Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies

Rujas, Edurne; Cui, Hong; Sicard, Taylor; Semesi, Anthony; Julien, Jean-Philippe

doi:10.1038/s41467-020-18828-4

Title: Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies

Journal Article · Thu Oct 08 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-18828-4· OSTI ID:1682336

Rujas, Edurne ^[1]; Cui, Hong ^[2]; Sicard, Taylor ^[3]; Semesi, Anthony ^[2];

^[3]

The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of the Basque Country (UPV/EHU), Bilbao (Spain)
The Hospital for Sick Children Research Inst., Toronto, ON (Canada)
The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of Toronto, ON (Canada)

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC’ loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: European Union (EU); Canadian Institutes of Health Research (CIHR); Canadian Institute for Advanced Research (CIFAR); Canada Research Chairs Program; National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: 790012; PJT-148811; S10 OD012289; AC02-06CH11357; SC0012704; P41GM111244

OSTI ID:: 1682336

Journal Information:: Nature Communications, Vol. 11, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (64)

The Interaction Properties of Costimulatory Molecules Revisited Collins, Alison V.; Brodie, Douglas W.; Gilbert, Robert J. C. Immunity, Vol. 17, Issue 2 https://doi.org/10.1016/S1074-7613(02)00362-X	journal	August 2002
Cemiplimab: First Global Approval Markham, Anthony; Duggan, Sean Drugs, Vol. 78, Issue 17 https://doi.org/10.1007/s40265-018-1012-5	journal	November 2018
De novo design of potent and selective mimics of IL-2 and IL-15 Silva, Daniel-Adriano; Yu, Shawn; Ulge, Umut Y. Nature, Vol. 565, Issue 7738 https://doi.org/10.1038/s41586-018-0830-7	journal	January 2019
Synthesis and Crystal Structure of the Copper Complex of 7,16-Bis(2-hydroxy-5-methylbenzyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Ma, Shu-Lan; Zhu, Wen-Xiang; Guo, Qian-Ling Chinese Journal of Chemistry, Vol. 22, Issue 1 https://doi.org/10.1002/cjoc.20040220114	journal	January 2004
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
T Follicular Helper Cell Differentiation, Function, and Roles in Disease Crotty, Shane Immunity, Vol. 41, Issue 4 https://doi.org/10.1016/j.immuni.2014.10.004	journal	October 2014
Crystal Structure of a Shark Single-Domain Antibody V Region in Complex with Lysozyme Stanfield, R. L. Science, Vol. 305, Issue 5691 https://doi.org/10.1126/science.1101148	journal	September 2004
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013
ICOS is essential for effective T-helper-cell responses Tafuri, Anna; Shahinian, Arda; Bladt, Friedhelm Nature, Vol. 409, Issue 6816 https://doi.org/10.1038/35051113	journal	January 2001
Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab Lee, Hyun Tae; Lee, Ju Yeon; Lim, Heejin Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-06002-8	journal	July 2017
A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications Nagai, Takeharu; Ibata, Keiji; Park, Eun Sun Nature Biotechnology, Vol. 20, Issue 1 https://doi.org/10.1038/nbt0102-87	journal	January 2002
Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma Ribas, Antoni; Hamid, Omid; Daud, Adil JAMA, Vol. 315, Issue 15 https://doi.org/10.1001/jama.2016.4059	journal	April 2016
Cutting Edge: Identification of GL50, a Novel B7-Like Protein That Functionally Binds to ICOS Receptor Ling, Vincent; Wu, Paul W.; Finnerty, Heather F. The Journal of Immunology, Vol. 164, Issue 4 https://doi.org/10.4049/jimmunol.164.4.1653	journal	February 2000
B7h, a Novel Costimulatory Homolog of B7.1 and B7.2, Is Induced by TNFα Swallow, Michelle M.; Wallin, Jeffrey J.; Sha, William C. Immunity, Vol. 11, Issue 4 https://doi.org/10.1016/S1074-7613(00)80117-X	journal	October 1999
Covalent Dimerization of CD28/CTLA-4 and Oligomerization of CD80/CD86 Regulate T Cell Costimulatory Interactions Greene, JoAnne L.; Leytze, Gina M.; Emswiler, John Journal of Biological Chemistry, Vol. 271, Issue 43 https://doi.org/10.1074/jbc.271.43.26762	journal	October 1996
A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1 Pedros, Christophe; Zhang, Yaoyang; Hu, Joyce K. Nature Immunology, Vol. 17, Issue 7 https://doi.org/10.1038/ni.3463	journal	May 2016
Muscle fibres and cultured muscle cells express the B7.1/2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies Wiendl, H.; Mitsdoerffer, M.; Schneider, D. Brain, Vol. 126, Issue 5 https://doi.org/10.1093/brain/awg114	journal	May 2003
Simultaneous blockade of co-stimulatory signals, CD28 and ICOS, induced a stable tolerance in rat heart transplantation Guo, Lei; Fujino, Masayuki; Kimura, Hiromitsu Transplant Immunology, Vol. 12, Issue 1 https://doi.org/10.1016/S0966-3274(03)00016-9	journal	October 2003
The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system Qian, Xuesong; Agematsu, Kazunaga; Freeman, Gordon J. European Journal of Immunology, Vol. 36, Issue 4 https://doi.org/10.1002/eji.200535253	journal	April 2006
Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency Grimbacher, Bodo; Hutloff, Andreas; Schlesier, Michael Nature Immunology, Vol. 4, Issue 3 https://doi.org/10.1038/ni902	journal	February 2003
Structure and T Cell Inhibition Properties of B7 Family Member, B7-H3 Vigdorovich, Vladimir; Ramagopal, Udupi A.; Lázár-Molnár, Eszter Structure, Vol. 21, Issue 5 https://doi.org/10.1016/j.str.2013.03.003	journal	May 2013
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma Hodi, F. Stephen; O'Day, Steven J.; McDermott, David F. New England Journal of Medicine, Vol. 363, Issue 8 https://doi.org/10.1056/NEJMoa1003466	journal	August 2010
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis Cheng, Laurence E.; Amoura, Zahir; Cheah, Benjamin Arthritis & Rheumatology, Vol. 70, Issue 7 https://doi.org/10.1002/art.40479	journal	May 2018
ICOS:ICOS-Ligand Interaction Is Required for Type 2 Innate Lymphoid Cell Function, Homeostasis, and Induction of Airway Hyperreactivity Maazi, Hadi; Patel, Nisheel; Sankaranarayanan, Ishwarya Immunity, Vol. 42, Issue 3 https://doi.org/10.1016/j.immuni.2015.02.007	journal	March 2015
ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 Hutloff, Andreas; Dittrich, Anna M.; Beier, Katja C. Nature, Vol. 397, Issue 6716 https://doi.org/10.1038/16717	journal	January 1999
ICOS controls the pool size of effector-memory and regulatory T cells Burmeister, Y.; Lischke, T.; Dahler, A. C. The Journal of Immunology, Vol. 180, Issue 5 https://doi.org/10.4049/jimmunol.180.5.3613	journal	February 2008
A framework for organizing cancer-related variations from existing databases, publications and NGS data using a High-performance Integrated Virtual Environment (HIVE) Wu, Tsung-Jung; Shamsaddini, Amirhossein; Pan, Yang Database, Vol. 2014 https://doi.org/10.1093/database/bau022	journal	January 2014
Characterization of Human Inducible Costimulator Ligand Expression and Function Aicher, Alexandra; Hayden-Ledbetter, Martha; Brady, William A. The Journal of Immunology, Vol. 164, Issue 9 https://doi.org/10.4049/jimmunol.164.9.4689	journal	May 2000
Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection Pan, Xuan-Chao; Guo, Lei; Deng, Ying-Bing Surgery Today, Vol. 38, Issue 9 https://doi.org/10.1007/s00595-007-3734-y	journal	August 2008
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 Zhou, T.; Georgiev, I.; Wu, X. Science, Vol. 329, Issue 5993 https://doi.org/10.1126/science.1192819	journal	July 2010
Mouse Inducible Costimulatory Molecule (ICOS) Expression Is Enhanced by CD28 Costimulation and Regulates Differentiation of CD4 ⁺ T Cells McAdam, Alexander J.; Chang, Tammy T.; Lumelsky, Anna E. The Journal of Immunology, Vol. 165, Issue 9 https://doi.org/10.4049/jimmunol.165.9.5035	journal	November 2000
Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist Koh, Kwi Hye; Cao, Yanxia; Mangos, Steve Journal of Clinical Investigation, Vol. 129, Issue 4 https://doi.org/10.1172/JCI123386	journal	March 2019
A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin Xu, Rui; Krause, Jens C.; McBride, Ryan Nature Structural & Molecular Biology, Vol. 20, Issue 3 https://doi.org/10.1038/nsmb.2500	journal	February 2013
Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility Xu, Heping; Li, Xuanying; Liu, Dan Nature, Vol. 496, Issue 7446 https://doi.org/10.1038/nature12058	journal	April 2013
Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond Panneton, Vincent; Chang, Jinsam; Witalis, Mariko Immunological Reviews, Vol. 291, Issue 1 https://doi.org/10.1111/imr.12771	journal	August 2019
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function Wang, Shengdian; Zhu, Gefeng; Tamada, Koji Journal of Experimental Medicine, Vol. 195, Issue 8 https://doi.org/10.1084/jem.20011607	journal	April 2002
Inhibition of Chronic Rejection and Development of Tolerogenic T Cells after ICOS-ICOSL and CD40-CD40L Co-stimulation Blockade Guillonneau, Carole; Aubry, Venceslas; Renaudin, Karine Transplantation, Vol. 80, Issue 4 https://doi.org/10.1097/01.TP.0000165429.57421.D6	journal	January 2005
T-cell co-stimulation through B7RP-1 and ICOS Yoshinaga, Steven K.; Whoriskey, John S.; Khare, Sanjay D. Nature, Vol. 402, Issue 6763 https://doi.org/10.1038/45582	journal	December 1999
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
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS) Simpson, Tyler R.; Quezada, Sergio A.; Allison, James P. Current Opinion in Immunology, Vol. 22, Issue 3 https://doi.org/10.1016/j.coi.2010.01.001	journal	June 2010
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
Structural Basis of Inducible Costimulator Ligand Costimulatory Function: Determination of the Cell Surface Oligomeric State and Functional Mapping of the Receptor Binding Site of the Protein Chattopadhyay, Kausik; Bhatia, Sumeena; Fiser, Andras The Journal of Immunology, Vol. 177, Issue 6 https://doi.org/10.4049/jimmunol.177.6.3920	journal	September 2006
Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy Fan, Xiaozhou; Quezada, Sergio A.; Sepulveda, Manuel A. Journal of Experimental Medicine, Vol. 211, Issue 4 https://doi.org/10.1084/jem.20130590	journal	March 2014
Review Article. cell Surface Carbohydrates as Prognostic Markers in Human Carcinomas Dabelsteen, Erik The Journal of Pathology, Vol. 179, Issue 4 https://doi.org/10.1002/(SICI)1096-9896(199608)179:4<358::AID-PATH564>3.0.CO;2-T	journal	August 1996
Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus Sullivan, B. A.; Tsuji, W.; Kivitz, A. Lupus Science & Medicine, Vol. 3, Issue 1 https://doi.org/10.1136/lupus-2016-000146	journal	April 2016
Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity Zamarin, Dmitriy; Holmgaard, Rikke B.; Ricca, Jacob Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14340	journal	February 2017
Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS Yoshinaga, Steven K.; Zhang, Ming; Pistillo, Jeanne International Immunology, Vol. 12, Issue 10 https://doi.org/10.1093/intimm/12.10.1439	journal	October 2000
ICOS is critical for CD40-mediated antibody class switching McAdam, Alexander J.; Greenwald, Rebecca J.; Levin, Michele A. Nature, Vol. 409, Issue 6816 https://doi.org/10.1038/35051107	journal	January 2001
A two-step, two-signal model for the primary activation of precursor helper T cells Bretscher, P. A. Proceedings of the National Academy of Sciences, Vol. 96, Issue 1 https://doi.org/10.1073/pnas.96.1.185	journal	January 1999
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
Inducible costimulator (ICOS) potentiates TCR-induced calcium flux by augmenting PLCγ1 activation and actin remodeling Leconte, Julien; Bagherzadeh Yazdchi, Sahar; Panneton, Vincent Molecular Immunology, Vol. 79 https://doi.org/10.1016/j.molimm.2016.09.022	journal	November 2016
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors Lin, D. Y. -w.; Tanaka, Y.; Iwasaki, M. Proceedings of the National Academy of Sciences, Vol. 105, Issue 8 https://doi.org/10.1073/pnas.0712278105	journal	February 2008
Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1 Li, Chia-Wei; Lim, Seung-Oe; Chung, Ezra M. Cancer Cell, Vol. 33, Issue 2 https://doi.org/10.1016/j.ccell.2018.01.009	journal	February 2018
Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. Jenkins, M. K.; Schwartz, R. H. Journal of Experimental Medicine, Vol. 165, Issue 2 https://doi.org/10.1084/jem.165.2.302	journal	February 1987
CCR5 Mimicry by Sulfated Human Anti-HIV-1 Antibodies Lin, George; Hoxie, James A. Cell, Vol. 114, Issue 2 https://doi.org/10.1016/S0092-8674(03)00564-6	journal	July 2003
ICOS co-stimulatory receptor is essential for T-cell activation and function Dong, Chen; Juedes, Amy E.; Temann, Ulla-Angela Nature, Vol. 409, Issue 6816 https://doi.org/10.1038/35051100	journal	January 2001
Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase Gigoux, M.; Shang, J.; Pak, Y. Proceedings of the National Academy of Sciences, Vol. 106, Issue 48 https://doi.org/10.1073/pnas.0911573106	journal	November 2009
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Structural Basis of Enhanced Crystallizability Induced by a Molecular Chaperone for Antibody Antigen-Binding Fragments Ereño-Orbea, June; Sicard, Taylor; Cui, Hong Journal of Molecular Biology, Vol. 430, Issue 3 https://doi.org/10.1016/j.jmb.2017.12.010	journal	February 2018

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