Anti-cd147 antibody

Abstract

An object of the present invention is to provide a novel anti-CD147 antibody exhibiting potent antitumor efficacy and having excellent safety. Another object of the present invention is to provide a pharmaceutical product comprising such an antibody. Another object of the present invention is to provide a method for treating tumors using the antibody or the pharmaceutical product, for example. The present invention provides a CD147-specific antibody that activates CD147 and exhibits high antitumor efficacy. The present invention provides the anti-CD147 antibody that exhibits high antitumor efficacy independent of effector functions. The present invention provides a pharmaceutical composition comprising such an anti-CD147 antibody. The present invention provides a method for treating tumors using such an anti-CD147 antibody and/or pharmaceutical composition.

1 . A polynucleotide which encodes an antibody against human CD147 or an antigen-binding fragment thereof, which competes with at least one antibody selected from the group consisting of the following (A) to (F) for binding to human CD147 and which activates signal transduction through CD147:
 (A) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 71 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 69;   (B) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 51 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 49;   (C) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 61 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 59;   (D) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 81 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 79;   (E) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 8; and   (F) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 20 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 18.   
     
     
         2 . The polynucleotide according to  claim 1 , which comprises a polynucleotide selected from the group consisting of the following (j1) to (j3):
 (j1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 75, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 76 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 77, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 72, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 73 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 74;   (j2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (j1); and   (j3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (j1) or (j2).   
     
     
         3 . The polynucleotide according to  claim 1 , which comprises a polynucleotide selected from the group consisting of the following (i1) to (i3):
 (i1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 55, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 56 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 57, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 52, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 53 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 54;   (i2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (i1); and   (i3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (i1) or (i2).   
     
     
         4 . The polynucleotide according to  claim 1 , which comprises a polynucleotide selected from the group consisting of the following (k1) to (k3):
 (k1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 65, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 66 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 67, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 62, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 63 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 64;   (k2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (k1); and   (k3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (k1) or (k2).   
     
     
         5 . The polynucleotide according to  claim 1 , which comprises a polynucleotide selected from the group consisting of the following (m1) to (m3):
 (m1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 85, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 86 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 87, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 82, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 83 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 84;   (m2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (m1); and   (m3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (m1) or (m2).   
     
     
         6 . An expression vector comprising the polynucleotide according to  claim 1 . 
     
     
         7 . A host cell transformed with the expression vector according to  claim 6 . 
     
     
         8 . A method for producing the antibody or the antigen-binding fragment thereof, comprising a step of culturing a host cell with an expression vector comprising a nucleotide that encodes the antibody or antigen-binding fragment thereof according to  claim 1  and collecting the target antibody or the antigen-binding fragment thereof from a culture supernatant. 
     
     
         9 . A polynucleotide which encodes an antibody against human CD147 or an antigen-binding fragment thereof, which binds to an epitope to which at least one antibody selected from the group consisting of the following (A) to (F) binds, and which activates signal transduction through CD147:
 (A) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 71 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 69;   (B) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 51 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 49;   (C) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 61 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 59;   (D) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 81 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 79;   (E) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 8; and   (F) an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 20 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 18.   
     
     
         10 . The polynucleotide according to  claim 9 , which comprises a polynucleotide selected from the group consisting of the following (j1) to (j3):
 (j1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 75, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 76 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 77, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 72, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 73 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 74;   (j2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (j1); and   (j3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (j1) or (j2).   
     
     
         11 . The polynucleotide according to  claim 9 , which comprises a polynucleotide selected from the group consisting of the following (i1) to (i3):
 (i1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 55, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 56 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 57, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 52, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 53 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 54;   (i2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (i1); and   (i3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (i1) or (i2).   
     
     
         12 . The polynucleotide according to  claim 9 , which comprises a polynucleotide selected from the group consisting of the following (k1) to (k3):
 (k1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 65, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 66 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 67, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 62, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 63 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 64;   (k2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (k1); and   (k3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (k1) or (k2).   
     
     
         13 . The polynucleotide according to  claim 9 , which comprises a polynucleotide selected from the group consisting of the following (m1) to (m3):
 (m1) a polynucleotide encoding CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 85, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 86 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 87, and a polynucleotide encoding CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 82, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 83 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 84;   (m2) a polynucleotide having at least 95% sequence identity with the nucleotide sequence according to (m1); and   (m3) a polynucleotide in which one to several nucleotides are substituted, deleted or added in the polynucleotide according to (m1) or (m2).   
     
     
         14 . An expression vector comprising the polynucleotide according to  claim 9 . 
     
     
         15 . A host cell transformed with the expression vector according to  claim 14 . 
     
     
         16 . A method for producing the antibody or the antigen-binding fragment thereof, comprising a step of culturing a host cell with an expression vector comprising a nucleotide that encodes the antibody or antigen-binding fragment thereof according to  claim 9  and collecting the target antibody or the antigen-binding fragment thereof from a culture supernatant.