Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer immunology research, 2015-09, Vol.3 (9), p.1052-1062

Ort / Verlag

United States

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.