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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Barnes, Christopher O. and Jette, Claudia A. and Abernathy, Morgan E. and Dam, Kim-Marie A. and Esswein, Shannon R. and Gristick, Harry B. and Malyutin, Andrey G. and Sharaf, Naima G. and Huey-Tubman, Kathryn E. and Lee, Yu E. and Robbiani, Davide F. and Nussenzweig, Michel C. and West, Anthony P., Jr. and Bjorkman, Pamela J. (2020) SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature, 588 (7839). pp. 682-687. ISSN 0028-0836. PMCID PMC8092461. https://resolver.caltech.edu/CaltechAUTHORS:20200928-142205501

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[img] Image (JPEG) (Extended Data Fig. 1: X-ray structure and epitope mapping of VH3-53 NAb C102) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Overview of VH3-53/VH3-66-encoded human NAb structures) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Cryo-EM data processing and validation for C144–S, C002–S and C121–S complexes) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Cryo-EM processing, validation and reconstruction for C119–S and C104–S complexes) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Primary and secondary epitopes of class 2 human NAbs) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Cryo-EM structure of C110–S complex and epitope mapping) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Possibilities for simultaneous engagement of C144 and C135 on spikes with different combinations of up and down RBDs) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: SPR binding data for NAbs) - Supplemental Material
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Abstract

The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to ‘up’ RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and ‘down’ RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-020-2852-1DOIArticle
https://rdcu.be/b8oLzPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092461PubMed CentralArticle
https://doi.org/10.1021/cen-09840-scicon1Featured InC&EN
ORCID:
AuthorORCID
Barnes, Christopher O.0000-0003-2754-5951
Jette, Claudia A.0000-0002-5085-8027
Dam, Kim-Marie A.0000-0002-1416-4757
Esswein, Shannon R.0000-0002-5142-0190
Gristick, Harry B.0000-0002-1957-2821
Malyutin, Andrey G.0000-0003-1716-5437
Sharaf, Naima G.0000-0002-3662-9228
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Lee, Yu E.0000-0001-5989-326X
Robbiani, Davide F.0000-0001-7379-3484
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2020 Nature Publishing Group. Received 30 August 2020; Accepted 06 October 2020; Published 12 October 2020. We thank J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance, J. Vielmetter and J. Keeffe for setting up automated polyreactivity assays, J. Keeffe for construct design, and N. Koranda for help with cloning and protein purification. Electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy with assistance from S. Chen. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (J. Kaiser, director), and S. Russi, A. Cohen and C. Smith and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. This work was supported by NIH grant P01-AI138938-S1 (P.J.B. and M.C.N.), the Caltech Merkin Institute for Translational Research (P.J.B.), NIH grant P50 8 P50 AI150464-13 (P.J.B.), and a George Mason University Fast Grant (P.J.B.). C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. M.C.N. is a Howard Hughes Medical Institute Investigator. Data availability: The atomic models generated from X-ray crystallographic studies of the C102–RBD complex, C102 Fab, C002 Fab, C110 Fab, C121 Fab and C135 Fab have been deposited at the Protein Data Bank (PDB) under accession codes 7K8M, 7K8N, 7K8O, 7K8P, 7K8Q and 7K8R, respectively. The atomic models and cryo-EM maps generated from cryo-EM studies of the C002–S 2P (state 1), C002–S 2P (state 2), C104–S 2P, C110–S 2P, C119–S 2P, C121–S 2P (state 1), C121–S 2P (state 2), C135–S 2P and C144–S 6P complexes have been deposited at the PDB and the Electron Microscopy Data Bank (EMDB) under the following accession codes: PDB 7K8S, 7K8T, 7K8U, 7K8V, 7K8W, 7K8X, 7K8Y, 7K8Z and 7K90; EMD EMD-22729, EMD-22730, EMD-22731, EMD-22372, EMD-22733, EMD-22734, EMD-22735, EMD-22736 and EMD-22737. Author Contributions: C.O.B., M.C.N., A.P.W. and P.J.B. conceived the study and analysed data; D.F.R. and M.C.N. provided monoclonal antibody sequences and plasmids derived from COVID-19-convalescent donors. C.O.B. and K.H.T. performed protein purifications and C.O.B. assembled complexes for cryo-EM and X-ray crystallography studies. C.O.B. performed cryo-EM and interpreted structures with assistance from M.E.A., K.A.D., S.R.E., A.G.M. and N.G.S. C.A.J. and C.O.B. performed and analysed crystallographic structures, with refinement assistance from M.E.A. and K.M.D. Y.E.L. performed polyreactivity assays. H.B.G. performed and analysed SPR experiments. A.P.W. analysed antibody sequences. C.O.B., M.C.N., A.P.W. and P.J.B. wrote the paper with contributions from other authors. Competing interests: The Rockefeller University has filed a provisional patent application in connection with this work on which D.F.R. and M.C.N. are inventors (US 63/021,387). Peer review information: Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work.
Group:Richard N. Merkin Institute for Translational Research, COVID-19
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
NIHP01-AI138938-S1
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
NIHP50 8 P50 AI150464-13
George Mason UniversityUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Subject Keywords:Antibodies; Cryoelectron microscopy; SARS-CoV-2
Issue or Number:7839
PubMed Central ID:PMC8092461
Record Number:CaltechAUTHORS:20200928-142205501
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200928-142205501
Official Citation:Barnes, C.O., Jette, C.A., Abernathy, M.E. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). https://doi.org/10.1038/s41586-020-2852-1
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105592
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:12 Oct 2020 17:28
Last Modified:30 Aug 2021 22:38

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