Toll-like receptor 2 binding epitope and binding member thereto

Abstract

The present invention relates to the identification of a TLR2 binding epitope wherein binding of a binding member to the epitope serves to inhibit TLR2 activation and/or signaling. Polypeptide fragments of TLR2 and three-dimensional structures comprising one or more amino acid residues His318, Pro320, Gln321 or Arg321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of TLR2 which define the identified epitope are provided for use in generating binding members. Also provided are binding members which bind to the identified epitope and methods of using same for the treatment and/or prevention of conditions associated with TLR2 activation and/or signaling.

1 - 20 . (canceled) 
     
     
         21 . A binding member that specifically binds to a polypeptide fragment of Toll-like receptor 2 (TLR2), the polypeptide fragment comprising:
 amino acid residues His318, Pro320, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of TLR2 as defined in SEQ ID NO:3 or SEQ ID NO:4,   wherein the amino acid residues His318, Pro320, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 form a functional epitope;   wherein the binding member specifically binds to the functional epitope;   wherein binding of the functional epitope by the binding member antagonises TLR2 activation and signalling; and   wherein the binding member is not T2.5 or a humanised version thereof.   
     
     
         22 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment comprises amino acid residues His318, Pro320, Gln321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of murine TLR2 as defined in SEQ ID NO:4 and said amino acid residues form the functional epitope. 
     
     
         23 . binding member as claimed in  claim 21 , wherein the polypeptide fragment comprises amino acid residues His318, Pro320, Arg321, Tyr323, Lys347, Phe349, Leu371, Glu375, Tyr376 and His398 of human TLR2 as defined in SEQ ID NO:3 and said amino acid residues form the functional epitope. 
     
     
         24 . The binding member as claimed in  claim 21 , wherein the binding member is an antibody or an antigen binding fragment thereof. 
     
     
         25 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment comprises less than about 200 amino acid residues of TLR2. 
     
     
         26 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment comprises less than about 102 amino acid residues of TLR2. 
     
     
         27 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment consists of SEQ ID NO:5 or SEQ ID NO:6. 
     
     
         28 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment consists of amino acid residues Thr311 to Thr411 of SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         29 . The binding member as claimed in  claim 21 , wherein the polypeptide fragment consists of amino acid residues Leu317 to His398 of SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         30 . The binding member as claimed in  claim 21 , wherein the binding member is selected from the group consisting of a protein, a peptide, a peptidomimetic, a nucleic acid, a carbohydrate, a lipid, an oligopeptide, an aptamer and a small molecule. 
     
     
         31 . A method for the treatment of a disease which is mediated by Toll-like Receptor 2 activation and signalling, the method comprising the step of administering to a subject in need of treatment a therapeutically effective amount of a binding member as claimed in claim  1 .