Cell
Volume 185, Issue 8, 14 April 2022, Pages 1389-1401.e18
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Article
Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

https://doi.org/10.1016/j.cell.2022.03.009Get rights and content
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Highlights

  • Conserved epitopes outside of the RBM of SARS-CoV-2 spike RBD

  • A bispecific single-domain antibody (bn03) broadly neutralizes SARS-CoV-2 variants

  • Two arms of bn03 can bind simultaneously and synergistically to one RBD of spike trimer

  • Inhalation of bn03 can effectively treat SARS-CoV-2 infection in hACE2 mice

Summary

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Keywords

SARS-CoV-2
single-domain antibody
bispecific antibody
broad neutralization
inhalation

Data and code availability

The cryo-EM map and the coordinates of SARS-CoV-2 Omicron S complexed with bn03 have been deposited to the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under the accession codes under accession code PDB: 7WHJ, 7WHI, and 7WHK and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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5

These authors contributed equally

6

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