Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease

Abstract

Cytotoxic anti-LAG-3 monoclonal antibodies or fragments thereof causing depletion of LAG-3 + activated T cells are described, as are related pharmaceuticals and methods of treating. Also described are related nucleic acid and protein sequences.

1 - 18 . (canceled) 
     
     
         19 ) A monoclonal antibody or a biologically active fragment thereof, wherein the monoclonal antibody or the biologically active fragment thereof is capable of depleting LAG-3+ activated T cells in a complement dependent cytotoxicity (CDC) assay and/or in an antibody-dependent cell cytotoxicity (ADCC) assay, and comprises:
 a) a light chain variable region comprising a CDR-L1 having the amino acid sequence as set forth in SEQ ID NO: 17, a CDR-L2 having the amino acid sequence of FAS, and a CDR-L3 having the amino acid sequence as set forth in SEQ ID NO: 18, and a heavy chain variable region comprising a CDR-H1 having the amino acid sequence as set forth in SEQ ID NO: 19, a CDR-H2 having the amino acid sequence as set forth in SEQ ID NO: 20, and a CDR-H3 having the amino acid sequence as set forth in SEQ ID NO: 21, or   b) a light chain variable region and a heavy chain variable region with minor amino acid differences from the light chain variable region and heavy chain variable region of (a).   
     
     
         20 ) A monoclonal antibody or biologically active fragment thereof according to  claim 19 , wherein the monoclonal antibody or biologically active fragment thereof comprises an Fc fragment from human IgG1, human IgM or mouse IgG2a. 
     
     
         21 ) A monoclonal antibody or biologically active fragment thereof according to  claim 19 , wherein the monoclonal antibody or biologically active fragment thereof have an EC50 of less than 5 ng/mL in an ADCC assay. 
     
     
         22 ) A monoclonal antibody or biologically active fragment thereof according to  claim 21 , wherein the monoclonal antibody or biologically active fragment thereof have an EC50 of less than 5 ng/mL in an ADCC assay comprising CMV-stimulated human CD4 and CD8 T cells. 
     
     
         23 ) A monoclonal antibody or biologically active fragment thereof according to  claim 19 , wherein the monoclonal antibody or biologically active fragment thereof comprises:
 a) a light chain variable region as set forth in SEQ ID NO:9 and a heavy chain variable region as set forth in SEQ ID NO: 11, or   b) a light chain variable region and a heavy chain variable region with minor amino acid differences from the light chain variable region and heavy chain variable region of (a).   
     
     
         24 ) A monoclonal antibody or biologically active fragment thereof according to  claim 19 , wherein the monoclonal antibody or biologically active fragment thereof comprises:
 a) a light chain kappa region as set forth in amino acids 21 to 240 of SEQ ID NO: 13 and a heavy chain gamma region as set forth in amino acids 20 to 465 of SEQ ID NO: 16, or   b) a light chain kappa region and a heavy chain gamma region with minor amino acid differences from the light chain kappa region and heavy chain gamma region of (a).   
     
     
         25 ) An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a monoclonal antibody or biologically active fragment thereof according to any of  claims 19  to  24 . 
     
     
         26 ) A pharmaceutical composition comprising the monoclonal antibody or biologically active fragment thereof according to any one of  claims 19  to  24