Antagonistic anti-tumor necrosis factor receptor superfamily polypeptides

Abstract

Described are antagonistic TNFR2 polypeptides, such as antibodies and antigen-binding fragments thereof, and the use of these polypeptides to inhibit the proliferation of regulatory T cells (T-regs) and/or myeloid-derived suppressor cells (MDSCs), to expand T effector cell populations or function, and to reduce the proliferation of, or directly kill, tumor cells, such as tumor cells that express TNFR2 antigen. The polypeptides, such as antibodies and antigen-binding fragments thereof, are TNFR2 antagonists, such as dominant TNFR2 antagonists. The polypeptides can be used to suppress the T-reg- or MDSC-mediated deactivation of tumor reactive T lymphocytes, expand populations of tumor-reactive cytotoxic T cells, and/or to directly kill TNFR2+ tumor cells. The antagonistic TNFR2 polypeptides described herein can be used to treat a wide variety of cancers and infectious diseases.

1 . A recombinant anti-tumor necrosis factor receptor (TNFR) superfamily antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain framework region having the amino acid sequence of:   
       
         
           
                 
               
                   MGWTLVFLFLLSVTAGVHSEVQLVQSGAEVKKPGASVKVSCKAS XXXXXX   
                 
                     
                 
                     XXXX WVRQAPGQGLEWMGW XXXXXXXXX YAEKFKKRVTMTRDTSTSTFYM 
                 
                     
                 
                   ELSSLRSDDTAVYFCAR XXXXXXXXX YWGQGTLVTVSSASTKGPSVFPLA 
                 
                     
                 
                   PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
                 
                     
                 
                   YSLSSVVTVPSSNFGTQTYTCNVDHKPS; 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
          and 
         (b) a light chain framework region having the amino acid sequence of: 
       
       
         
           
                 
               
                   MVSSAQFLGLLLLCFQGTRCDIQMTQSPSSLSASVGDRVTITCQAS XXXX   
                 
                     
                 
                     XX IAWYQQKPGKVPTLLIF XXX TLESGVPSRFSGSGSGTDFTLTISSLQS 
                 
                     
                 
                   EDVATYFC XXXXXXXX FGGGTKVEIK; 
                 
             
                
                
                
                
                
               
            
           
         
         and wherein “X” designates amino acid residues corresponding to complementarity-determining regions (CDRs). 
       
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to a TNFR superfamily protein. 
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 2 , wherein the TNFR superfamily protein is TNFR2. 
     
     
         4 . A recombinant anti-TNFR superfamily antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain having the amino acid sequence of:   
       
         
           
                 
               
                   MGWTLVFLFLLSVTAGVHSEVQLVQSGAEVKKPGASVKVSCKAS XXXXXX   
                 
                     
                 
                     XXXX WVRQAPGQGLEWMGW XXXXXXXXX YAEKFKKRVTMTRDTSTSTFYM 
                 
                     
                 
                   ELSSLRSDDTAVYFCAR XXXXXXXXX YWGQGTLVTVSSASTKGPSVFPLA 
                 
                     
                 
                   PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
                 
                     
                 
                   YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSSVECPPCPAP 
                 
                     
                 
                   PVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVE 
                 
                     
                 
                   VHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIE 
                 
                     
                 
                   KTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
                 
                     
                 
                   NGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH 
                 
                     
                 
                   NHYTQKSLSLSPGK; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
          and 
         (b) a light chain having the amino acid sequence of: 
       
       
         
           
                 
               
                   MVSSAQFLGLLLLCFQGTRCDIQMTQSPSSLSASVGDRVTITCQAS XXXX   
                 
                     
                 
                     XX IAWYQQKPGKVPTLLIF XXX TLESGVPSRFSGSGSGTDFTLTISSLQS 
                 
                     
                 
                   EDVATYFC XXXXXXXX FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS 
                 
                     
                 
                   VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL 
                 
                     
                 
                   SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC; 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         and wherein “X” designates amino acid residues corresponding to CDRs. 
       
     
     
         5 . The antibody or antigen-binding fragment thereof of  claim 4 , wherein the antibody or antigen-binding fragment thereof binds to a TNFR superfamily protein. 
     
     
         6 . The antibody or antigen-binding fragment thereof of  claim 5 , wherein the TNFR superfamily protein is TNFR2.