Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo

The continuous emergence of antibody-escape variants of SARS-CoV-2 demands the identification of alternative methods of protection against infection that do not directly target viral proteins. Here, we generated heavy-chain-only antibody (VHHs) from an alpaca immunized with the human angiotensin-converting enzyme 2 (hACE2), the major entry receptor for SARS-CoV-2. The VHHs bind hACE2 without affecting its enzymatic activity, and two of them (B07 and B09) inhibit all SARS-CoV-2 isolates tested (Delta, BA.1, BQ1.1, XBB.1.5, XBB.1.16.1, EG.5.1.3, BA.2.86.1). Their X-ray structure in complex with hACE2 show that their epitope overlaps with the footprint of the receptor binding domain (RBD) of the SARS-CoV-2 spike on hACE2. A dimeric B07-Fc fusion construct avidly binds hACE2 with an apparent dissociation constant of 0.1 nM and inhibits in vitro infection of previously tested variants and, of JN.1.1 and KP.3.3 variants, with an IC50 ~ 1 nM. In vivo experiments using K18-hACE2 mice show that intranasal prophylactic administration of B07-Fc confer a dose-dependent protection against SARS-CoV-2 D614G and Omicron variants. These VHHs targeting hACE2 represent potential broad-spectrum therapeutic candidates against potential new emerging coronaviruses using hACE2 as a receptor.

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Publication Details

Journal
Nature Communications
Published
2025-11-21
DOI
https://doi.org/10.1038/s41467-025-65144-w
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo

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SARS-CoV-2 and COVID-19 Research
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Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo

Jaouen Tran-Rajau, Pierre Lafaye, Stéphane Pêtres, Émilie Giraud, Alix Boucharlat, Vincent Michel, Jost Enninga, Evelyne Dufour, Xavier Montagutelli, F.A. Rey, Delphine Planas, Laurine Conquet, Isabelle Staropoli, Ignacio Fernández, Olivier Schwartz, Fruzsina Szilagyi, Salomé Guez, Anne Brelot, M.C. Vaney, Jeanne Chiaravalli, Atousa Arbabian, Simon Blachier, Gabriel Aymé, Fabrice Agou, Ahmed Haouz
article en

Abstract

The continuous emergence of antibody-escape variants of SARS-CoV-2 demands the identification of alternative methods of protection against infection that do not directly target viral proteins. Here, we generated heavy-chain-only antibody (VHHs) from an alpaca immunized with the human angiotensin-converting enzyme 2 (hACE2), the major entry receptor for SARS-CoV-2. The VHHs bind hACE2 without affecting its enzymatic activity, and two of them (B07 and B09) inhibit all SARS-CoV-2 isolates tested (Delta, BA.1, BQ1.1, XBB.1.5, XBB.1.16.1, EG.5.1.3, BA.2.86.1). Their X-ray structure in complex with hACE2 show that their epitope overlaps with the footprint of the receptor binding domain (RBD) of the SARS-CoV-2 spike on hACE2. A dimeric B07-Fc fusion construct avidly binds hACE2 with an apparent dissociation constant of 0.1 nM and inhibits in vitro infection of previously tested variants and, of JN.1.1 and KP.3.3 variants, with an IC50 ~ 1 nM. In vivo experiments using K18-hACE2 mice show that intranasal prophylactic administration of B07-Fc confer a dose-dependent protection against SARS-CoV-2 D614G and Omicron variants. These VHHs targeting hACE2 represent potential broad-spectrum therapeutic candidates against potential new emerging coronaviruses using hACE2 as a receptor.

Nature CommunicationsVol. 16(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Institut Pasteur (FR), Université Paris Cité (FR), Institut de Recherche Vaccinale (FR)
Sanofi, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale
Openalex Percentile: Top 58%
SARS-CoV-2 and COVID-19 Research
DOIOpen Access PDFOpenAlex
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