Antibody variants

Abstract

Antibody variants of parent antibodies are disclosed which have one or more amino acids inserted in a hypervariable region of the parent antibody and a binding affinity for a target antigen which is at least about two fold stronger than the binding affinity of the parent antibody for the antigen.

1 . An antibody variant of a parent antibody, which antibody variant comprises an amino acid insertion in a hypervariable region of the parent antibody and has a binding affinity for a target antigen which is at least about two fold stronger than the binding affinity of the parent antibody for said antigen, wherein the hypervariable region is the Complementarity Determining Region (CDR) H3 of a heavy chain variable domain. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The antibody variant of  claim 1  wherein about one to about 30 amino acid residues have been inserted in the hypervariable region of the parent antibody. 
     
     
         5 . The antibody variant of  claim 4  wherein about two to about ten amino acid residues have been inserted in the hypervariable region of the parent antibody. 
     
     
         6 . The antibody variant of  claim 1  which has a binding affinity for said antigen that is at least about five fold stronger than the binding affinity of the parent antibody for said antigen. 
     
     
         7 . The antibody variant of  claim 1  wherein the antibody variant has a potency in a biological activity assay which is at least about 20 fold greater than the potency of the parent antibody in the biological activity assay. 
     
     
         8 . The antibody variant of  claim 7  wherein the potency of the antibody variant in the biological activity assay is at least about 50 fold greater than the potency of the parent antibody in the biological activity assay. 
     
     
         9 . The antibody variant of  claim 1  wherein the parent antibody is a humanized antibody. 
     
     
         10 . The antibody variant of  claim 1  wherein the parent antibody is a human antibody. 
     
     
         11 . The antibody variant of  claim 1  wherein at least one of the inserted residues has a net positive charge or a net negative charge. 
     
     
         12 . The antibody variant of  claim 11  wherein at least one of the inserted residues is arginine or lysine. 
     
     
         13 . The antibody variant of  claim 1  wherein the insertion is adjacent to residue number 100 of the heavy chain variable domain of the parent antibody, utilizing the variable domain residue numbering as in Kabat. 
     
     
         14 . The antibody variant of  claim 13  wherein the insertion consists of about three inserted amino acid residues. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A composition comprising the antibody variant of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         19 - 28 . (canceled) 
     
     
         29 . A process of producing an antibody variant comprising culturing a host cell that expresses the antibody variant of  claim 1 . 
     
     
         30 . The process of  claim 29  further comprising recovering the antibody variant from the host cell culture. 
     
     
         31 . The process of  claim 30  wherein the antibody variant is recovered from the host cell culture medium.