Cell Rep . Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD

[tetano]

Cell Rep


. 2021 Oct 8;109881.
doi: 10.1016/j.celrep.2021.109881. Online ahead of print.
Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD


John M Errico ¹ , Haiyan Zhao ¹ , Rita E Chen ² , Zhuoming Liu ³ , James Brett Case ⁴ , Meisheng Ma ¹ , Aaron J Schmitz ¹ , Michael J Rau ⁵ , James A J Fitzpatrick ⁶ , Pei-Yong Shi ⁷ , Michael S Diamond ⁸ , Sean P J Whelan ³ , Ali H Ellebedy ⁹ , Daved H Fremont ¹⁰



Affiliations

• PMID: 34655519
• DOI: 10.1016/j.celrep.2021.109881

Abstract

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 SARS-CoV-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.

Keywords: ACE2; COVID-19; RBD; SARS-CoV-2; antibody neutralization; biolayer interferometry; cryo-EM; spike; variants of concern.