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

• DOI: 10.1016/j.celrep.2021.109881
• Publication Date: 2021-10-09T14:16:19Z
• Authors: John M. Errico; Haiyan Zhao; Rita E. Chen; Zhuoming Liu; James Brett Case; Meisheng Ma; Aaron J. Schmitz; Michael J. Rau; James A.J. Fitzpa...; Pei-Yong Shi; Michael S. Diamond; Sean P.J. Whelan; Ali H. Ellebedy; Daved H. Fremont
• Keywords: HEK 293 cells; Coronavirus

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 spike protein, revealing similarities between epitopes targeted by human B cells. more neutralizing mAb, 2B04, binds receptor-binding motif (RBM) domain (RBD) competes angiotensin-converting enzyme (ACE2). By contrast, 2H04 adjacent RBM does not compete for ACE2 binding. Naturally occurring sequence variants SARS-CoV-2 corresponding neutralization escape selected vitro map our structurally defined epitopes, suggesting that might evade therapeutic a limited set mutations, underscoring importance combination mAb therapeutics. Finally, show 2B04 neutralizes infection preventing engagement, whereas reduces host cell attachment without directly disrupting ACE2-RBM interactions, providing distinct inhibitory mechanisms used RBD-specific mAbs.