Compositions and methods for regulating nk cell activity

Abstract

The present invention relates to novel compositions and methods for regulating an immune response in a subject. More particularly, the invention relates to specific antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects. The invention also relates to fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly in therapy, to increase NK cell activity or cytotoxicity in subjects.

What is claimed is: 
     
         1 - 7 . (canceled) 
     
     
         8 . An isolated antibody or antibody fragment that (a) cross-reacts with at least two different human KIR2DL polypeptides that each recognizes a different group of HLA-C class I allotypes, and (b) neutralizes the inhibitory activity of such polypeptides. 
     
     
         9 . The isolated antibody or antibody fragment of  claim 8 , wherein the antibody binds to substantially the same epitope as does DF-200 (deposited as CNCM I-3224). 
     
     
         10 . The isolated antibody or antibody fragment of  claim 8 , wherein said antibody competes with DF-200 (deposited as CNCM I-3224) for binding to said KIR2DL polypeptides. 
     
     
         11 . The isolated antibody or antibody fragment of  claim 8 , comprising (i) a light chain CDR1 having the amino acid sequence of SEQ ID NO:3, (ii) a light chain CDR2 having the amino acid sequence of SEQ ID NO:5, and (iii) a light chain CDR3 having the amino acid sequence of SEQ ID NO:7. 
     
     
         12 . The isolated antibody or antibody fragment of  claim 8 , comprising a light chain variable region having the amino acid sequence of SEQ ID NO:1. 
     
     
         13 . The isolated antibody or antibody fragment of  claim 8 , comprising (i) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:20, (ii) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:21, and (iii) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:22. 
     
     
         14 . The isolated antibody or antibody fragment of  claim 8 , comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO:19. 
     
     
         15 . The isolated antibody or antibody fragment of  claim 8 , wherein the at least two different human KIR2DL polypeptides comprise KIR2DL1 and KIR2DL2/KIR2DL3. 
     
     
         16 . The isolated antibody or antibody fragment of  claim 8 , wherein the antibody or antibody fragment is a monoclonal antibody. 
     
     
         17 . The isolated antibody or antibody fragment of  claim 8 , wherein the antibody or antibody fragment is a human, humanized or chimeric antibody. 
     
     
         18 . The isolated antibody or antibody fragment of  claim 8 , wherein the antibody fragment is a Fab, Fab′, Fab′-SH, F(ab′)2, Fv, diabody, single-chain antibody fragment, or a multi-specific antibody comprising a number of different antibody fragments. 
     
     
         19 . The isolated antibody or antibody fragment of  claim 8 , which causes an at least about 50% potentiation in NK cytotoxicity, as measured by a chromium release test of cytotoxicity. 
     
     
         20 . The isolated antibody or antibody fragment of  claim 8 , which inhibits the binding of (i) a HLA-c allele molecule having a Lys residue at position 80 to a human KIR2DL1 receptor, and (ii) a HLA-C allele molecule having an Asn residue at position 80 to human KIR2DL2/KIR2DL3 receptors. 
     
     
         21 . The isolated antibody or antibody fragment of  claim 8 , which promotes lysis of matched or HLA compatible target cells by NK cells expressing KIR2DL1, KIR2DL2, and/or KIR2DL3, wherein said target cells are not effectively lysed by NK cells in the absence of said antibody or antibody fragment. 
     
     
         22 . The isolated antibody or antibody fragment of  claim 8 , which comprises an Fc region that mediates low effector function. 
     
     
         23 . The isolated antibody or antibody fragment of  claim 8 , which has an Fc region of the human IgG4 isotype. 
     
     
         24 . A composition suitable for human administration comprising a pharmaceutically acceptable excipient and an antibody or antibody fragment that (a) cross-reacts with at least two different human KIR2DL polypeptides that each recognizes a different group of HLA-C class I allotypes, and (b) neutralizes the inhibitory activity of such polypeptides.