Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base

Abstract Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previou...

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Main Authors: Sieglinde De Cae, Inge Van Molle, Loes van Schie, Sophie R. Shoemaker, Julie Deckers, Nincy Debeuf, Sahine Lameire, Wim Nerinckx, Kenny Roose, Daria Fijalkowska, Simon Devos, Anne-Sophie De Smet, Jackeline Cecilia Zavala Marchan, Toon Venneman, Koen Sedeyn, Lejla Mujanovic, Marlies Ballegeer, Manon Vanheerswynghels, Caroline De Wolf, Hans Demol, Jasper Zuallaert, Pieter Vanhaverbeke, Gholamreza Hassanzadeh Ghassabeh, Chiara Lonigro, Viki Bockstal, Manuela Rinaldi, Rana Abdelnabi, Johan Neyts, Susan Marqusee, Bart N. Lambrecht, Nico Callewaert, Han Remaut, Xavier Saelens, Bert Schepens
Format: Article
Language:English
Published: Nature Portfolio 2025-05-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60250-1
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Summary:Abstract Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and −2 with unusually high potency. One of these VHHs tightly clamps the spike’s monomers at a highly conserved, quaternary epitope in the membrane proximal part of the trimeric Heptad Repeat 2 (HR2) coiled-coil, thereby locking the HR2 in its prefusion conformation. Low dose systemic administration of a VHH-human IgG1 Fc fusion prevented SARS-CoV-2 infection in two animal models. Pseudovirus escape selection experiments demonstrate that the very rare escape variants are rendered almost non-infectious. This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins.
ISSN:2041-1723

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