Compositions and methods of use for augmented immune response and cancer therapy

Abstract

The present invention provides antibody compositions, including, e.g., antibodies, engineered antibodies and antibody fragments that bind to a tumor necrosis factor receptor superfamily member (i.e., 18). Provided compositions are useful in enhancing CD4+ and CD8+ T cell responses, and in the treatment, amelioration and prevention of diseases that can be counteracted with an augmented immune response, e.g., cancers. Also provided in the invention are polynucleotides and vectors that encode such molecules and host cells that harbor the polynucleotides or vectors; as well as pharmaceutical compositions that comprise such molecules and methods of use thereof.

1 - 58 . (canceled) 
     
     
         59 . A method of enhancing a T cell response in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the antibody or antibody fragment comprising:
 (a) a heavy chain variable region (VH) comprising:
 a VHCDR1 of SEQ ID NO:22, 
 a VHCDR2 of a sequence selected from any one of SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109; and 
 a light chain variable region (VL) comprising: 
 a VLCDR1 of SEQ ID NO:30 or SEQ ID NO:31, 
 a VLCDR2 of SEQ ID NO:33, and 
 a VLCDR3 of SEQ ID NO:34; or 
   (b) a VH comprising:
 a VHCDR1 of SEQ ID NO:84, 
 a VHCDR2 of SEQ ID NO:80, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109, and 
 a VL comprising: 
 a VLCDR1 of SEQ ID NO:85 or SEQ ID NO:86, 
 a VLCDR2 of SEQ ID NO:82, and 
   a VLCDR3 of SEQ ID NO:83.   
     
     
         60 . The method of claim  91 , further comprising administering to the individual an antagonist of CTLA4, LAG3, or TIM3, or an inhibitor of PD-1/PD-L1 interaction. 
     
     
         61 . The method of  claim 59 , further comprising administering to the individual a chemotherapeutic agent or a cytotoxin. 
     
     
         62 . The method of  claim 59 , wherein the T cell response is a CD8+ cytotoxic T lymphocyte (CTL) T cell response. 
     
     
         63 . The method of  claim 59 , wherein the T cell response is a CD4+ helper T cell (Th) response. 
     
     
         64 . The method of  claim 59 , wherein the individual has a cancer selected from epithelial cancers, carcinomas, sarcomas or lymphomas. 
     
     
         65 . The method of  claim 59 , wherein the individual has a cancer selected from renal cancer, lung cancer including non-small cell lung cancer (NSCLC), glioma, fibrosarcoma, pancreatic cancer, melanomas, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematological tissues, or head and neck squamous cell carcinoma (HNSCC). 
     
     
         66 . A method of treating a cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the antibody or antibody fragment comprising:
 (a) a heavy chain variable region (VH) comprising:
 a VHCDR1 of SEQ ID NO:22, 
 a VHCDR2 of a sequence selected from any one of SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109; and 
 a light chain variable region (VL) comprising: 
 a VLCDR1 of SEQ ID NO:30 or SEQ ID NO:31, 
 a VLCDR2 of SEQ ID NO:33, and 
 a VLCDR3 of SEQ ID NO:34; or 
   (b) a VH comprising:
 a VHCDR1 of SEQ ID NO:84, 
 a VHCDR2 of SEQ ID NO:80, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109, and 
 a VL comprising: 
 a VLCDR1 of SEQ ID NO:85 or SEQ ID NO:86, 
 a VLCDR2 of SEQ ID NO:82, and 
   a VLCDR3 of SEQ ID NO:83.   
     
     
         67 . The method of  claim 66 , further comprising administering to the individual an antagonist of CTLA4, LAG3, or TIM3, or an inhibitor of PD-1/PD-L1 interaction. 
     
     
         68 . The method of  claim 66 , further comprising administering to the individual a chemotherapeutic agent or a cytotoxin. 
     
     
         69 . The method of  claim 66 , wherein the cancer is selected from epithelial cancers, carcinomas, sarcomas or lymphomas. 
     
     
         70 . The method of  claim 66 , wherein the cancer is selected from renal cancer, lung cancer including non-small cell lung cancer (NSCLC), glioma, fibrosarcoma, pancreatic cancer, melanomas, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematological tissues, or head and neck squamous cell carcinoma (HNSCC). 
     
     
         71 . A method of treating an infectious disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the antibody or antibody fragment comprising:
 (a) a heavy chain variable region (VH) comprising:
 a VHCDR1 of SEQ ID NO:22, 
 a VHCDR2 of a sequence selected from any one of SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, or SEQ ID NO:27, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109; and 
 a light chain variable region (VL) comprising: 
 a VLCDR1 of SEQ ID NO:30 or SEQ ID NO:31, 
 a VLCDR2 of SEQ ID NO:33, and 
 a VLCDR3 of SEQ ID NO:34; or 
   (b) a VH comprising :
 a VHCDR1 of SEQ ID NO:84, 
 a VHCDR2 of SEQ ID NO:80, and 
 a VHCDR3 of SEQ ID NO:29 or SEQ ID NO:109, and 
 a VL comprising: 
 a VLCDR1 of SEQ ID NO:85 or SEQ ID NO:86, 
 a VLCDR2 of SEQ ID NO:82, and 
   a VLCDR3 of SEQ ID NO:83.   
     
     
         72 . The method of  claim 71 , wherein the infectious disease is selected from a bacterial infection, a fungal infection, a viral infection or a parasitic infection. 
     
     
         73 . The method of  claim 71 , further comprising administering to the individual an antagonist of CTLA4, LAG3, or TIM3, or an inhibitor of PD-1/PD-L1 interaction.