CD14, CD16 (FcR for IgE), CD28 or the T cell receptor antigen.

Claim 63

Dependent Claim 31 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that induces the expression of the cytokine IL-1, TNF-α, IFN-γ, IL-4 or TNF-β by said leukocyte cell.

Claim 64

Dependent Claim 36 words

The method of claim 55, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker VCAM-1, E-selectin, endoglin, ICAM-1 or an MHC Class II antigen.

Claim 65

Dependent Claim 30 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD14 and induces the expression of IL-1 by monocyte/macrophage cells.

Claim 66

Dependent Claim 49 words

The method of claim 61, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to the activating antigen CD14 and to the tumor-associated antigen that binds to the antibody KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 67

Dependent Claim 27 words

The method of claim 61, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker VCAM-1.

Claim 68

Dependent Claim 27 words

The method of claim 61, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker E-selectin.

Claim 69

Dependent Claim 27 words

The method of claim 61, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker endoglin.

Claim 70

Dependent Claim 27 words

The method of claim 55, wherein said first pharmaceutical composition comprises a bispecific antibody that binds to CD28 and induces the expression of IFN-γ by T cells.

Claim 71

Dependent Claim 31 words

The method of claim 66, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the cytokine-inducible marker, an MHC Class II antigen.

Claim 72

Dependent Claim 48 words

The method of claim 66, wherein MHC Class II molecule expression by endothelial cells in the normal tissues of the animal is suppressed by cyclosporin administration, and MHC Class II molecule expression by endothelial cells in the intratumoral vasculature is induced by administration of said first pharmaceutical composition.

Claim 73

Dependent Claim 67 words

The method of claim 54, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor cell, a component of tumor vasculature or a component of tumor stroma, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; said antibody being effective to induce thrombin deposition within a tumor.

Claim 74

Dependent Claim 24 words

The method of claim 69, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor cell.

Claim 75

Dependent Claim 84 words

The method of claim 70, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to the tumor cell antigen p185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor-associated antigen that binds to an antibody selected from the group consisting of B3 (ATCC HB 10573), 260F9 (ATCC HB 8488), D612 (ATCC HB 9796) and KS1/4, said KS1/4 antibody obtained from a cell comprising the vectors pGKC2310 (NRRL B-18356) and pG2A52 (NRRL B-18357).

Claim 76

Dependent Claim 26 words

The method of claim 69, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component of tumor stroma.

Claim 77

Dependent Claim 26 words

The method of claim 72, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a tumor-associated basement membrane component.

Claim 78

Dependent Claim 26 words

The method of claim 72, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VEGF within the tumor stroma.

Claim 79

Dependent Claim 26 words

The method of claim 69, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component of tumor vasculature.

Claim 80

Dependent Claim 30 words

The method of claim 75, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a component expressed by a tumor vascular endothelial cell.

Claim 81

Dependent Claim 29 words

The method of claim 76, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VCAM-1, E-selectin, P-selectin, a VEGF receptor or endoglin.

Claim 82

Dependent Claim 36 words

The method of claim 75, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a ligand or growth factor that binds to a tumor vascular endothelial cell surface receptor.

Claim 83

Dependent Claim 24 words

The method of claim 78, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to VEGF or FGF.

Claim 84

Dependent Claim 62 words

The method of claim 75, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region that binds to a ligand:receptor complex or a growth factor:receptor complex, but does not bind to the ligand or growth factor or to the receptor when the ligand or growth factor or the receptor is not in the ligand:receptor or the growth factor:receptor complex.

Claim 85

Dependent Claim 24 words

The method of claim 69, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region operatively linked to a coagulation factor.

Claim 86

Dependent Claim 31 words

The method of claim 69, wherein said first pharmaceutical composition comprises an antibody comprising a first binding region operatively linked to a second binding region that binds to a coagulation factor.

Claim 87

Dependent Claim 37 words

The method of claim 69, wherein the coagulation factor in said first pharmaceutical composition is Tissue Factor, a Tissue Factor derivative, prothrombin, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, Factor XI/XIa or Russell's viper venom Factor X activator.

Claim 88

Dependent Claim 31 words

The method of claim 69, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker E-selectin, P-selectin, PDGF or ICAM-1.

Claim 89

Dependent Claim 27 words

The method of claim 84, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker E-selectin.

Claim 90

Dependent Claim 27 words

The method of claim 84, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region that binds to the coagulant-inducible marker P-selectin.

Claim 91

Dependent Claim 26 words

The method of claim 50, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region operatively linked to a coagulation factor.

Claim 92

Dependent Claim 33 words

The method of claim 50, wherein said second pharmaceutical composition comprises a binding ligand that comprises a first binding region operatively linked to a second binding region that binds to a coagulation factor.

Claim 93

Dependent Claim 58 words

The method of claim 50, wherein the coagulation factor in said second pharmaceutical composition is Factor II/IIa, Factor VII/VIIa, Factor IX/IXa, Factor X/Xa, a vitamin K-dependent coagulation factor that lacks the Gla modification, Tissue Factor, a truncated Tissue Factor, a mutant Tissue Factor, a dimeric Tissue Factor, Russell's viper venom Factor X activator, thromboxane A 2 or α2-antiplasmin.

Claim 94

Dependent Claim 38 words

The method of claim 89, wherein the coagulation factor in said second pharmaceutical composition is Tissue Factor, a truncated Tissue Factor, a mutant Tissue Factor deficient in the ability to activate Factor VII or a dimeric Tissue Factor.

Claim 95

Dependent Claim 16 words

The method of claim 50, further comprising administering to said animal an anti-tumor cell antibody-therapeuticagent conjugate.

Claim 96

Dependent Claim 13 words

The method of claim 50, wherein the animal is a human cancer patient.

Claim 97

Independent Claim 107 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first pharmaceutical composition comprising a biological agent effective to induce the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor; and (b) introducing into the bloodstream of the animal a biologically effective amount of a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 98

Independent Claim 107 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first pharmaceutical composition comprising a biological agent effective to induce the expression of an inducible marker in the intratumoral vasculature of a vascularized tumor; and (b) introducing into the bloodstream of the animal a biologically effective amount of a second pharmaceutical composition comprising a binding ligand that comprises a first binding region that binds to said inducible marker of intratumoral vasculature; the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 99

Dependent Claim 116 words

The method of claim 93, comprising the steps of: (a) introducing into the bloodstream of the animal a first bispecific antibody, said bispecific antibody binding to both an activating antigen on the cell surface of a leukocyte and to a tumor cell surface antigen, the bispecific antibody being effective to induce the expression of a cytokine by leukocytes in the tumor; and (b) introducing into the animal's bloodstream a biologically effective amount of a second antibody operatively linked to a coagulation factor or a second binding region that binds a coagulation factor, the second antibody binding to an antigen that is induced on the surface of intratumoral blood vessels of the vascularized tumor by said cytokine.

Claim 100

Dependent Claim 110 words

The method of claim 93, comprising the steps of: (a) introducing into the bloodstream of the animal a first antibody, said antibody binding to a coagulation factor and to a tumor cell, tumor stroma or tumor vascular antigen of the tumor, the antibody being effective to induce the deposition of thrombin within the tumor; and (b) introducing into the animal's bloodstream a biologically effective amount of a second antibody operatively linked to a coagulation factor or a second binding region that binds a coagulation factor, the second antibody binding to an antigen that is induced on the surface of intratumoral blood vessels of the vascularized tumor by the thrombin deposition.

Claim 101

Independent Claim 125 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first antibody that comprises a first binding region that binds to a component of the intratumoral vasculature or stroma of a vascularized tumor, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; and (b) introducing into the bloodstream of the animal a second antibody comprising a distinct first binding region that binds to a distinct component of the intratumoral vasculature or stroma of a vascularized tumor, the distinct first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 102

Independent Claim 125 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) introducing into the bloodstream of the animal a first antibody that comprises a first binding region that binds to a component of the intratumoral vasculature or stroma of a vascularized tumor, the first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor; and (b) introducing into the bloodstream of the animal a second antibody comprising a distinct first binding region that binds to a distinct component of the intratumoral vasculature or stroma of a vascularized tumor, the distinct first binding region operatively linked to a coagulation factor or a second binding region that binds to a coagulation factor.

Claim 103

Dependent Claim 31 words

The method of claim 96, wherein said first or second antibody comprises a first binding region that binds to VCAM-1, E-selectin, endoglin, ICAM-1, an MHC Class II antigen, VEGF or FGF.

Claim 104

Dependent Claim 29 words

The method of claim 96, wherein said first antibody is an anti-VEGF-Tissue Factor antibody; and wherein said second antibody is an anti-VCAM-1-Tissue Factor antibody or an anti-E-selectin-Tissue Factor antibody.

Claim 105

Independent Claim 105 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) administering to said animal a biological agent effective to suppress the expression of MHC Class II molecules by endothelial cells in the normal tissues of the animal; (b) administering to said animal a biological agent effective to induce the specific expression of MHC Class II molecules in the intratumoral vasculature of the vascularized tumor; and (c) administering to said animal an antibody that binds to the induced MHC Class II molecules, the antibody linked to a coagulation factor or a second binding region that binds a coagulation factor.

Claim 106

Independent Claim 105 words

A method for treating an animal having a vascularized tumor, the method comprising the steps of: (a) administering to said animal a biological agent effective to suppress the expression of MHC Class II molecules by endothelial cells in the normal tissues of the animal; (b) administering to said animal a biological agent effective to induce the specific expression of MHC Class II molecules in the intratumoral vasculature of the vascularized tumor; and (c) administering to said animal an antibody that binds to the induced MHC Class II molecules, the antibody linked to a coagulation factor or a second binding region that binds a coagulation factor.

Claim 107

Dependent Claim 72 words

The method of claim 99, wherein: (a) the agent that suppresses MHC Class II molecule expression in the normal tissues is a cyclosporin; and (b) the agent that induces MHC Class II molecule expression in the intratumoral vasculature of the vascularized tumor is a bispecific antibody that binds to a tumor cell antigen and to CD28 on the cell surface of a T cell, and induces IFN-γ expression by said T cell.

Claim 108

Dependent Claim 70 words

The method of claim 99, wherein: (a) the agent that suppresses MHC Class II molecule expression in the normal tissues is an anti-CD4 antibody that suppresses IFN-γ production by the T cells of the animal; and (b) the agent that induces MHC Class II molecule expression in the intratumoral vasculature of the vascularized tumor is an IFN-γ-producing T cell clone that binds to a tumor antigen of the vascularized tumor.

Claim 109

Dependent Claim 54 words

The method of claim 101, wherein the IFN-γ-producing T cell clone is prepared by a method comprising the steps of: (a) removing a tissue section from the vascularized tumor of the animal; (b) extracting infiltrating leukocytes from the tissue section; and (c) expanding the infiltrating leukocytes in vitro to provide the IFN-γ producing clone.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2003-03-14	2003-09-13	2004-03-14	$2000.00	Window Closed / Lapsed
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11.5 Years (Year 12)	2011-03-14	2011-09-13	2012-03-14	$7700.00	Window Closed / Lapsed

Kits and methods for the specific coagulation of vasculature

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