Cell Reports
Volume 36, Issue 13, 28 September 2021, 109760
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Article
Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

https://doi.org/10.1016/j.celrep.2021.109760Get rights and content
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Highlights

  • Donor-derived antibodies C118 and C022 recognize a highly conserved RBD epitope

  • Both antibodies cross-react and neutralize sarbecoviruses and SARS-CoV-2 VOCs

  • C118-RBD and C022-RBD crystal structures show long CDRH3s that extend RBD β sheet

  • C118-S cryo-EM structure suggests intra- and inter-spike crosslinking by C118 IgG

Summary

Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (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 they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (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 main-chain H-bond interactions that extend an RBD β sheet, thus reducing sensitivity to RBD side-chain 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.

Keywords

cryo-EM
coronavirus
neutralizing antibody
receptor-binding domain
sarbecovirus
SARS-CoV-2
Spike trimer: structural biology
virology: X-ray crystallography

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) (https://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 (https://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.

  • 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.

Cited by (0)

5

Present address: Department of Biology, Stanford University, Stanford, CA 94305, USA

6

These authors contributed equally

7

Lead contact