Use of anti-tissue factor antibodies for treating thromboses

Abstract

Disclosed is a method for preventing or treating thrombosis in a mammal such as a primate and particularly a human patient. A preferred method includes administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to human tissue factor (TF). Additional methods and kits are provided.

1 . A method for preventing or treating a thrombosis in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one antibody, or fragment thereof that binds specifically to human tissue factor (TF) to form a complex, the administration being sufficient to prevent or treat the thrombosis in the mammal, wherein the antibody or the fragment has a binding specificity for the TF about equal or greater than the antibody obtained from cell line H36.D2.B7 deposited under ATCC Accession No. HB-12255  
   
   
       2 . The method of  claim 1 , wherein after administration of the antibody or fragment, the mammal exhibits a blood clotting time of between from about 50 to about 350 seconds as determined by a standard prothrombin (PT) time assay.  
   
   
       3 . The method of  claim 1 , wherein the amount of the administered antibody, or fragment is sufficient to inhibit platelet deposition time by at least about 50% as determined by a standard platelet deposition assay.  
   
   
       4 . The method of  claim 1 , wherein the amount of the administered antibody, or fragment reduces platelet deposition as determined by vessel injury to blood ratio by at least about 50% as determined by a standard vessel injury to blood ratio assay.  
   
   
       5 . The method of  claim 1 , wherein the amount of the administered antibody, or fragment increases vessel patency by at least about 100%.  
   
   
       6 . The method of  claim 1 , wherein the mammal is a primate.  
   
   
       7 . The method of  claim 6 , wherein the primate is a human patient.  
   
   
       8 . The method of claim  1 - 5 , wherein the antibody is a humanized or chimeric antibody and the fragment is a Fab, Fab′, F(ab′) 2  where the fragment can be derived from a humanized or chimeric antibody or single chain Fv engineered using the variable domains of an antibody.  
   
   
       9 . The method of  claim 1 , wherein the antibody or the fragment exhibits at least one of: 1) a dissociation constant (K d ) for the TF of less than about 0.5 nM ; and 2) an affinity constant (K a ) for the TF of less than about 10×10 10  M −1 .  
   
   
       9 . The method of  claim 1 , wherein the humanized antibody used in the method comprises at least one fully murine complimentarity determining region (CDR).  
   
   
       10 . The method of  claim 9 , wherein the humanized antibody further comprises at least one fully human framework (FR) region.  
   
   
       11 . The method of  claim 10 , wherein the humanized antibody has at least about 90% amino acid sequence identity to a human antibody.  
   
   
       12 . The method of  claim 10 , wherein the variable region of the humanized antibody has at least about 70% amino acid sequence identity to a human antibody variable region.  
   
   
       13 . The method of  claim 10 , wherein each of frameworks (FRs) 1, 2, 3 and 4 of the humanized antibody has at least about 95% amino acid sequence identity to the light chain FR sequences shown in  FIG. 6A  (SEQ ID NO. ___).  
   
   
       14 . The method of  claim 10 , wherein the antibody comprises a light chain constant region having at least about 95% amino acid sequence identity to the sequence shown in  FIG. 8A  or 9A (SEQ ID NO. ___).  
   
   
       15 . The method of  claim 10 , wherein each of frameworks (FRs) 1, 2, 3 and 4 of the humanized antibody has at least about 95% amino acid sequence identity to the heavy chain sequences shown in  FIG. 7A  (SEQ ID NO. ___).  
   
   
       16 . The method of  claim 10 , wherein the antibody further comprises a heavy chain constant region having at least about 95% amino acid sequence identity to sequence shown in  FIG. 8B  or 9B (SEQ ID NO. ___).  
   
   
       17 . The method of  claim 1 , wherein the humanized antibody has an IgG1 (hOAT) or IgG4 (hFAT) isotype.  
   
   
       18 . The method of  claim 1 , wherein the human TF binding fragment is Fab, Fab′, or F(ab) 2 .  
   
   
       19 . The method of  claim 1 , wherein the humanized antibody is a monoclonal antibody.  
   
   
       20 . The method of  claim 1 , wherein the humanized antibody is a single-chain.  
   
   
       21 . A method for performing plastic, reconstructive, or transplant surgery in a mammal, the method comprising introducing a graft into the mammal and contacting the graft with a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to human tissue factor (TF) to form a complex, the contact being sufficient to maintain or increase patency of the graft, wherein the humanized antibody, chimeric antibody or the fragment has a binding specificity for the TF about equal or greater than the antibody obtained from cell line H36.D2.B7 deposited under ATCC Accession No. HB-12255  
   
   
       22 . The method of  claim 21  wherein the amount of the humanized antibody, chimeric antibody or fragment administered to the mammal is sufficient to prevent or reduce thrombosis by at least about 50% as determined by a standard skin flap assay.  
   
   
       23 . The method of  claim 21 , wherein the method further comprises preventing or reducing devascularization of the graft as determined by a standard skin flap assay.  
   
   
       24 . The method of  claim 21 , wherein the method further comprises preventing or reducing at( least one of edema, erythema, and necrosis in the graft.  
   
   
       25 . The method of  claim 1  or  21 , wherein the amount of the humanized antibody, chimeric antibody or fragment administered to the mammal is between about 0.01 to about 25 mg/kg.  
   
   
       26 . The method of  claim 1 , wherein the thrombosis is associated with cardiovascular disease.  
   
   
       27 . The method of  claim 26 , wherein the cardiovascular disease is at least one of coronary artery disease, acute coronary syndrome, and atherosclerosis.  
   
   
       28 . The method of  claim 1 , wherein the thrombosis is associated with angioplasty or restenosis.  
   
   
       29 . A kit for performing the method of  claim 1  or  21 , wherein the kit includes at least one of the humanized antibody, chimeric antibody, or fragment thereof and optionally, directions for using the kit.  
   
   
       30 . The kit of  claim 29 , wherein the humanized antibody, chimeric antibody, or fragment thereof is provided in a pharmaceutically acceptable vehicle.  
   
   
       31 . The kit of  claim 29 , wherein the humanized antibody, chimeric antibody, or fragment thereof is lyophilized and the kit further includes a pharmaceutically acceptable vehicle for dissolving the humanized antibody, chimeric antibody or fragment.