Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab
Abstract
The 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 β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographicallymore »
- Authors:
-
[1];
- Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Biochemistry
- Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Biochemistry and Dept. of Microbiology and Immunology
- Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Microbiology and Immunology
- Bristol–Myers Squibb, Redwood City, CA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1437464
- Grant/Contract Number:
- HG008325; GM094662; GM094665
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 114; Journal Issue: 21; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; immunotherapy; X-ray crystallography; CTLA-4; ipilimumab; cancer
Citation Formats
Ramagopal, Udupi A., Liu, Weifeng, Garrett-Thomson, Sarah C., Bonanno, Jeffrey B., Yan, Qingrong, Srinivasan, Mohan, Wong, Susan C., Bell, Alasdair, Mankikar, Shilpa, Rangan, Vangipuram S., Deshpande, Shrikant, Korman, Alan J., and Almo, Steven C. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. United States: N. p., 2017.
Web. doi:10.1073/pnas.1617941114.
Ramagopal, Udupi A., Liu, Weifeng, Garrett-Thomson, Sarah C., Bonanno, Jeffrey B., Yan, Qingrong, Srinivasan, Mohan, Wong, Susan C., Bell, Alasdair, Mankikar, Shilpa, Rangan, Vangipuram S., Deshpande, Shrikant, Korman, Alan J., & Almo, Steven C. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. United States. https://doi.org/10.1073/pnas.1617941114
Ramagopal, Udupi A., Liu, Weifeng, Garrett-Thomson, Sarah C., Bonanno, Jeffrey B., Yan, Qingrong, Srinivasan, Mohan, Wong, Susan C., Bell, Alasdair, Mankikar, Shilpa, Rangan, Vangipuram S., Deshpande, Shrikant, Korman, Alan J., and Almo, Steven C. Mon .
"Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab". United States. https://doi.org/10.1073/pnas.1617941114. https://www.osti.gov/servlets/purl/1437464.
@article{osti_1437464,
title = {Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab},
author = {Ramagopal, Udupi A. and Liu, Weifeng and Garrett-Thomson, Sarah C. and Bonanno, Jeffrey B. and Yan, Qingrong and Srinivasan, Mohan and Wong, Susan C. and Bell, Alasdair and Mankikar, Shilpa and Rangan, Vangipuram S. and Deshpande, Shrikant and Korman, Alan J. and Almo, Steven C.},
abstractNote = {The 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 β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 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.},
doi = {10.1073/pnas.1617941114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 21,
volume = 114,
place = {United States},
year = {Mon May 08 00:00:00 EDT 2017},
month = {Mon May 08 00:00:00 EDT 2017}
}
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