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.

What is claimed is: 
     
         1 . A method of treating a T-cell mediated autoimmune disease in a mammal, the method comprising: administering to the mammal a therapeutically effective amount of a cytotoxic anti-LAG-3 monoclonal antibody or a biologically active fragment thereof causing depletion of LAG-3 activated T cells, wherein the monoclonal antibody or biologically active fragment thereof comprises an Fc fragment from human IgG1, human IgM, or mouse IgG2a and an Fab fragment that binds LAG-3 protein, and wherein the antibody or fragment thereof is capable of depleting LAG-3+ activated T cells in a complement dependent cytotoxicity (CDC) assay, or in an antibody-dependent cell cytotoxicity (ADCC) assay, or both. 
     
     
         2 . The method of  claim 1 , wherein the monoclonal antibody or the biologically active fragment thereof comprises 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. 
     
     
         3 . The method of  claim 1 , wherein the monoclonal antibody or the biologically active fragment thereof comprises 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. 
     
     
         4 . The method of  claim 1 , wherein the monoclonal antibody or the biologically active fragment thereof comprises a kappa light chain variable region polypeptide encoded by a nucleic acid molecule as set forth in SEQ ID NO: 8 and a gamma heavy chain variable region polypeptide encoded by a nucleic acid molecule as set forth in SEQ ID NO: 10. 
     
     
         5 . The method of  claim 4 , wherein the monoclonal antibody or the biologically active fragment thereof comprises two polypeptides having the following amino acid sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 9) 
                 
                     
                   QSPKLLVYFASTRDSGVPDRFIGSGSGTDFTLTISSVQAE 
                 
                     
                     
                 
                     
                   DLADYFCLQHFGTPPTFGGGTKLEIKR; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 11)  
                 
                     
                   QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQ 
                 
                     
                     
                 
                     
                   PPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNSKSQV 
                 
                     
                     
                 
                     
                   FLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSS. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . The method of  claim 1 , wherein the T-cell mediated autoimmune disease is selected from the group consisting of: autoimmune hemolytic anemia, autoimmune thrombocytopenia purpura, Goodpasture's syndrome, pemphigus vulgaris, acute rheumatic fever, mixed essential cryoglobulinemia, systemic lupus erythematosus, insulin-dependent diabetes mellitus, rheumatoid arthritis, Grave's disease, Hashimoto's thyroiditis, myasthenia gravis, psoriasis and multiple sclerosis. 
     
     
         7 . The method of  claim 1 , wherein the T-cell mediated autoimmune disease is psoriasis. 
     
     
         8 . The method of  claim 1 , wherein the T-cell mediated autoimmune disease is rheumatoid arthritis.