Btla antibodies

Abstract

This invention relates generally to antibodies or antigen binding fragments that bind to human B and T lymphocyte attenuator (BTLA) and uses thereof. More specifically, the invention relates to agonistic antibodies that bind human BTLA and modulate its activity, and their use in treating inflammatory, autoimmune and proliferative diseases and disorders.

1 - 95 . (canceled) 
     
     
         96 . A method of modulating an immune response in a subject, comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds B and T Lymphocyte Attenuator (BTLA),
 wherein the antibody or antigen-binding fragment thereof:   (i) comprises a heavy chain and a light chain;   (ii) agonizes BTLA expressed on the surface of an immune cell; and   (iii) binds a residue of BTLA selected from the group consisting of: D52, P53, E55, E57, E83, Q86, E103, L106 and E92.   
     
     
         97 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof does not inhibit binding of BTLA to herpes virus entry mediator (HVEM). 
     
     
         98 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof binds human BTLA at a KD of less than 10 nM, as determined by surface plasmon resonance at 37° C. 
     
     
         99 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof binds human BTLA at a KD of less than 2 nM, as determined by surface plasmon resonance at 37° C. 
     
     
         100 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof binds cynomolgus BTLA at a KD of less than 20 nM, as determined by surface plasmon resonance at 37° C. 
     
     
         101 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof inhibits proliferation of T cells in the subject. 
     
     
         102 . The method of  claim 96 , wherein:
 (a) the light chain comprises a light chain variable region that comprises a CDR that has an amino acid sequence as set forth in any of SEQ ID NO: 142, SEQ ID NO: 143, or SEQ ID NO: 210, with from 0 to 3 amino acid modifications; and   (b) the heavy chain comprises a heavy chain variable region that comprises a CDR that has an amino acid sequence as set forth in SEQ ID NO: 205, SEQ ID NO: 387, and SEQ ID NO: 207, with from 0 to 3 amino acid modifications.   
     
     
         103 . The method of  claim 96 , wherein the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence as set forth in SEQ ID NO: 378. 
     
     
         104 . The method of  claim 103 , wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence as set forth in SEQ ID NO: 390. 
     
     
         105 . The method of  claim 96 , wherein:
 (a) the light chain comprises a light chain variable region that comprises three CDRs: CDRL1, CDRL2, and CDRL3, wherein (a) CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 142, with 0 to 1 amino acid modification; (b) CDRL2 has the amino acid sequence as set forth in SEQ ID NO: 143, with 0 to 1 amino acid modification; and (c) CDRL3 has the amino acid sequence as set forth in SEQ ID NO: 210, with 0 to 1 amino acid modification; and   (b) the heavy chain comprises a heavy chain variable region comprising three CDRs: CDRH1, CDRH2, and CDRH3, wherein (a) CDRH1 has the amino acid sequence as set forth in SEQ ID NO: 205, with 0 to 1 amino acid modification; (b) CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 387, with 0 to 2 amino acid modifications; and (c) CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 207, with 0 to 1 amino acid modification.   
     
     
         106 . The method of 105, wherein CDRL2 has no amino acid modifications as compared to SEQ ID NO: 143. 
     
     
         107 . The method of 105, wherein CDRH2 has an amino acid modification at position 5, position 7, or both, numbered according to SEQ ID NO: 387. 
     
     
         108 . The method of 107, wherein CDRL2 has no amino acid modifications as compared to SEQ ID NO: 143. 
     
     
         109 . The method of 105, wherein the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 378. 
     
     
         110 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof further comprises a domain that binds to an Fc receptor. 
     
     
         111 . The method of  claim 110 , wherein said Fc receptor is FcγRIIB 
     
     
         112 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody. 
     
     
         113 . The method of  claim 96 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody. 
     
     
         114 . The method of  claim 96 , wherein the heavy chain or light chain also comprise a constant region. 
     
     
         115 . The method of  claim 96 , wherein the heavy chain and light chain are connected by a flexible linker to form a single-chain antibody. 
     
     
         116 . An antibody or an antigen-binding fragment thereof that specifically binds BTLA, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising three CDRs: CDRH1, CDRH2 and CDRH3, wherein (1) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, with from 0 to 3 amino acid modifications; (2) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively, with from 0 to 3 amino acid modifications; (3) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 43, SEQ ID NO: 44, and SEQ ID NO: 45, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 6, SEQ ID NO: 47, and SEQ ID NO: 48, respectively, with from 0 to 3 amino acid modifications; (4) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 43, SEQ ID NO: 56, and SEQ ID NO: 57, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, and SEQ ID NO: 60, respectively, with from 0 to 3 amino acid modifications; (5) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 61, SEQ ID NO: 62, and SEQ ID NO: 63, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively, with from 0 to 3 amino acid modifications; (6) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 69, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 72, respectively, with from 0 to 3 amino acid modifications; (7) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 75, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 76, SEQ ID NO: 47, and SEQ ID NO: 78, respectively, with from 0 to 3 amino acid modifications; (8) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 79, SEQ ID NO: 80, and SEQ ID NO: 81, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 82, SEQ ID NO: 83, and SEQ ID NO: 84, respectively, with from 0 to 3 amino acid modifications; (9) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 85, SEQ ID NO: 86, and SEQ ID NO: 87, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 88, SEQ ID NO: 89, and SEQ ID NO: 90, respectively, with from 0 to 3 amino acid modifications; (10) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 61, SEQ ID NO: 92, and SEQ ID NO: 93, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 94, SEQ ID NO: 95, and SEQ ID NO: 96, respectively, with from 0 to 3 amino acid modifications; (11) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 97, SEQ ID NO: 98, and SEQ ID NO: 99, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 100, SEQ ID NO: 101, and SEQ ID NO: 102, respectively, with from 0 to 3 amino acid modifications; (12) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 103, SEQ ID NO: 104, and SEQ ID NO: 105, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 64, SEQ ID NO: 107, and SEQ ID NO: 108, respectively, with from 0 to 3 amino acid modifications; (13) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 88, SEQ ID NO: 89, and SEQ ID NO: 114, respectively, with from 0 to 3 amino acid modifications; (14) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 85, SEQ ID NO: 110, and SEQ ID NO: 117, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 88, SEQ ID NO: 89, and SEQ ID NO: 114, respectively, with from 0 to 3 amino acid modifications; (15) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 121, SEQ ID NO: 122, and SEQ ID NO: 123, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 124, SEQ ID NO: 125, and SEQ ID NO: 126, respectively, with from 0 to 3 amino acid modifications; (16) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 127, SEQ ID NO: 128, and SEQ ID NO: 129, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, with from 0 to 3 amino acid modifications; (17) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 133, SEQ ID NO: 134, and SEQ ID NO: 135, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 136, SEQ ID NO: 137, and SEQ ID NO: 138, respectively, with from 0 to 3 amino acid modifications; (18) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 139, SEQ ID NO: 140, and SEQ ID NO: 141, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 142, SEQ ID NO: 143, and SEQ ID NO: 144, respectively, with from 0 to 3 amino acid modifications; (19) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 145, SEQ ID NO: 146, and SEQ ID NO: 147, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 148, SEQ ID NO: 149, and SEQ ID NO: 150, respectively, with from 0 to 3 amino acid modifications; (20) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 148, SEQ ID NO: 149, and SEQ ID NO: 150, respectively, with from 0 to 3 amino acid modifications; (21) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 159, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 136, SEQ ID NO: 137, and SEQ ID NO: 162, respectively, with from 0 to 3 amino acid modifications; (22) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 169, SEQ ID NO: 170, and SEQ ID NO: 171, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 172, SEQ ID NO: 173, and SEQ ID NO: 174, respectively, with from 0 to 3 amino acid modifications; (23) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 61, SEQ ID NO: 62, and SEQ ID NO: 63, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 180, respectively, with from 0 to 3 amino acid modifications; (24) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 31, SEQ ID NO: 182, and SEQ ID NO: 183, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 136, SEQ ID NO: 137, and SEQ ID NO: 186, respectively, with from 0 to 3 amino acid modifications; (25) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 187, SEQ ID NO: 188, and SEQ ID NO: 189, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 190, SEQ ID NO: 191, and SEQ ID NO: 192, respectively, with from 0 to 3 amino acid modifications; (26) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 193, SEQ ID NO: 194, and SEQ ID NO: 195, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 12, respectively, with from 0 to 3 amino acid modifications; (27) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 199, SEQ ID NO: 200, and SEQ ID NO: 201, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 202, SEQ ID NO: 203, and SEQ ID NO: 6, respectively, with from 0 to 3 amino acid modifications; (28) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 211, SEQ ID NO: 212, and SEQ ID NO: 213, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 214, SEQ ID NO: 35, and SEQ ID NO: 216, respectively, with from 0 to 3 amino acid modification; (29) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 127, SEQ ID NO: 386, and SEQ ID NO: 129, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, with from 0 to 3 amino acid modification; ; or (30) CDRH1, CDRH2, CDRH3 have an amino acid sequence as set forth in SEQ ID NO: 127, SEQ ID NO: 388, and SEQ ID NO: 129, respectively, with from 0 to 3 amino acid modification, and CDRL1, CDRL2, and CDRL3 have an amino acid sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively, with from 0 to 3 amino acid modification.