Anti b7-h3 antibody

Abstract

The present invention relates to an antibody having a therapeutic effect on a tumor. That is, the invention relates to an antibody which binds to B7-H3 to exhibit an antitumor activity. An object of the invention is to provide a pharmaceutical having a therapeutic effect on a tumor. By obtaining an anti-B7-H3 antibody which binds to B7-H3 to exhibit an antitumor activity, a pharmaceutical composition for treating a tumor comprising the antibody and the like are obtained.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . An antibody characterized by having the following properties:
 (a) having a competitive inhibitory activity against M30 antibody consisting of heavy chain comprising an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO:51 and light chain comprising an amino acid sequence consisting of amino acid residues 23 to 235 of SEQ ID NO:53 for the binding to an IgC1 and/or IgC2 domain of B7-H3 comprising SEQ ID NO:6 or SEQ ID NO:10;   (b) having an antibody-dependent cell-mediated phagocytosis (ADCP) activity; and   (c) having an in vivo antitumor activity against tumors expressing B7-H3 comprising SEQ ID NO:6 or SEQ ID NO:10.   
     
     
         2 . The antibody according to  claim 1 , which has an antibody-dependent cellular cytotoxicity (ADCC) activity and/or a complement-dependent cytotoxicity (CDC) activity. 
     
     
         3 . The antibody according to  claim 1 , wherein the tumor is cancer. 
     
     
         4 . The antibody according to  claim 3 , wherein the cancer is lung cancer, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, a melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, or kidney cancer. 
     
     
         5 . The antibody according to  claim 1 , wherein a constant region is a human constant region. 
     
     
         6 . The antibody according to  claim 1 , which is humanized. 
     
     
         7 . The antibody according to  claim 6 , which comprises a heavy chain variable region consisting of (a) an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85, (b) an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:87, (c) an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:89, (d) an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:91, (e) an amino acid sequence having a homology of at least 95% or more with any of the framework amino acid residues of the sequences (a) to (d), or (f) an amino acid sequence wherein one or several amino acids are deleted, substituted or added within any of the framework region sequences of (a) to (d); and a light chain variable region consisting of (g) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:71, (h) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:73, (i) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:75, (j) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:77, (k) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:79, (1) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:81, (m) an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:83, (n) an amino acid sequence having a homology of at least 95% or more with any of the framework amino acids of the sequences (g) to (m), or (o) an amino acid sequence wherein one or several amino acids are deleted, substituted or added within any of the framework region sequences of (g) to (m). 
     
     
         8 . The antibody according to  claim 7 , which comprises a heavy chain variable region and a light chain variable region consisting of a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:71; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:73; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:75; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:77; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:79; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:81; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:85 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:83; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:91 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:71; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:91 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:73; a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:91 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:75; or a heavy chain variable region consisting of an amino acid sequence comprising amino acid numbers 20 to 141 in SEQ ID NO:91 and a light chain variable region consisting of an amino acid sequence comprising amino acid numbers 21 to 128 in SEQ ID NO:77. 
     
     
         9 . The antibody according to  claim 8 , which comprises a heavy chain and a light chain consisting of a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:71; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:73; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO: 85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:75; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:77; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:79; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:81; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:83; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:71; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO: 91 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:73; a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:75; or a heavy chain consisting of an amino acid sequence comprising amino acid numbers 20 to 471 in SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising amino acid numbers 21 to 233 in SEQ ID NO:77. 
     
     
         10 . The antibody according to  claim 7 , which comprises a heavy chain and a light chain consisting of a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:71; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:73; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:75; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO: 85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:77; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:79; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:81; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:85 and a light chain consisting of an amino acid sequence SEQ ID NO:83; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:71; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:73; a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:75; or a heavy chain consisting of an amino acid sequence comprising SEQ ID NO:91 and a light chain consisting of an amino acid sequence comprising SEQ ID NO:77. 
     
     
         11 . The antibody according to  claim 1 , wherein the modification of a glycan, when present, is regulated to enhance an antibody-dependent cellular cytotoxic activity as compared with an unmodified antibody. 
     
     
         12 . A polynucleotide encoding the antibody according to  claim 1 . 
     
     
         13 . The polynucleotide according to  claim 12 , which comprises a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:50 and a nucleotide sequence comprising nucleotide numbers 67 to 390 in SEQ ID NO:52. 
     
     
         14 . The polynucleotide according to  claim 12 , which comprises a nucleotide sequence comprising SEQ ID NO:62 and a nucleotide sequence comprising SEQ ID NO:58. 
     
     
         15 . The polynucleotide according to  claim 12 , which comprises a nucleotide sequence consisting of (a) a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84, (b) a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:86, (c) a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:88, (d) a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:90, and (e) a nucleotide sequence comprising a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to any of the nucleotide sequences (a) to (d) under stringent conditions; and a nucleotide sequence selected (f) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:70, (g) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:72, (h) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:74, (i) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:76, (j) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:78, (k) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:80, (l) a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:82, or (m) a nucleotide sequence comprising a polynucleotide which hybridizes to a polynucleotide consisting of a nucleotide sequence complementary to any of the nucleotide sequences (f) to (l) under stringent conditions. 
     
     
         16 . The polynucleotide according to  claim 15 , which comprises nucleotide sequences consisting of a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:70; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:72; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:74; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:76; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:78; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:80; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:82; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:70; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:72; a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:74; or a nucleotide sequence comprising nucleotide numbers 58 to 423 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 384 in SEQ ID NO:76. 
     
     
         17 . The polynucleotide according to  claim 15 , which comprises nucleotide sequences consisting of a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:70; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:72; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:74; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:76; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:78; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:80; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:84 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:82; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:70; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:72; a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:74; or a nucleotide sequence comprising nucleotide numbers 58 to 1413 in SEQ ID NO:90 and a nucleotide sequence comprising nucleotide numbers 61 to 699 in SEQ ID NO:76. 
     
     
         18 . The polynucleotide according to  claim 12 , which comprises nucleotide sequences consisting of a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:70; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:72; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:74; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:76; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:78; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:80; a nucleotide sequence comprising SEQ ID NO:84 and a nucleotide sequence comprising SEQ ID NO:82; a nucleotide sequence comprising SEQ ID NO:90 and a nucleotide sequence comprising SEQ ID NO:70; a nucleotide sequence comprising SEQ ID NO:90 and a nucleotide sequence comprising SEQ ID NO:72; a nucleotide sequence comprising SEQ ID NO:90 and a nucleotide sequence comprising SEQ ID NO:74; or a nucleotide sequence comprising SEQ ID NO:90 and a nucleotide sequence comprising SEQ ID NO:76. 
     
     
         19 . An expression vector comprising a polynucleotide according to  claim 12 . 
     
     
         20 . A host cell which is transformed in vitro with the expression vector according to  claim 19 . 
     
     
         21 . The host cell according to  claim 20 , wherein the host cell is a eukaryotic cell. 
     
     
         22 . A method of producing an antibody, comprising a step of culturing a host cell according to  claim 20  and a step of collecting the antibody from a cultured product obtained in the culturing step. 
     
     
         23 . An antibody obtained by a production method according to  claim 22 . 
     
     
         24 . The antibody according to  claim 23 , wherein the modification of a glycan, when present, is regulated to enhance an antibody-dependent cellular cytotoxic activity as compared with an unmodified antibody. 
     
     
         25 . A pharmaceutical composition comprising at least one of the antibodies according to  claim 1 . 
     
     
         26 . A pharmaceutical composition, comprising at least one of the antibodies according to  claim 1  and at least one therapeutic agent for cancer. 
     
     
         27 . The pharmaceutical composition according to  claim 25 , wherein the tumor is cancer. 
     
     
         28 . The pharmaceutical composition according to  claim 27 , wherein the cancer is lung cancer, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, a melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, or kidney cancer. 
     
     
         29 . A pharmaceutical composition, comprising at least one of the antibodies according to  claim 23 . 
     
     
         30 . A pharmaceutical composition, comprising at least one of the antibodies according to  claim 23  and at least one therapeutic agent for cancer. 
     
     
         31 . The pharmaceutical composition according to  claim 29 , wherein the tumor is cancer. 
     
     
         32 . The pharmaceutical composition according to  claim 31 , wherein the cancer is lung cancer, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, a melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, or kidney cancer. 
     
     
         33 . A method of treating a tumor expressing B7-H3, comprising administering at least one of the antibodies according to  claim 1  to an individual. 
     
     
         34 . A method of treating a tumor expressing B7-H3, comprising administering (1) at least one of the antibodies according to  claim 1  and (2) at least one therapeutic agent for cancer simultaneously, separately, or sequentially to an individual. 
     
     
         35 . The method according to  claim 33 , wherein the tumor is cancer. 
     
     
         36 . The method according to  claim 35 , wherein the cancer is lung cancer, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, a melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, or kidney cancer. 
     
     
         37 . A method of treating a tumor expressing B7-H3, comprising administering at least one of the antibodies according to  claim 23  to an individual. 
     
     
         38 . A method of treating a tumor expressing B7-H3, comprising administering (1) at least one of the antibodies according to  claim 23  and (2) at least one therapeutic agent for cancer simultaneously, separately, or sequentially to an individual. 
     
     
         39 . The method according to  claim 37 , wherein the tumor is cancer. 
     
     
         40 . The method according to  claim 39 , wherein the cancer is lung cancer, breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, a melanoma, liver cancer, ovarian cancer, bladder cancer, stomach cancer, esophageal cancer, or kidney cancer.