Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy

Ju Yeon Lee, Hyun Tae Lee, Woori Shin, Jongseok Chae, Jaemo Choi, Sung Hyun Kim, Heejin Lim, Tae Won Heo, Kyeong Young Park, Yeon Ji Lee, Seong Eon Ryu, Ji Young Son, Jee Un Lee and Yong-Seok Heo ()
Additional contact information
Ju Yeon Lee: Konkuk University
Hyun Tae Lee: Konkuk University
Woori Shin: Konkuk University
Jongseok Chae: Konkuk University
Jaemo Choi: Konkuk University
Sung Hyun Kim: Konkuk University
Heejin Lim: Konkuk University
Tae Won Heo: Konkuk University
Kyeong Young Park: Konkuk University
Yeon Ji Lee: Konkuk University
Seong Eon Ryu: Hanyang University
Ji Young Son: Konkuk University
Jee Un Lee: Konkuk University
Yong-Seok Heo: Konkuk University

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13354

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DOI: 10.1038/ncomms13354

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