Anti-tfpi antibody variants with differential binding across ph range for improved pharmacokinetics

Abstract

Antibodies are disclosed that bind to and inhibit the anti-coagulant function of TFPI and have a lower affinity for TFPi at pH 6.0 than at pH 7.4. The lower affinity at pH 6 improves circulating half-life (T1/2) due to reduced target mediated clearance, a process by which an antibody/antigen complex, is endocytased and trafficked to the lysosome where both components are degraded. The lower affinity at pH 6.0 results in disruption of the complex prior to lysosome targeting and allows for re-circulation of the antibody. Specific modifications to antibody binding by histidine residue substitution are disclosed along with methods of use.

1 . A therapeutic composition comprises an isolated human monoclonal IgG antibody that binds specifically to human tissue -factor pathway inhibitor (TFPI) and has increased plasma half-life, wherein the antibody comprises at least one histidine substitution in a CDR region in either a human heavy chain or a human light chain and antibody binds to TFPI at pH 7.4 with at least two fold higher affinity than at pH 6.0. 
     
     
         2 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 5 
     
     
         3 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 6 
     
     
         4 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 7 
     
     
         5 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEO ID NO: 8 
     
     
         6 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 9 
     
     
         7 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 10 
     
     
         8 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 11 
     
     
         9 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID MO; 12 
     
     
         10 . The isolated human antibody of  claim 1 , wherein the fight chain comprises SEQ ID NO: 13 
     
     
         11 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 14 
     
     
         12 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 15 
     
     
         13 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 18 
     
     
         14 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 17 
     
     
         15 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO 10 
     
     
         16 . The isolated human antibody of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 10 and the histidine substitution is selected from the group consisting of Y102H, Y32H and Y100H, and combinations thereof. 
     
     
         17 . The isolated human antibody of  claim 1 , wherein the light chain comprises SEQ ID NO: 17 and the histidine substitution is selected from the group consisting of Y31H, F48HS S50H, Y49R L27H, V45N, W90H and combinations thereof. 
     
     
         18 . The isolated monoclonal antibody of  claim 1 , having at least two histidine substitutions selected from the group consisting of VL-Y31H, VH-Y102H, VH-Y100H, VB-Y32H, VL-F48H, VL-S50H, VL-Y49H, VL-L27H, VL-Y4SH, VL-W90H and combinations thereof.