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Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Yong-Seo, 2016. "Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13354
    DOI: 10.1038/ncomms13354
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    Cited by:

    1. Sayedali Shetab Boushehri & Katharina Essig & Nikolaos-Kosmas Chlis & Sylvia Herter & Marina Bacac & Fabian J. Theis & Elke Glasmacher & Carsten Marr & Fabian Schmich, 2023. "Explainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Gyunghee Jo & Jeomil Bae & Ho Jeong Hong & Ah-reum Han & Do-Kyun Kim & Seon Pyo Hong & Jung A Kim & Sangkyu Lee & Gou Young Koh & Ho Min Kim, 2021. "Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    3. Wataru Nishi & Ei Wakamatsu & Hiroaki Machiyama & Ryohei Matsushima & Kensho Saito & Yosuke Yoshida & Tetsushi Nishikawa & Tomohiro Takehara & Hiroko Toyota & Masae Furuhata & Hitoshi Nishijima & Arat, 2023. "Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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