Anti-glypican-3 antibody

Abstract

An anti-glypican-3 antibody comprising one or more amino acid substitutions introduced in the Fc region is disclosed. Preferably, in the anti-glypican-3 antibody, one or more of the amino acid residues at the positions 239, 298, 326, 330 and 332 in the Fc region are substituted with other amino acid residues. Since the Fc-modified anti-glypican-3 antibody of the invention exhibit enhanced ADCC activity, it is useful in treating cancers, such as hepatic cancer. Also disclosed are an anticancer agent comprising the anti-glypican-3 antibody of the invention and a pharmaceutically acceptable carrier, as well as a method of treating a patient with cancer comprising administering to the patient the anticancer agent of the invention.

1 . An anti-glypican-3 antibody comprising one or more amino acid substitutions introduced in the Fc region.  
     
     
         2 . An anti-glypican-3 antibody in which one or more of the amino acid residues at the positions 239, 298, 326, 330 and 332 in the Fc region are substituted with other amino acid residues.  
     
     
         3 . An anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody in which the amino acid residue at the position 332 of the Fc region is substituted with another amino acid residue;    (b) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 330 and 332 of the Fc region are substituted with other amino acid residues;    (c) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298 and 332 of the Fc region are substituted with other amino acid residues;    (d) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 326 and 332 of the Fc region are substituted with other amino acid residues;    (e) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298, 326 and 332 of the Fc region are substituted with other amino acid residues.    
     
     
         4 . An anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody having glutamic acid at the position 332 of the Fc region;    (b) an anti-glypican-3 antibody having aspartic acid at the position 239, leucine at the position 330, and glutamic acid at the position 332 of the Fc region;    (c) an anti-glypican-3 antibody having aspartic acid at the position 239, alanine at the position 298, and glutamic acid at the position 332 of the Fc region;    (d) an anti-glypican-3 antibody having aspartic acid at the position 239, threonine at the position 326, and glutamic acid at the position 332 of the Fc region;    (e) an anti-glypican-3 antibody having aspartic acid at the position 239, alanine at the position 298, glutamic acid at the position 326, and glutamic acid at the position 332 of the Fc region.    
     
     
         5 . An anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody in which the amino acid residue at the position 332 of the Fc region is substituted with glutamic acid;    (b) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 330 and 332 of the Fc region are substituted with aspartic acid, leucine, and glutamic acid, respectively;    (c) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298 and 332 of the Fc region are substituted with aspartic acid, alanine, and glutamic acid, respectively;    (d) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 326 and 332 of the Fc region are substituted with aspartic acid, threonine, and glutamic acid, respectively;    (e) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298, 326 and 332 of the Fc region are substituted with aspartic acid, alanine, glutamic acid, and glutamic acid, respectively.    
     
     
         6 . An anticancer agent comprising the anti-glypican-3 antibody as claimed in any one of claims  1 - 5  and a pharmaceutically acceptable carrier.  
     
     
         7 . A method of treating a patient with cancer comprising administering to the patient the anticancer agent as claimed in  claim 6 .  
     
     
         8 . A method for producing an anti-glypican-3 antibody with enhanced cytotoxicity comprising: 
 (i) culturing a host cell engineered to express a polynucleotide coding for an anti-glypican-3 antibody in which one or more of the amino acid residues at the positions 239, 298, 326, 330 and 332 of the Fc region are substituted by other amino acid residues; and    (ii) isolating the antibody from the culture.    
     
     
         9 . A method for producing an anti-glypican-3 antibody with enhanced cytotoxicity comprising: 
 (i) culturing a host cell engineered to express a polynucleotide coding for an anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody in which the amino acid residue at the position 332 of the Fc region is substituted with another amino acid residue;  
 (b) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 330 and 332 of the Fc region are substituted with other amino acid residues;  
 (c) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298 and 332 of the Fc region are substituted with other amino acid residues;  
 (d) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 326 and 332 of the Fc region are substituted with other amino acid residues;  
 (e) an anti-glypican-3 antibody in which the amino acid residues at the positions 239, 298, 326 and 332 of the Fc region are substituted with other amino acid residues; and  
   (ii) isolating said antibody from the culture.    
     
     
         10 . A method for producing an anti-glypican-3 antibody with enhanced cytotoxicity comprising: 
 (i) culturing a host cell engineered to express a polynucleotide coding for an anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody having glutamic acid at the position 332 of the Fc region;  
 (b) an anti-glypican-3 antibody having aspartic acid at the position 239, leucine at the position 330, and glutamic acid at the position 332 of the Fc region;  
 (c) an anti-glypican-3 antibody aspartic acid at the position 239, alanine at the position 298, and glutamic acid at the position 332 of the Fc region;  
 (d) an anti-glypican-3 antibody having aspartic acid at the position 239, threonine at the position 326, and glutamic acid at the position 332 of the Fc region;  
 (e) an anti-glypican-3 antibody having aspartic acid at the position 239, alanine at the position 298, glutamic acid at the position 326, and glutamic acid at the position 332 of the Fc region; and  
   (ii) isolating said antibody from the culture.    
     
     
         11 . An anti-glypican-3 antibody selected from the group consisting of: 
 (a) an anti-glypican-3 antibody having the CH2-CH3 domain comprising the amino acid sequence set forth in SEQ ID NO: 34;    (b) an anti-glypican-3 antibody having the CH2-CH3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35;    (c) an anti-glypican-3 antibody having the CH2-CH3 domain comprising the amino acid sequence set forth in SEQ ID NO: 36;    (d) an anti-glypican-3 antibody having the CH2-CH3 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; and    (e) an anti-glypican-3 antibody having the CH2-CH3 domain comprising the amino acid sequence set forth in SEQ ID NO: 38.