Neutralizing and protective human monoclonal antibodies recognizing the N-terminaldomain of the SARS-CoV-2 spike protein

Suryadevara, N.; Shrihari, S.; Gilchuk, P.; VanBlargan, L.; Binshtein, E.; Zost, S.; Nargi, R.; Sutton, R.; Winkler, E. S.; Chen, E. C.; Fouch, M. E.; Davidson, E.; Doranz, B.; Carnahan, R. H.; Thackray, L.; Diamond, M. D.; Crowe, J. E.

doi:10.1101/2021.01.19.427324

bioRxiv · 10.1101/2021.01.19.427324

Neutralizing and protective human monoclonal antibodies recognizing the N-terminaldomain of the SARS-CoV-2 spike protein

Suryadevara, N.·Shrihari, S.·Gilchuk, P.·VanBlargan, L.·Binshtein, E.·Zost, S.·Nargi, R.·Sutton, R.·Winkler, E. S.·Chen, E. C.·Fouch, M. E.·Davidson, E.·Doranz, B.·Carnahan, R. H.·Thackray, L.·Diamond, M. D.·Crowe, J. E.

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Abstract

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

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Suryadevara, N., Shrihari, S., Gilchuk, P., VanBlargan, L., Binshtein, E., Zost, S., Nargi, R., Sutton, R., Winkler, E. S., Chen, E. C., Fouch, M. E., Davidson, E., Doranz, B., Carnahan, R. H., Thackray, L., Diamond, M. D., Crowe, J. E.. 2021-01-20. Neutralizing and protective human monoclonal antibodies recognizing the N-terminaldomain of the SARS-CoV-2 spike protein. https://doi.org/10.1101/2021.01.19.427324

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