Btla-binding antibodies for modulating immune response and treating disease

Abstract

The invention provides novel anti-BTLA antibodies, pharmaceutical compositions comprising such antibodies, and therapeutic methods of using such antibodies and pharmaceutical compositions for the treatment of diseases such as cancer or autoimmune disease.

Whast is claimed is: 
     
         1 - 34 . (canceled) 
     
     
         35 . An antibody that binds to BTLA, or a BTLA binding fragment thereof, comprising:
 a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:22; or   b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26; or   c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:30; or   d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:31 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:32; or   e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:35 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36.   
     
     
         36 . The antibody according to  claim 35 , wherein the antibody serves as a BTLA antagonist and induces pro-inflammatory T cell functions; or the antibody serves as a BTLA agonist and suppresses pro-inflammatory T cells functions. 
     
     
         37 . An antibody that binds to BTLA, or a BTLA binding fragment thereof, comprising:
 a) a vhCDR1 comprising SEQ ID NO:107, a vhCDR2 comprising SEQ ID NO:108, a vhCDR3 comprising SEQ ID NO:109, a vlCDR1 comprising SEQ ID NO:110, a vlCDR2 comprising SEQ ID NO: 111, and a vlCDR3 comprising SEQ ID NO:112; or   b) a vhCDR1 comprising SEQ ID NO:119, a vhCDR2 comprising SEQ ID NO:120, a vhCDR3 comprising SEQ ID NO:121, a vlCDR1 comprising SEQ ID NO:122, a vlCDR2 comprising SEQ ID NO: 123, and a vlCDR3 comprising SEQ ID NO:124; or   c) a vhCDR1 comprising SEQ ID NO:131, a vhCDR2 comprising SEQ ID NO:132, a vhCDR3 comprising SEQ ID NO:133, a vlCDR1 comprising SEQ ID NO:134, a vlCDR2 comprising SEQ ID NO: 135, and a vlCDR3 comprising SEQ ID NO:136; or   d) a vhCDR1 comprising SEQ ID NO:137, a vhCDR2 comprising SEQ ID NO:138, a vhCDR3 comprising SEQ ID NO:139, a vlCDR1 comprising SEQ ID NO: 140, a vlCDR2 comprising SEQ ID NO: 141, and a vlCDR3 comprising SEQ ID NO:142; or   e) a vhCDR1 comprising SEQ ID NO:149, a vhCDR2 comprising SEQ ID NO:150, a vhCDR3 comprising SEQ ID NO:151, a vlCDR1 comprising SEQ ID NO:152, a vlCDR2 comprising SEQ ID NO: 153, and a vlCDR3 comprising SEQ ID NO:154.   
     
     
         38 . The antibody according to  claim 37 , wherein the antibody serves as a BTLA antagonist and induces pro-inflammatory T cell functions; or the antibody serves as a BTLA agonist and suppresses pro-inflammatory T cells functions. 
     
     
         39 . The antibody according to  claim 37 , wherein the antibody comprises a constant region with an amino acid sequence at least 90% identical to a human IgG. 
     
     
         40 . The antibody according to  claim 39 , wherein the antibody binds to human or cynomolgus BTLA. 
     
     
         41 . The antibody according to  claim 39 , wherein the human IgG is selected from a group consisting of IgG1, IgG2, IgG3 and IgG4. 
     
     
         42 . The antibody according to  claim 41 , wherein the IgG is an IgG2. 
     
     
         43 . The BTLA binding fragment according to  claim 37 . 
     
     
         44 . The BTLA binding fragment according to  claim 43 , wherein the BTLA binding fragment is an Fv fragment, a Fab fragment, or a scFv fragment. 
     
     
         45 . An isolated nucleic acid molecule or a nucleic acid composition encoding the antibody or BTLA binding fragment according to  claim 37 . 
     
     
         46 . The nucleic acid composition according to  claim 45 , wherein the composition comprises:
 a first nucleic acid molecule encoding the vhCDR1, vhCDR2, and vhCDR3; and   a second nucleic acid molecule encoding the vlCDR1, vlCDR2, and vlCDR3.   
     
     
         47 . The nucleic acid composition according to  claim 45 , wherein the composition comprises:
 a) the first nucleic acid molecule comprising SEQ ID NO: 205, and the second nucleic acid molecule comprising SEQ ID NO: 206; or   b) the first nucleic acid molecule comprising SEQ ID NO: 209, and the second nucleic acid molecule comprising SEQ ID NO: 210; or   c) the first nucleic acid molecule comprising SEQ ID NO: 213, and the second nucleic acid molecule comprising SEQ ID NO: 214; or   d) the first nucleic acid molecule comprising SEQ ID NO: 215, and the second nucleic acid molecule comprising SEQ ID NO: 216; or   e) the first nucleic acid molecule comprising SEQ ID NO: 219, and the second nucleic acid molecule comprising SEQ ID NO: 220.   
     
     
         48 . An expression vector comprising the isolated nucleic acid molecule or nucleic acid composition according to  claim 45 . 
     
     
         49 . A host cell comprising the expression vector of  claim 48 . 
     
     
         50 . A method of making an antibody comprising:
 culturing said host cell of  claim 49  under conditions wherein the antibody is expressed, and   recovering the antibody.   
     
     
         51 . A composition comprising the antibody according to  claim 37 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         52 . A method of modulating an immune response in a subject, the method comprising administering to the subject an effective amount of the antibody according to  claim 37 . 
     
     
         53 . A method of treating cancer in a subject comprising administering to the subject an effective amount of the antibody according to  claim 37 , wherein the antibody serves as a BTLA antagonist. 
     
     
         54 . A method of treating an autoimmune disease in a subject comprising administering to the subject an effective amount of the antibody according to  claim 37 , wherein the antibody serves as a BTLA agonist.