title: Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy.
abstract: Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four therapeutic antibodies targeting these checkpoint molecules have been approved by the FDA for the treatment of several types of cancer. Here, we report the crystal structures of checkpoint molecules in complex with the Fab fragments of therapeutic antibodies, including PD-1/pembrolizumab, PD-1/nivolumab, PD-L1/BMS-936559 and CTLA-4/tremelimumab. These complex structures elucidate the precise epitopes of the antibodies and the molecular mechanisms underlying checkpoint blockade, providing useful information for the improvement of monoclonal antibodies capable of attenuating checkpoint signalling for the treatment of cancer.
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Ju Yeon
authors: JY
authors: Lee
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Hyun Tae
authors: HT
authors: Lee
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Woori
authors: W
authors: Shin
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Jongseok
authors: J
authors: Chae
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Jaemo
authors: J
authors: Choi
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Sung Hyun
authors: SH
authors: Kim
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Heejin
authors: H
authors: Lim
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Tae
authors: T
authors: Won Heo
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Kyeong Young
authors: KY
authors: Park
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Yeon Ji
authors: YJ
authors: Lee
authors: Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors: Seong Eon
authors: SE
authors: Ryu
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Ji Young
authors: JY
authors: Son
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Jee Un
authors: JU
authors: Lee
authors: Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
authors: Yong-Seok
authors: YS
authors: Heo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000737:chemistry; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab; C520704:tremelimumab; C000627113:BMS-936559