期刊
CELL REPORTS
卷 37, 期 4, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109881
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- National Institute of Allergy and Infectious Diseases [75N93019C00062, HHSN272201700060C, R01 AI157155]
This study utilized cryo-EM to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies, revealing similarities between epitopes targeted by human and murine B cells. The findings suggest that SARS-CoV-2 might evade therapeutic antibodies with a limited set of mutations, underscoring the importance of combination mAb therapeutics. It also showed distinct inhibitory mechanisms used by RBD-specific mAbs in neutralizing SARS-CoV-2 infection.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARSCoV-2 and corresponding neutralization escape variants selected in vitro map to our structurally defined epitopes, suggesting that SARS-CoV-2 might evade therapeutic antibodies with a limited set of mutations, underscoring the importance of combination mAb therapeutics. Finally, we show that 2B04 neutralizes SARS-CoV-2 infection by preventing ACE2 engagement, whereas 2H04 reduces host cell attachment without directly disrupting ACE2-RBM interactions, providing distinct inhibitory mechanisms used by RBD-specific mAbs.
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