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

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 inve...

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Autores: Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, Julien, Jean-Philippe
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/339716
Acesso em linha:http://hdl.handle.net/10261/339716
https://api.elsevier.com/content/abstract/scopus_id/85092320371
Access Level:acceso abierto
Palavra-chave:Immunotherapy
X-ray crystallography
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spelling Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodiesRujas, EdurneCui, HongSicard, TaylorSemesi, AnthonyJulien, Jean-PhilippeImmunotherapyX-ray crystallographyThe 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.This work was supported by the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant 790012 (E.R.), by operating grant PJT-148811 from the Canadian Institutes of Health Research (J.P.J.), the CIFAR Azrieli Global Scholar program (J.P.J.), the Ontario Early Researcher Awards program (J.P.J.), and the Canada Research Chairs program (J.P.J.). T.S. is a recipient of a Vanier Canada Graduate Scholarship.Peer reviewedNature Publishing GroupCanadian Institutes of Health ResearchAzrieli FoundationJulien, Jean-Philippe [0000-0001-7602-3995]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/339716https://api.elsevier.com/content/abstract/scopus_id/85092320371reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/790012https://doi.org/10.1038/s41467-020-18828-4Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3397162026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
title Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
spellingShingle Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
Rujas, Edurne
Immunotherapy
X-ray crystallography
title_short Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
title_full Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
title_fullStr Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
title_full_unstemmed Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
title_sort Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
dc.creator.none.fl_str_mv Rujas, Edurne
Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author Rujas, Edurne
author_facet Rujas, Edurne
Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author_role author
author2 Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Canadian Institutes of Health Research
Azrieli Foundation
Julien, Jean-Philippe [0000-0001-7602-3995]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Immunotherapy
X-ray crystallography
topic Immunotherapy
X-ray crystallography
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/339716
https://api.elsevier.com/content/abstract/scopus_id/85092320371
url http://hdl.handle.net/10261/339716
https://api.elsevier.com/content/abstract/scopus_id/85092320371
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/790012
https://doi.org/10.1038/s41467-020-18828-4
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
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