B7-h4 antibodies and methods of use thereof

Abstract

The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to human B7-H4 (and optionally cynomolgus monkey, mouse, and/or rat B7-H4) and compositions comprising such antibodies or antigen-binding fragments thereof. In a specific aspect, the antibodies or antigen-binding fragments thereof that specifically bind to human B7-H4 increase T cell proliferation, increase interferon-gamma production, and/or deplete B7-H4 expressing cells via ADCC activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering an antibody or antigen-binding fragment thereof that specifically binds to human B7-H4.

What is claimed: 
     
         1 . An isolated IgG antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, comprising a heavy chain variable region (VH) complementarity determining region (CDR) 1, a VH CDR2, a VH CDR3 and a light chain variable region (VL) CDR1, a VL CDR2, and a VL CDR3 wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise amino acid sequences selected from the group consisting of:
 (a) SEQ ID NOs:458-463, respectively;   (b) SEQ ID NOs:5-10, respectively;   (c) SEQ ID NOs:15-20, respectively;   (d) SEQ ID NOs:25-30, respectively;   (e) SEQ ID NOs:35-40, respectively;   (f) SEQ ID NOs:45-50, respectively;   (g) SEQ ID NOs:55-60, respectively;   (h) SEQ ID NOs:65-70, respectively;   (i) SEQ ID NOs:75-80, respectively;   (j) SEQ ID NOs:85-90, respectively;   (k) SEQ ID NOs:95-100, respectively;   (l) SEQ ID NOs:105-110, respectively;   (m) SEQ ID NOs:115-120, respectively;   (n) SEQ ID NOs:125-130, respectively;   (o) SEQ ID NOs:135-140, respectively;   (p) SEQ ID NOs:145-150, respectively;   (q) SEQ ID NOs:155-160, respectively;   (r) SEQ ID NOs:165-170, respectively;   (s) SEQ ID NOs:175-180, respectively;   (t) SEQ ID NOs:185-190, respectively; and   (u) SEQ ID NOs:195-200, respectively.   
     
     
         2 . A composition comprising the IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment thereof is conjugated to a toxin or radioisotope. 
     
     
         3 . The composition of  claim 2 , wherein the IgG antibody or antigen-binding fragment thereof is conjugated to a cytotoxin. 
     
     
         4 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:11, 21, 31, 41, 464, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, or 201 and/or comprises a VL comprising the amino acid sequence of SEQ ID NO:12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172, 182, 192, or 202. 
     
     
         5 . An isolated IgG antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, wherein the IgG antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising the amino acid sequences of:
 (a) SEQ ID NOs:464 and 42, respectively;   (b) SEQ ID NOs:11 and 12, respectively;   (c) SEQ ID NOs:21 and 22, respectively;   (d) SEQ ID NOs:31 and 32, respectively;   (e) SEQ ID NOs:41 and 42, respectively;   (f) SEQ ID NOs:51 and 52, respectively;   (g) SEQ ID NOs:61 and 62, respectively;   (h) SEQ ID NOs:71 and 72, respectively;   (i) SEQ ID NOs:81 and 82, respectively;   (j) SEQ ID NOs:91 and 92, respectively;   (k) SEQ ID NOs:101 and 102, respectively;   (l) SEQ ID NOs:111 and 112, respectively;   (m) SEQ ID NOs:121 and 122, respectively;   (n) SEQ ID NOs:131 and 132, respectively;   (o) SEQ ID NOs:141 and 142, respectively;   (p) SEQ ID NOs:151 and 152, respectively;   (q) SEQ ID NOs:161 and 162, respectively;   (r) SEQ ID NOs:171 and 172, respectively;   (s) SEQ ID NOs:181 and 182, respectively;   (t) SEQ ID NOs:191 and 192, respectively; or   (u) SEQ ID NOs:201 and 202, respectively.   
     
     
         6 . A composition comprising the IgG antibody or antigen-binding fragment thereof of  claim 5 , wherein the IgG antibody or antigen-binding fragment thereof is conjugated to a toxin or a radioisotope. 
     
     
         7 . The composition of  claim 6 , wherein the IgG antibody or antigen-binding fragment thereof is conjugated to a cytotoxin. 
     
     
         8 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment further comprises a heavy chain constant region. 
     
     
         9 . The IgG antibody or antigen-binding fragment thereof of  claim 8 , wherein the heavy chain constant region is selected from the group consisting of human immunoglobulins IgG1, IgG2, IgG3, and IgG4 heavy chain constant regions. 
     
     
         10 . The IgG antibody or antigen-binding fragment thereof of  claim 8 , wherein the IgG antibody or antigen-binding fragment further comprises a light chain constant region. 
     
     
         11 . The IgG antibody or antigen-binding fragment thereof of  claim 10 , wherein the light chain constant region is selected from the group consisting of human immunoglobulins IgGκ and IgGλ light chain constant regions. 
     
     
         12 . An isolated IgG antibody or antigen-binding fragment thereof that specifically binds to human B7-H4, wherein the IgG antibody or antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of an antibody selected from the group consisting of 15461, 20500, 20501, 20502, 20502.1, 22208, 15462, 22213, 15465, 20506, 15483, 20513, 22216, 15489, 20516, 15472, 15503, 15495, 15478, 15441, and 20496. 
     
     
         13 . The IgG antibody or antigen-binding fragment thereof of  claim 12 , wherein the CDRs are the Kabat-defined CDRs, the Chothia-defined CDRs, or the AbM-defined CDRs. 
     
     
         14 . An isolated IgG antibody or antigen-binding fragment thereof that binds to the same epitope of human B7-H4 as the IgG antibody or antigen-binding fragment thereof of  claim 5 . 
     
     
         15 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody is a human antibody, a humanized antibody, a chimeric antibody, or an antigen-binding fragment thereof. 
     
     
         16 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment thereof:
 (a) induces T cell proliferation   (b) induces CD4+ T cell proliferation,   (c) induces CD8+ T cell proliferation,   (d) induces interferon-gamma (IFNγ) production,   (e) is capable of inducing antibody dependent cell mediated cytotoxicity (ADCC) in a B7-H4-expressing cell,   (f) inhibits tumor growth in a murine CT26 colorectal carcinoma model, a murine breast carcinoma 4T1 model, or a melanoma cell line B16-moB7-H4/H3 model, and/or   (g) inhibits T cell checkpoint blockade activity of B7-H4.   
     
     
         17 . The IgG antibody of antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment:
 (a) increases T cell proliferation by at least 5% as compared to treatment with a control antibody,   (b) increases CD4+ T cell proliferation by at least 5% as compared to treatment with a control antibody,   (c) increases CD8+ T cell proliferation by at least 5% as compared to treatment with a control antibody.   (d) is capable of increasing production of IFNγ by at least 2 fold,   (e) induces specific lysis in at least 20% of B7-H4 expressing cells, and/or   (f) reduces tumor growth by at least 25% as compared to treatment with a control antibody.   
     
     
         18 . The IgG antibody or antigen-binding fragment thereof of  claim 16 , wherein the induction of T cell proliferation, the induction of CD4+ T cell proliferation, the induction of CD8+ T cell proliferation, the induction of IFNγ production, the ADCC activity, the inhibition of tumor growth, and/or the inhibition of T cell checkpoint blockade activity is dose-dependent. 
     
     
         19 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment thereof binds to cynomolgus monkey, rat, and/or mouse B7-H4. 
     
     
         20 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment thereof binds to the IgV domain of human B7-H4. 
     
     
         21 . The IgG antibody or antigen-binding fragment thereof of  claim 1 , wherein the IgG antibody or antigen-binding fragment thereof is afucosylated. 
     
     
         22 . A composition comprising the IgG antibody or antigen-binding fragment thereof of  claim 1 , and a detectable label. 
     
     
         23 . An isolated polynucleotide or polynucleotides encoding the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         24 . An isolated vector or vectors comprising a polynucleotide or polynucleotides encoding the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         25 . A host cell comprising a polynucleotide or polynucleotides encoding the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         26 . A method of producing an IgG antibody or antigen-binding fragment thereof that binds to human B7-H4 comprising culturing the host cell of  claim 25  so that the polynucleotide or polynucleotides are expressed and the IgG antibody or antigen-binding fragment thereof is produced. 
     
     
         27 . An isolated IgG antibody or antigen-binding fragment thereof that specifically binds to human B7-H4 and is encoded by the polynucleotide or polynucleotides of  claim 23 . 
     
     
         28 . A pharmaceutical composition comprising the IgG antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         29 . A pharmaceutical composition comprising (i) the IgG antibodies or antigen-binding fragments of  claim 1  and (ii) a pharmaceutically acceptable excipient, wherein at least 95% of the IgG antibodies or antigen-binding fragments thereof in the composition are afucosylated. 
     
     
         30 . The pharmaceutical composition of  claim 28 , further comprising an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof. 
     
     
         31 . A method for inducing T cell proliferation comprising contacting a T cell with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         32 . A method for inducing CD4+ T cell proliferation comprising contacting a CD4+ T cell with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         33 . A method for inducing CD8+ T cell proliferation comprising contacting a CD8+ T cell with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         34 . A method for inducing interferon gamma production comprising contacting a T cell with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         35 . A method for killing a cell expressing B7-H4 comprising contacting the cell with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         36 . A method for depleting B7-H4-expressing cells from a population of cells comprising contacting the population of cells with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         37 . A method for inducing CD4+ T cell proliferation comprising contacting a CD4+ T cell with the IgG antibody or antigen-binding fragment thereof of  claim 1  and contacting the T cell with an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof. 
     
     
         38 . A method of treating a B7-H4 expressing cancer in a subject, the method comprising administering to the subject an effective amount of the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         39 . A method of treating a cancer selected from the group consisting of head and neck cancer, small cell lung cancer, gastric cancer, melanoma, breast cancer, ductal carcinoma, endometrial carcinoma, ovarian cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, kidney cancer and bladder cancer, comprising administering to the subject an effective amount of the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         40 . A method of treating cancer, wherein the cancer is a PD-1 inhibitor inadequate responder, and/or wherein the cancer is a PD-L1 inhibitor inadequate responder, and/or wherein the cancer expresses a low level of PD-L1, the method comprising administering to the subject an effective amount of the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         41 . A method of treating cancer comprising administering to a subject an effective amount of the IgG antibody or antigen-binding fragment thereof of  claim 1  and administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof or an anti-PD-L1 antibody or an antigen-binding fragment thereof. 
     
     
         42 . A method for detecting B7-H4 in a sample comprising contacting said sample with the IgG antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         43 . A kit comprising the IgG antibody or antigen-binding fragment thereof of  claim 1 , a detection reagent, and instructions for use for detection of a B7-H4 antigen. 
     
     
         44 . The IgG antibody or antigen-binding fragment thereof of  claim 5 , wherein the IgG antibody or antigen-binding fragment further comprises a heavy chain constant region. 
     
     
         45 . The IgG antibody or antigen-binding fragment thereof of  claim 44 , wherein the heavy chain constant region is selected from the group consisting of human immunoglobulins IgG1, IgG2, IgG3, and IgG4 heavy chain constant regions. 
     
     
         46 . The IgG antibody or antigen-binding fragment thereof of  claim 5 , wherein the IgG antibody or antigen-binding fragment thereof is afucosylated. 
     
     
         47 . A pharmaceutical composition comprising the IgG antibody or antigen-binding fragment thereof of  claim 5  and a pharmaceutically acceptable excipient. 
     
     
         48 . A pharmaceutical composition comprising (i) the IgG antibodies or antigen-binding fragments of  claim 1 , (ii) a pharmaceutically acceptable excipient, and (iii) an anti-PD-1 antibody or antigen-binding fragment thereof, or an anti-PD-L1 antibody or an antigen-binding fragment thereof;
 wherein at least 95% of the IgG antibodies or antigen-binding fragments thereof of  claim 1  in the composition are afucosylated.   
     
     
         49 . The IgG antibody or antigen-binding fragment of  claim 44 , wherein the IgG antibody or antigen-binding fragment comprises a light chain constant region. 
     
     
         50 . The IgG antibody or antigen-binding fragment thereof of  claim 49 , wherein the light chain constant region is selected from the group consisting of human immunoglobulins IgGκ and IgGλ light chain constant regions.