Cell Host & Microbe
Volume 30, Issue 6, 8 June 2022, Pages 887-895.e4
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Short Article
35B5 antibody potently neutralizes SARS-CoV-2 Omicron by disrupting the N-glycan switch via a conserved spike epitope

https://doi.org/10.1016/j.chom.2022.03.035Get rights and content
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Highlights

  • 35B5 antibody exhibits nanomolar neutralizing efficacy to SARS-CoV-2 Omicron

  • 35B5 targets the Omicron RBD via an invariant epitope

  • The 35B5 epitope is essential for ACE2 binding and RBD conformational dynamics

  • 35B5 displaces the conserved N-glycan switch from the RBD

Summary

The SARS-CoV-2 Omicron variant harbors more than 30 mutations in the spike protein, leading to immune evasion from many therapeutic neutralizing antibodies. We reveal that a receptor-binding domain (RBD)-targeting monoclonal antibody, 35B5, exhibits potent neutralizing efficacy to Omicron. Cryo-electron microscopy structures of the extracellular domain trimer of Omicron spike with 35B5 Fab reveal that Omicron spike exhibits tight trimeric packing and high thermostability, as well as significant antigenic shifts and structural changes, within the RBD, N-terminal domain (NTD), and subdomains 1 and 2. However, these changes do not affect targeting of the invariant 35B5 epitope. 35B5 potently neutralizes SARS-CoV-2 Omicron and other variants by causing significant conformational changes within a conserved N-glycan switch that controls the transition of RBD from the “down” state to the “up” state, which allows recognition of the host entry receptor ACE2. This mode of action and potent neutralizing capacity of 35B5 indicate its potential therapeutic application for SARS-CoV-2.

Keywords

SARS-CoV-2
Omicron
monoclonal antibody
neutralization
spike protein
RBD
35B5
antigenic shift
glycan
dissociation

Data and code availability

  • The cryo-EM map and coordinates have been deposited in the Electron Microscopy Data Bank and Protein Data Bank under accession numbers PDB: 7WLY and EMBD: EMD-32594 (Omicron S-ECD-35B5 Fab [1 down- and 2 up-RBDs]), PDB: 7WLZ and EMBD: EMD-32595 (Omicron S-ECD-35B5 Fab [1 up-, 1 down-, and 1 invisible up-RBD]), and PDB: 7WM0 and EMBD: EMD-32596 (Omicron RBD-35B5 Fab [local refinement]).

  • This paper does not report any original code.

  • Any additional information required for reanalyzing the data reported in this work paper is available from the lead contact upon request.

Cited by (0)

10

These authors contributed equally

11

Lead contact