Protease-regulated antibodies

Abstract

This disclosure provides protease-regulated antibodies which specifically bind to tissue factor pathway inhibitor (TFPI). The antibodies are useful for treating bleeding disorders such as hemophilia.

What is claimed is: 
     
         1 . A protease-regulated antibody which specifically binds to tissue factor pathway inhibitor (TFPI), comprising a variable domain, a constant domain, and an amino acid sequence joining the variable domain to the constant domain, wherein the amino acid sequence comprises a protease cleavage site. 
     
     
         2 . The protease-regulated antibody of  claim 1 , wherein the protease cleavage site is a thrombin cleavage site. 
     
     
         3 . The protease-regulated antibody of  claim 1 , wherein the protease cleavage site is a plasmin cleavage site. 
     
     
         4 . The protease-regulated antibody of  claim 1 , wherein the protease cleavage site is a Factor Xa cleavage site. 
     
     
         5 . The protease-regulated antibody of  claim 1  which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 131, amino acids 1-239 of SEQ ID NO: 133, SEQ :ID NO: 135, amino acids 1-229 of SEQ ID NO: 136, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 143, and SEQ ID NO: 144. 
     
     
         6 . The protease-regulated antibody of  claim 1 , wherein the amino acid sequence further comprises an amino acid linker. 
     
     
         7 . The protease-regulated antibody of  claim 1 , wherein the protease-regulated antibody is a full-length antibody. 
     
     
         8 . The protease-regulated antibody of  claim 1 , wherein the protease-regulated antibody is an antibody fragment. 
     
     
         9 . A pharmaceutical composition comprising the protease-regulated antibody of  claim 1 , and a pharmaceutically acceptable vehicle. 
     
     
         10 . An isolated nucleic acid molecule encoding the protease-regulated antibody of  claim 1 . 
     
     
         11 . A method of treating a coagulopathy, comprising administering to a patient in need thereof a therapeutically effective amount of the protease-regulated antibody of  claim 1 . 
     
     
         12 . The method of  claim 11 , wherein the coagulopathy is hemophilia. 
     
     
         13 . A method of modulating procoagulant activity of an anti-TFPI antibody, comprising adding a protease cleavage site into the anti-TFPI antibody. 
     
     
         14 . The method of  claim 13 , wherein the protease cleave site is a thrombin cleavage site. 
     
     
         15 . The method of  claim 13 , wherein the protease cleavage site is a plasmin cleavage site. 
     
     
         16 . The method of  claim 13 , wherein the protease cleavage site is a Factor Xa cleavage site. 
     
     
         17 . A method of promoting generation of thrombin or plasmin, comprising contacting TFPI with a protease-regulated antibody of  claim 1 .