Immunity
Volume 54, Issue 10, 12 October 2021, Pages 2385-2398.e10
Journal home page for Immunity

Article
A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site

https://doi.org/10.1016/j.immuni.2021.08.025Get rights and content
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open access

Highlights

  • NT-193 broadly and potently neutralizes SARS-related coronaviruses and variants

  • IgG3 switching enhances cross-neutralizing activity of NT-193

  • Structural analysis of the antibody footprints reveals a vulnerable virus site

  • Therapeutic NT-193 reduces the virus titers and morbidity during SARS-CoV-2 challenge

Summary

Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.

Keywords

SARS-CoV-2
variants of concern
SARS-CoV
neutralizing antibody
receptor-binding domain
IgG3
X-ray crystallography

Data and code availability

Coordinates and structure factors have been deposited in the Protein Data Bank. Sequences data for NT-108 and NT-193 have been deposited in GenBank. All NGS reads were deposited in the DNA Data Bank of Japan. Accession numbers are listed in the Key Resources Table. Data 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)

18

These authors contributed equally

19

Lead contact