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

Simon Blachier, Marie-Christine Vaney, Laurine Conquet, Isabelle Staropoli, Ignacio Fernández, Emilie Giraud, Atousa Arbabian, Vincent Michel, Fruzsina Szilagyi, Salomé Guez, Alix Boucharlat, Jeanne Chiaravalli, Jaouen Tran-Rajau, Evelyne Dufour, Ahmed Haouz, Stéphane Petres, Delphine Planas, Xavier Montagutelli, Fabrice Agou, Pierre Lafaye, Gabriel Ayme, Olivier Schwartz, Felix A. Rey, Jost Enninga and Anne Brelot ()
Additional contact information
Simon Blachier: CNRS UMR3691, Institut Pasteur, Université Paris Cité, Dynamics of Host-Pathogen Interactions Unit
Marie-Christine Vaney: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Structural Virology Unit
Laurine Conquet: Mouse Genetics Laboratory, Institut Pasteur, Université Paris Cité
Isabelle Staropoli: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Virus and Immunity Unit
Ignacio Fernández: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Structural Virology Unit
Emilie Giraud: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Atousa Arbabian: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Structural Virology Unit
Vincent Michel: INSERM U1225, Institut Pasteur, Université Paris Cité, Pathogenesis of Vascular Infections Unit
Fruzsina Szilagyi: CNRS UMR3691, Institut Pasteur, Université Paris Cité, Dynamics of Host-Pathogen Interactions Unit
Salomé Guez: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Alix Boucharlat: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Jeanne Chiaravalli: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Jaouen Tran-Rajau: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Evelyne Dufour: CNRS UMR3528, Institut Pasteur, Université Paris Cité, Production and Purification of recombinant Proteins Platform
Ahmed Haouz: CNRS UMR3528, Institut Pasteur, Université Paris Cité, Crystallography Platform-C2RT
Stéphane Petres: CNRS UMR3528, Institut Pasteur, Université Paris Cité, Production and Purification of recombinant Proteins Platform
Delphine Planas: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Virus and Immunity Unit
Xavier Montagutelli: Mouse Genetics Laboratory, Institut Pasteur, Université Paris Cité
Fabrice Agou: CNRS UMR3523, Institut Pasteur, Université Paris Cité, Chemogenomic and Biological Screening Core Facility, C2RT
Pierre Lafaye: CNRS UMR3528, Institut Pasteur, Université Paris Cité, Antibody Engineering Platform
Gabriel Ayme: CNRS UMR3528, Institut Pasteur, Université Paris Cité, Antibody Engineering Platform
Olivier Schwartz: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Virus and Immunity Unit
Felix A. Rey: CNRS UMR3569, Institut Pasteur, Université Paris Cité, Structural Virology Unit
Jost Enninga: CNRS UMR3691, Institut Pasteur, Université Paris Cité, Dynamics of Host-Pathogen Interactions Unit
Anne Brelot: CNRS UMR3691, Institut Pasteur, Université Paris Cité, Dynamics of Host-Pathogen Interactions Unit

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65144-w

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