Compositions and methods for modulating lymphocyte activity

Abstract

The present invention provides a novel lymphocyte inhibitory receptor termed BTLA which is expressed on both T and B cells, and identifies HVEM as interacting with BTLA. Methods and compositions for modulating BTLA-mediated signaling and interfering with the interaction of BTLA and HVEM for therapeutic, diagnostic and research purposes are also provided.

1 . An antibody capable of specifically binding to a protein having an amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is capable of reducing binding of a BTLA protein to an HVEM protein. 
     
     
         2 . An antibody capable of specifically binding to a protein having an amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is capable of reducing binding of a BTLA Ig domain to an HVEM CRD1 domain. 
     
     
         3 . The antibody of  claim 2 , wherein the BTLA Ig domain comprises amino acids 43 to 134 of SEQ ID NO:8. 
     
     
         4 . An anti-BTLA antibody capable of specifically binding to a BTLA protein, wherein the antibody is capable of reducing binding of the BTLA protein to an HVEM protein. 
     
     
         5 . An antibody capable of specifically binding to a protein having at least about 95% identity to the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is capable of reducing binding of a BTLA protein to an HVEM protein. 
     
     
         6 . The antibody of  claim 5 , wherein the protein has at least about 98% identity to the amino acid sequence set forth in SEQ ID NO:8. 
     
     
         7 . An antibody capable of specifically binding to a protein having at least about 95% identity to the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is capable of reducing binding of a BTLA Ig domain to an HVEM CRD1 domain. 
     
     
         8 . The antibody of  claim 7 , wherein the protein has at least about 98% identity to the amino acid sequence set forth in SEQ ID NO:8. 
     
     
         9 . The antibody of  claim 7 , wherein the BTLA Ig domain comprises amino acids 43 to 134 of SEQ ID NO:8. 
     
     
         10 . An antibody capable of specifically binding to a protein having an amino acid sequence set forth in SEQ ID NO:6, wherein the antibody is capable of reducing binding of a BTLA protein to an HVEM protein. 
     
     
         11 . An antibody capable of specifically binding to a protein having an amino acid sequence set forth in SEQ ID NO:6, wherein the antibody is capable of reducing binding of a BTLA Ig domain to an HVEM CRD1 domain. 
     
     
         12 . The antibody of  claim 11 , wherein the BTLA Ig domain comprises amino acids 43 to 134 of SEQ ID NO:6. 
     
     
         13 . A BTLA antibody, wherein said antibody is capable of specifically binding to a BTLA protein, and wherein said antibody is capable of reducing the binding of said BTLA protein to an HVEM protein. 
     
     
         14 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of specifically binding to a mouse BTLA protein. 
     
     
         15 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of specifically binding to a human BTLA protein. 
     
     
         16 . The BTLA antibody according to  claim 13 , wherein said BTLA protein and said HVEM protein are on the surface of a first cell and a second cell, respectively. 
     
     
         17 . The BTLA antibody according to  claim 13 , wherein said BTLA protein is a recombinantly produced tetramer. 
     
     
         18 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of binding toward the DEBA face of the Ig fold of said BTLA protein. 
     
     
         19 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of binding to a region of the Ig domain of said BTLA protein, which region is capable of binding to the complementarity determining region (CRD) 1 domain of said HVEM protein. 
     
     
         20 . The BTLA antibody according to  claim 13 , wherein said antibody binds to an epitope comprising one or more residues selected from the group consisting of V42, Q43, L44, R55, Q63, Q102, and C85 of SEQ ID NO:1. 
     
     
         21 . The BTLA antibody according to  claim 13 , wherein said antibody binds to an epitope comprising one or more residues selected from the group consisting of V36, Q37, L38, L49, E57, C79, K93, and S96 in the human BTLA sequence set forth in SEQ ID NO:2. 
     
     
         22 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of binding to a polypeptide selected from the group consisting of the amino acid sequences set forth by residues 37-47, 39-49, 41-49, 50-60, 58-68, 80-90, 97-107, 50-90, 55-85, 58-90, 63-85, 80-107, 85-102, 127-137, 55-102, 50-107, and 41-137 of SEQ ID NO:1. 
     
     
         23 . The BTLA antibody according to  claim 13 , wherein said antibody is capable of binding to a polypeptide selected from the group consisting of the amino acid sequences set forth by residues 31-41, 32-42, 35-43, 44-54, 52-62, 74-84, 88-98, 44-84, 49-79, 52-84, 57-79, 74-98, 79-93, 118-128, 49-93, 44-98, 35-98, and 35-128 of the human BTLA isoform set forth in SEQ ID NO:2. 
     
     
         24 . The BTLA antibody according to  claim 13 , wherein said antibody is a monoclonal antibody. 
     
     
         25 . The BTLA antibody according to  claim 13 , wherein said antibody is a human antibody. 
     
     
         26 . A pharmaceutical composition, comprising a BTLA antibody according to  claim 13 .