Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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, Anne Brelot
Institutions: Centre National de la Recherche Scientifique, Institut Pasteur, Université Paris Cité, Biologie cellulaire physiologique et pathologique, Department of Virology, Department of Genomes & Genetics, Chimie Biologique pour le Vivant, Inserm, Pathogenèse des infections vasculaires, Biologie Moléculaire Structurale et Processus Infectieux, Institut de Recherche Vaccinale
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4416469286