Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody

• Published in: Cancer immunology research Vol. 3; no. 9; p. 1052
• Main Authors: Stewart, Ross, Morrow, Michelle, Hammond, Scott A, Mulgrew, Kathy, Marcus, Danielle, Poon, Edmund, Watkins, Amanda, Mullins, Stefanie, Chodorge, Matthieu, Andrews, John, Bannister, David, Dick, Emily, Crawford, Nicola, Parmentier, Julie, Alimzhanov, Marat, Babcook, John S, Foltz, Ian N, Buchanan, Andrew, Bedian, Vahe, Wilkinson, Robert W, McCourt, Matthew
• Format: Journal Article
• Language: English
• Published: United States 01.09.2015
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antibody-Dependent Cell Cytotoxicity - drug effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7-1 Antigen - metabolism; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Binding, Competitive; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Female; Humans; Lymphocyte Activation - drug effects; Lymphocyte Culture Test, Mixed; Melanoma - immunology; Melanoma - pathology; Melanoma - prevention & control; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Organoplatinum Compounds - administration & dosage; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Programmed Cell Death 1 Receptor - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.cir-14-0191

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.