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Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV
Naveenchandra Suryadevara, … , Ralph S. Baric, James E. Crowe Jr
Naveenchandra Suryadevara, … , Ralph S. Baric, James E. Crowe Jr
Published November 26, 2024
Citation Information: J Clin Invest. 2025;135(3):e178880. https://doi.org/10.1172/JCI178880.
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Research Article Immunology Virology

Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV

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Abstract

The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence; therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here, we report a monoclonal antibody COV1-65, encoded by the IGHV1-69 gene, that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the mAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact fragment crystallizable region (Fc) effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65–SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.

Authors

Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru, Elad Binshtein, Jennifer Munt, David R. Martinez, Alexandra Schäfer, Luke Myers, Trevor D. Scobey, Robert H. Carnahan, Andrew B. Ward, Ralph S. Baric, James E. Crowe Jr

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Figure 6

SARS-CoV and SARS-COV-2 mAbs mediate prophylactic protection in mice challenged with SARS-CoV-MA15.

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SARS-CoV and SARS-COV-2 mAbs mediate prophylactic protection in mice cha...
Ten-week-old female BALB/c mice were inoculated with 1 × 105 PFU of SARS-CoV-MA15. A day before the virus challenge, mice were given i.p. administration of 200 μg of SARS-CoV, SARS-CoV-2 mAbs or DENV-2D22, an isotype-control mAb. A–C WT IgG and D–F LALA-PG. (A and D) Body weight change of mice over time. Data consist of mean ± S.E.M. comparisons to isotype control for 2 independent experiments (n = 9–10 for each experimental group: 2-way ANOVA with Dunnett’s post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). (B and E) Gross pathology of mice lungs at day 4 post-infection. Data consists of the mean ± SEM. comparisons between all groups for 2 independent experiments: 1-way ANOVA with Tukey’s post hoc test: n = 10, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (C and F) Lung tissues were harvested 4 days after virus inoculation from mice. Viral burden in the lung was assessed by plaque assay. Data consists of the mean ± S.E.M. comparisons between all groups for 2 independent experiments: 1-way ANOVA with Tukey’s post hoc test: n = 10, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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