Factor x binders enhancing fx activation

Abstract

The application relates to unique FX binding molecules, such as antibodies and fragments thereof which are useful in the treatment of haemophilia.

1 . A nanobody capable of binding FX, wherein the nanobody is capable of making FX more prone to proteolysis by FIXa and wherein the nanobody is capable of binding the activation peptide of FX (amino acid residues 143-194 of SEQ ID NO:2),
 wherein the common minimal epitope, as determined by peptide array, comprises amino acid residues “LL” (amino acid residues 177-178 of SEQ ID NO:2), and   wherein the nanobody is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the sequence identified by SEQ ID NO:10.   
     
     
         2 . A nanobody capable of binding FX
 a. comprising SEQ ID NO:10, or   b. comprising three CDR sequences, wherein the three CDR sequences have at most amino acid changes compared to those of SEQ ID NO:10,
 wherein the antibody or antigen-binding fragment thereof is capable of making FX more prone to proteolysis by FIXa. 
   
     
     
         3 . The nanobody according to  claim 1 , wherein the nanobody is capable of making FX more prone to proteolysis by FIXa independently of the presence of a FIXa binder. 
     
     
         4 . The nanobody according to  claim 2 , wherein the nanobody is capable of making FX more prone to proteolysis by FIXa independently of the presence of a FIXa binder. 
     
     
         5 . The nanobody according to  claim 1 , wherein the nanobody has a binding affinity determined as the equilibrium dissociation constant (K D ) that is less than 10 μM. 
     
     
         6 . The nanobody according to  claim 2 , wherein the nanobody has a binding affinity determined as the equilibrium dissociation constant (K D ) that is less than 10 μM. 
     
     
         7 . A bi- or multi-specific antibody comprising the nanobody according to  claim 1 . 
     
     
         8 . A bi- or multi-specific antibody comprising the nanobody according to  claim 2 . 
     
     
         9 . A method of treating a haemophilia, comprising administering the nanobody according to  claim 1  to a subject in need thereof. 
     
     
         10 . The method of  claim 9 , wherein haemophilia is haemophilia A with inhibitors, haemophilia A without inhibitors, haemophilia B with inhibitors, or haemophilia B without inhibitors. 
     
     
         11 . A method of treating a haemophilia, comprising administering the nanobody according to  claim 2  to a subject in need thereof. 
     
     
         12 . The method of  claim 11 , wherein haemophilia is haemophilia A with inhibitors, haemophilia A without inhibitors, haemophilia B with inhibitors, or haemophilia B without inhibitors.