Use of anti-factor xi antibodies for prevention of thrombus formation

Abstract

The present invention relates to binding molecules such as antibodies that specifically bind plasma coagulation factor XI and that inhibit factor XI activation and/or activity. The factor XI-binding molecules of the invention maybe sued in methods for preventing or treating diseases, disorders and/or condition that are mediated by factor XI activation and/or wherein inhibition of factor XI has a beneficial effect.

1 . A method of identifying an anti-factor XI (FXI) antibody or fragment thereof as being therapeutically active, the method comprising:
 a. subjecting the anti-FXI antibody or fragment thereof to an assay to determine whether the antibody inhibits factor XIIa-dependent activation of FXI; and/or   b. subjecting the anti-FXI antibody or fragment thereof to an assay to determine whether the antibody inhibits activated factor XI (FXIa)-dependent activation of factor IX (FIX); and then   c. identifying the antibody or fragment thereof as therapeutically active if the antibody or fragment thereof inhibits activation in step (a) and/or step (b).   
     
     
         2 . The method of  claim 1  further comprising at least one clotting assay comprising incubating FXI with the antibody or fragment thereof and/or incubating FXIa with the antibody or fragment thereof. 
     
     
         3 . The method of  claim 1 , wherein the assay to determine whether the antibody inhibits factor XIIa-dependent activation of FXI is an assay that uses a peptide substrate comprsing a proline-arginine sequence for FXIa substrate specificity. 
     
     
         4 . The method of  claim 3 , wherein the assay is a chromogenic assay. 
     
     
         5 . The method of  claim 4 , wherein the chromogenic assay comprises a chromogenic substrate comprising a peptide coupled to p-nitroanilide (pNA). 
     
     
         6 . The method of  claim 5 , wherein the chromogenic substrate comprises the formula L-pyroglutamyl-L-prolyl-L-arginine-pNA. 
     
     
         7 . The method of  claim 1 , wherein the assay to determine whether the antibody inhibits factor XIa-dependent activation of factor IX is a chromogenic assay. 
     
     
         8 . The method of  claim 7 , wherein the chromogenic assay comprises a chromogenic substrate comprising a peptide coupled to pNA. 
     
     
         9 . The method of  claim 8 , wherein the chromogenic substrate comprises the formula Methyl-sulfonyl-D-cyclo-hexylglycyl-glycyl-arginine-pNA. 
     
     
         10 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof binds to the light chain of FXIa. 
     
     
         11 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof binds to the active site of FXIa. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof binds Arg 369 -Ile 370  of native FXI. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof binds to the FIX binding site of FXI. 
     
     
         14 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof binds to the H-kininogen (HK) binding site of FXI. 
     
     
         15 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof preferentially binds to FXIa over FXI. 
     
     
         16 . The method of  claim 1 , wherein the therapeutically active anti-FXI antibody or fragment thereof has a Kd for FXIa less than or equal to 1 nM.