BTLA-BINDING ANTIBODIES FOR MODULATING IMMUNE RESPONSE AND TREATING DISEASE
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.
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.