Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab

• Published in: Scientific reports Vol. 7; no. 1; pp. 5532 - 12
• Main Authors: Lee, Hyun Tae, Lee, Ju Yeon, Lim, Heejin, Lee, Sang Hyung, Moon, Yu Jeong, Pyo, Hyo Jeong, Ryu, Seong Eon, Shin, Woori, Heo, Yong-Seok
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 631/535/1266; 631/67/1059/2325; 692/4028/67/1059/2325; 82; 82/80; 82/83; Amino Acid Sequence; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antigen-Antibody Complex - chemistry; Antigen-antibody interactions; Binding Sites; Clinical trials; Crystal structure; Crystallography, X-Ray; Epitopes; Epitopes - chemistry; Epitopes - immunology; Humanities and Social Sciences; Humans; Immunoglobulins; Immunotherapy; Monoclonal antibodies; multidisciplinary; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Protein Structure, Quaternary; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Science; Science (multidisciplinary); Sequence Alignment; Targeted cancer therapy
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-06002-8

In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.