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

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.

doi:10.1073/pnas.1617941114

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

Journal Article · Mon May 08 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1617941114· OSTI ID:1437464

^[1]; Liu, Weifeng ^[2]; Garrett-Thomson, Sarah C. ^[1]; Bonanno, Jeffrey B. ^[1]; Yan, Qingrong ^[3]; Srinivasan, Mohan ^[4]; Wong, Susan C. ^[4]; Bell, Alasdair ^[4]; Mankikar, Shilpa ^[4]; Rangan, Vangipuram S. ^[4]; Deshpande, Shrikant ^[4]; Korman, Alan J. ^[4]; Almo, Steven C. ^[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)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: HG008325; GM094662; GM094665

OSTI ID:: 1437464

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 21; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 103 works

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References (63)

Domain association in immunoglobulin molecules Chothia, Cyrus; Novotný, Jirí; Bruccoleri, Robert Journal of Molecular Biology, Vol. 186, Issue 3 https://doi.org/10.1016/0022-2836(85)90137-8	journal	December 1985
An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies Schonfeld, D.; Matschiner, G.; Chatwell, L. Proceedings of the National Academy of Sciences, Vol. 106, Issue 20 https://doi.org/10.1073/pnas.0813399106	journal	May 2009
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
A solution for the best rotation to relate two sets of vectors Kabsch, W. Acta Crystallographica Section A, Vol. 32, Issue 5 https://doi.org/10.1107/S0567739476001873	journal	September 1976
Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses Stamper, Carin C.; Zhang, Yan; Tobin, James F. Nature, Vol. 410, Issue 6828 https://doi.org/10.1038/35069118	journal	March 2001
Structural basis for co-stimulation by the human CTLA-4/B7-2 complex Schwartz, Jean-Claude D.; Zhang, Xuewu; Fedorov, Alexander A. Nature, Vol. 410, Issue 6828 https://doi.org/10.1038/35069112	journal	March 2001
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells Quezada, S. A. Journal of Clinical Investigation, Vol. 116, Issue 7 https://doi.org/10.1172/JCI27745	journal	July 2006
CTLA-4 blockade increases IFN -producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients Liakou, C. I.; Kamat, A.; Tang, D. N. Proceedings of the National Academy of Sciences, Vol. 105, Issue 39 https://doi.org/10.1073/pnas.0806075105	journal	September 2008
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade McGranahan, N.; Furness, A. J. S.; Rosenthal, R. Science, Vol. 351, Issue 6280 https://doi.org/10.1126/science.aaf1490	journal	March 2016
Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness Ostrov, D. A. Science, Vol. 290, Issue 5492 https://doi.org/10.1126/science.290.5492.816	journal	October 2000
Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity Caruso, H. G.; Hurton, L. V.; Najjar, A. Cancer Research, Vol. 75, Issue 17 https://doi.org/10.1158/0008-5472.CAN-15-0139	journal	August 2015
Crystallization and preliminary X-ray analysis of the complex between human CTLA-4 and B7-2 Zhang, Xuewu; Schwartz, Jean-Claude D.; Nathenson, Stanley G. Acta Crystallographica Section D Biological Crystallography, Vol. 57, Issue 6 https://doi.org/10.1107/S0907444901005777	journal	May 2001
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients Hodi, F. S.; Butler, M.; Oble, D. A. Proceedings of the National Academy of Sciences, Vol. 105, Issue 8 https://doi.org/10.1073/pnas.0712237105	journal	February 2008
Cancer Immunotherapy Couzin-Frankel, J. Science, Vol. 342, Issue 6165 https://doi.org/10.1126/science.342.6165.1432	journal	December 2013
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma Simpson, Tyler R.; Li, Fubin; Montalvo-Ortiz, Welby The Journal of Experimental Medicine, Vol. 210, Issue 9 https://doi.org/10.1084/jem.20130579	journal	July 2013
Cancer immunotherapy: new applications in urologic oncology Hurwitz, Michael E.; Sokhn, Joseph; Petrylak, Daniel P. Current Opinion in Urology, Vol. 26, Issue 6 https://doi.org/10.1097/mou.0000000000000345	journal	January 2016
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma Larkin, James; Chiarion-Sileni, Vanna; Gonzalez, Rene New England Journal of Medicine, Vol. 373, Issue 1 https://doi.org/10.1056/nejmoa1504030	journal	July 2015
Cancer immunotherapy Plotkin, D. JAMA: The Journal of the American Medical Association, Vol. 236, Issue 9 https://doi.org/10.1001/jama.236.9.1012	journal	August 1976
Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma Ribas, Antoni; Kefford, Richard; Marshall, Margaret A. Journal of Clinical Oncology, Vol. 31, Issue 5 https://doi.org/10.1200/JCO.2012.44.6112	journal	February 2013
Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma Schadendorf, Dirk; Hodi, F. Stephen; Robert, Caroline Journal of Clinical Oncology, Vol. 33, Issue 17 https://doi.org/10.1200/JCO.2014.56.2736	journal	June 2015
Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells Selby, M. J.; Engelhardt, J. J.; Quigley, M. Cancer Immunology Research, Vol. 1, Issue 1 https://doi.org/10.1158/2326-6066.CIR-13-0013	journal	April 2013
Acidic extracellular microenvironment and cancer Kato, Yasumasa; Ozawa, Shigeyuki; Miyamoto, Chihiro Cancer Cell International, Vol. 13, Issue 1 https://doi.org/10.1186/1475-2867-13-89	journal	January 2013
Rigid-body Ligand Recognition Drives Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) Receptor Triggering Yu, Chao; Sonnen, Andreas F. -P.; George, Roger Journal of Biological Chemistry, Vol. 286, Issue 8 https://doi.org/10.1074/jbc.M110.182394	journal	December 2010
Pembrolizumab versus Ipilimumab in Advanced Melanoma Robert, Caroline; Schachter, Jacob; Long, Georgina V. New England Journal of Medicine, Vol. 372, Issue 26 https://doi.org/10.1056/NEJMoa1503093	journal	June 2015
Considerations for Combined Immune Checkpoint Modulation and Radiation Treatment Almo, Steven C.; Guha, Chandan Radiation Research, Vol. 182, Issue 2 https://doi.org/10.1667/RR13667.1	journal	August 2014
Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4 Qureshi, O. S.; Zheng, Y.; Nakamura, K. Science, Vol. 332, Issue 6029 https://doi.org/10.1126/science.1202947	journal	April 2011
Cutting Edge: Cell-Extrinsic Immune Regulation by CTLA-4 Expressed on Conventional T Cells Wang, Chun Jing; Kenefeck, Rupert; Wardzinski, Lukasz The Journal of Immunology, Vol. 189, Issue 3 https://doi.org/10.4049/jimmunol.1200972	journal	June 2012
Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans Corse, Emily; Allison, James P. The Journal of Immunology, Vol. 189, Issue 3 https://doi.org/10.4049/jimmunol.1200695	journal	July 2012
The blockade of immune checkpoints in cancer immunotherapy Pardoll, Drew M. Nature Reviews Cancer, Vol. 12, Issue 4 https://doi.org/10.1038/nrc3239	journal	March 2012
gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma Schwartzentruber, Douglas J.; Lawson, David H.; Richards, Jon M. New England Journal of Medicine, Vol. 364, Issue 22 https://doi.org/10.1056/NEJMoa1012863	journal	June 2011
Cancer immunotherapy comes of age Mellman, Ira; Coukos, George; Dranoff, Glenn Nature, Vol. 480, Issue 7378 https://doi.org/10.1038/nature10673	journal	December 2011
Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice Liu, X.; Jiang, S.; Fang, C. Cancer Research, Vol. 75, Issue 17 https://doi.org/10.1158/0008-5472.CAN-15-0159	journal	August 2015
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations Zou, Weiping; Wolchok, Jedd D.; Chen, Lieping Science Translational Medicine, Vol. 8, Issue 328 https://doi.org/10.1126/scitranslmed.aad7118	journal	March 2016
Interactions of protein antigens with antibodies. Davies, D. R.; Cohen, G. H. Proceedings of the National Academy of Sciences, Vol. 93, Issue 1 https://doi.org/10.1073/pnas.93.1.7	journal	January 1996
Acidity Generated by the Tumor Microenvironment Drives Local Invasion Estrella, V.; Chen, T.; Lloyd, M. Cancer Research, Vol. 73, Issue 5 https://doi.org/10.1158/0008-5472.CAN-12-2796	journal	January 2013
Cancer Immunotherapy Gajewski, T. F. Oncologic Therapies https://doi.org/10.1007/978-3-642-97988-0_6	book	January 1999
Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules Fraczkiewicz, Robert; Braun, Werner Journal of Computational Chemistry, Vol. 19, Issue 3 https://doi.org/10.1002/(SICI)1096-987X(199802)19:3<319::AID-JCC6>3.0.CO;2-W	journal	February 1998
Cancer Immunotherapy Comes of Age Topalian, Suzanne L.; Weiner, George J.; Pardoll, Drew M. Journal of Clinical Oncology, Vol. 29, Issue 36 https://doi.org/10.1200/jco.2011.38.0899	journal	December 2011
Nivolumab plus Ipilimumab in Advanced Melanoma Wolchok, Jedd D.; Kluger, Harriet; Callahan, Margaret K. New England Journal of Medicine, Vol. 369, Issue 2 https://doi.org/10.1056/NEJMoa1302369	journal	July 2013
Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28 Metzler, William J.; Bajorath, Jürgen; Fenderson, William Nature Structural Biology, Vol. 4, Issue 7 https://doi.org/10.1038/nsb0797-527	journal	July 1997
Expression, Refolding, Purification, Molecular Characterization, Crystallization, and Preliminary X-ray Analysis of the Receptor Binding Domain of Human B7-2 Zhang, Xuewu; Schwartz, Jean-Claude D.; Almo, Steven C. Protein Expression and Purification, Vol. 25, Issue 1 https://doi.org/10.1006/prep.2002.1616	journal	June 2002
The interpretation of protein structures: Estimation of static accessibility Lee, B.; Richards, F. M. Journal of Molecular Biology, Vol. 55, Issue 3 https://doi.org/10.1016/0022-2836(71)90324-X	journal	February 1971
Structure and Cancer Immunotherapy of the B7 Family Member B7x Jeon, Hyungjun; Vigdorovich, Vladimir; Garrett-Thomson, Sarah C. Cell Reports, Vol. 9, Issue 3 https://doi.org/10.1016/j.celrep.2014.09.053	journal	November 2014
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
Molecular replacement with MOLREP Vagin, Alexei; Teplyakov, Alexei Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042589	journal	December 2009
Cancer Immunotherapy Silverstein, Melvin J.; Morton, Donald L. AJN, American Journal of Nursing, Vol. 73, Issue 7 https://doi.org/10.1097/00000446-197307000-00006	journal	January 1973
Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab Eroglu, Zeynep; Kim, Dae Won; Wang, Xiaoyan European Journal of Cancer, Vol. 51, Issue 17 https://doi.org/10.1016/j.ejca.2015.08.012	journal	November 2015
Humanization of an anti-p185HER2 antibody for human cancer therapy. Carter, P.; Presta, L.; Gorman, C. M. Proceedings of the National Academy of Sciences, Vol. 89, Issue 10, p. 4285-4289 https://doi.org/10.1073/pnas.89.10.4285	journal	May 1992
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study Antonia, Scott; Goldberg, Sarah B.; Balmanoukian, Ani The Lancet Oncology, Vol. 17, Issue 3 https://doi.org/10.1016/S1470-2045(15)00544-6	journal	March 2016
Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer Rocconi, Rodney P.; Stevens, Erin E.; Bottsford-Miller, Justin N. Cancer Gene Therapy https://doi.org/10.1038/s41417-021-00317-5	journal	March 2021
Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma Postow, Michael A.; Chesney, Jason; Pavlick, Anna C. New England Journal of Medicine, Vol. 372, Issue 21 https://doi.org/10.1056/NEJMoa1414428	journal	May 2015
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients Romano, Emanuela; Kusio-Kobialka, Monika; Foukas, Periklis G. Proceedings of the National Academy of Sciences, Vol. 112, Issue 19 https://doi.org/10.1073/pnas.1417320112	journal	April 2015
The case for open-source software in drug discovery DeLano, Warren L. Drug Discovery Today, Vol. 10, Issue 3 https://doi.org/10.1016/S1359-6446(04)03363-X	journal	February 2005
Crystal structure of a soluble CD28-Fab complex Evans, Edward J.; Esnouf, Robert M.; Manso-Sancho, Raquel Nature Immunology, Vol. 6, Issue 3 https://doi.org/10.1038/ni1170	journal	February 2005
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies Peggs, Karl S.; Quezada, Sergio A.; Chambers, Cynthia A. The Journal of Experimental Medicine, Vol. 206, Issue 8 https://doi.org/10.1084/jem.20082492	journal	July 2009
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-021-81903-3	journal	January 2021
Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202) Rubenstein, James L.; Hsi, Eric D.; Johnson, Jeffrey L. Journal of Clinical Oncology, Vol. 31, Issue 25 https://doi.org/10.1200/JCO.2012.46.9957	journal	September 2013
Prediction of glycosylation sites using random forests Hamby, Stephen E.; Hirst, Jonathan D. BMC Bioinformatics, Vol. 9, Issue 1 https://doi.org/10.1186/1471-2105-9-500	journal	November 2008
The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors Bellone, Matteo; Calcinotto, Arianna; Filipazzi, Paola OncoImmunology, Vol. 2, Issue 1 https://doi.org/10.4161/onci.22058	journal	January 2013
Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis Alrabadi, N. N.; Abushukair, H. M.; Ababneh, O. E. Clinical and Translational Oncology, Vol. 23, Issue 9 https://doi.org/10.1007/s12094-021-02598-6	journal	April 2021
Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models. Selby, Mark; Engelhardt, John; Lu, Li-Sheng Journal of Clinical Oncology, Vol. 31, Issue 15_suppl https://doi.org/10.1200/jco.2013.31.15_suppl.3061	journal	May 2013
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997

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

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