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Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.

ABSTRACT: Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front ?-sheet of CTLA-4 and intersects with the CTLA-4:?7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

SUBMITTER: Ramagopal UA

PROVIDER: S-EPMC5448203 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.

Ramagopal Udupi A UA Liu Weifeng W Garrett-Thomson Sarah C SC Bonanno Jeffrey B JB Yan Qingrong Q Srinivasan Mohan M Wong Susan C SC Bell Alasdair A Mankikar Shilpa S Rangan Vangipuram S VS Deshpande Shrikant S Korman Alan J AJ Almo Steven C SC

Proceedings of the National Academy of Sciences of the United States of America 20170508 21

Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the tr ...[more]

PMID: 28484017

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Dataset Information

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.

Publications

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.

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