Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
Abstract
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.
- Authors:
-
[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)
- Publication Date:
- Research Org.:
- 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 Org.:
- 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)
- OSTI Identifier:
- 1682336
- Grant/Contract Number:
- 790012; PJT-148811; S10 OD012289; AC02-06CH11357; SC0012704; P41GM111244
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; Immunotherapy; X-ray crystallography
Citation Formats
Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, and Julien, Jean-Philippe. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. United States: N. p., 2020.
Web. doi:10.1038/s41467-020-18828-4.
Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, & Julien, Jean-Philippe. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. United States. https://doi.org/10.1038/s41467-020-18828-4
Rujas, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, and Julien, Jean-Philippe. Thu .
"Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies". United States. https://doi.org/10.1038/s41467-020-18828-4. https://www.osti.gov/servlets/purl/1682336.
@article{osti_1682336,
title = {Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies},
author = {Rujas, Edurne and Cui, Hong and Sicard, Taylor and Semesi, Anthony and Julien, Jean-Philippe},
abstractNote = {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.},
doi = {10.1038/s41467-020-18828-4},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {Thu Oct 08 00:00:00 EDT 2020},
month = {Thu Oct 08 00:00:00 EDT 2020}
}
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