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Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Jette, Claudia A. and Cohen, Alexander A. and Gnanapragasam, Priyanthi N. P. and Muecksch, Frauke and Lee, Yu E. and Huey-Tubman, Kathryn E. and Schmidt, Fabian and Hatziioannou, Theodora and Bieniasz, Paul D. and Nussenzweig, Michel C. and West, Anthony P., Jr. and Keeffe, Jennifer R. and Bjorkman, Pamela J. and Barnes, Christopher O. (2021) Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies. Cell Reports . ISSN 2211-1247. PMCID PMC8423902; PMC8095199. doi:10.1016/j.celrep.2021.109760. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20210429-094548605

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Abstract

Many anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). Potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding, and CDRH3-RBD mainchain H-bond interactions that extend an RBD β-sheet, thus reducing sensitivity to RBD sidechain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2021.109760DOIArticle
https://doi.org/10.1101/2021.04.23.441195DOIDiscussion Paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423902PubMed CentralArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095199PubMed CentralDiscussion Paper
http://dx.doi.org/10.17632/kkf4zdz2x7.1DOIData
ORCID:
AuthorORCID
Jette, Claudia A.0000-0002-5085-8027
Cohen, Alexander A.0000-0002-2818-656X
Lee, Yu E.0000-0001-5989-326X
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Hatziioannou, Theodora0000-0002-7889-0766
Bieniasz, Paul D.0000-0002-2368-3719
Nussenzweig, Michel C.0000-0003-0592-8564
Keeffe, Jennifer R.0000-0002-5317-6398
Bjorkman, Pamela J.0000-0002-2277-3990
Barnes, Christopher O.0000-0003-2754-5951
Additional Information:© 2021 The Author(s). Under an Attribution 4.0 International (CC BY 4.0). Received 28 April 2021, Revised 5 August 2021, Accepted 1 September 2021, Available online 8 September 2021. We thank J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance and K. Dam for assistance with soluble ACE2 purification. Electron microscopy was performed in the Caltech Cryo-EM Center with assistance from S. Chen and A. Malyutin. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory. We thank J. Kaiser, director of the Molecular Observatory at Caltech, and beamline staff C. Smith and S. Russi at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. 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 (P30GM133894). 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 (P01-AI138938-S1 to P.J.B. and M.C.N.), the Caltech Merkin Institute for Translational Research (P.J.B.), a George Mason University Fast Grant (P.J.B.), NIH R01AI078788 (to T.H.) and R01AI640511 (to P.D.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 an HHMI investigator. Author Contributions: C.A.J., A.A.C., P.J.B., and C.O.B. conceived and designed experiments. Proteins were produced and characterized by A.A.C., K.H.T., C.O.B., and C.A.J. Binding and neutralization studies were done by A.A.C., and F.M. with assistance from P.N.P.G., Y.L., and F.S. SPR binding competition experiments were done by C.A.J. with assistance from J.R.K. Structural studies were performed by C.A.J. with assistance from C.O.B. Structure analysis was done by C.A.J. with assistance from C.O.B. and A.A.C. Sequence analysis was done by A.P.W. Paper was written by C.A.J., P.J.B., and C.O.B. with assistance from A.A.C., T.H., M.C.N., P.D.B., and other authors. Declaration of interest: The Rockefeller University has filed provisional patent applications in connection with this work on which M.C.N. (US patent 63/021,387) is listed as an inventor. Data and Code Availability: Atomic models of C118 Fab complexed with SARS-CoV RBD and C022 Fab complexed with SARS-CoV-2 RBD have been deposited in the Protein Data Bank (PDB) (http://www.rcsb.org/) under accession codes 7RKS and 7RKU, respectively. The atomic model and cryo-EM maps generated for the C118 Fab–SARS-CoV-2 S complex have been deposited at the PDB (http://www.rcsb.org/) and the Electron Microscopy Databank (EMDB) (http://www.emdataresource.org/) under accession codes 7RKV (state 1 coordinates), EMD-24504 (state 1) and EMD-24505 (state 2). All models and maps are publicly available as of the date of publication. Additional Supplemental Items are available from Mendeley Data at http://dx.doi.org/10.17632/kkf4zdz2x7.1. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Group:COVID-19, Richard N. Merkin Institute for Translational Research
Funders:
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-76SF00515
NIHP30GM133894
NIHP01-AI138938-S1
NIHR01AI078788
NIHR01AI640511
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Subject Keywords:Cryo-EM; Coronavirus; Neutralizing antibody; receptor-binding domain; Sarbecovirus; SARS-CoV-2; Spike trimer: Structural biology; Virology: X-ray crystallography
PubMed Central ID:PMC8423902; PMC8095199
DOI:10.1016/j.celrep.2021.109760
Record Number:CaltechAUTHORS:20210429-094548605
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210429-094548605
Official Citation:Claudia A. Jette, Alexander A. Cohen, Priyanthi N.P. Gnanapragasam, Frauke Muecksch, Yu E. Lee, Kathryn E. Huey-Tubman, Fabian Schmidt, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig, Anthony P. West, Jennifer R. Keeffe, Pamela J. Bjorkman, Christopher O. Barnes, Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies, Cell Reports, 2021, 109760, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2021.109760.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108864
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:29 Apr 2021 18:31
Last Modified:10 Sep 2021 15:28

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