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

Sieglinde Cae, Inge Molle, Loes Schie, Sophie R. Shoemaker, Julie Deckers, Nincy Debeuf, Sahine Lameire, Wim Nerinckx, Kenny Roose, Daria Fijalkowska, Simon Devos, Anne-Sophie Smet, Jackeline Cecilia Zavala Marchan, Toon Venneman, Koen Sedeyn, Lejla Mujanovic, Marlies Ballegeer, Manon Vanheerswynghels, Caroline 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 () and Bert Schepens ()
Additional contact information
Sieglinde Cae: VIB
Inge Molle: VIB
Loes Schie: VIB
Sophie R. Shoemaker: University of California
Julie Deckers: VIB Center for Inflammation Research
Nincy Debeuf: VIB Center for Inflammation Research
Sahine Lameire: VIB Center for Inflammation Research
Wim Nerinckx: VIB
Kenny Roose: VIB
Daria Fijalkowska: VIB
Simon Devos: VIB
Anne-Sophie Smet: VIB
Jackeline Cecilia Zavala Marchan: VIB
Toon Venneman: ExeVir Bio BV
Koen Sedeyn: VIB
Lejla Mujanovic: VIB
Marlies Ballegeer: VIB
Manon Vanheerswynghels: VIB Center for Inflammation Research
Caroline Wolf: VIB Center for Inflammation Research
Hans Demol: VIB
Jasper Zuallaert: VIB
Pieter Vanhaverbeke: VIB
Gholamreza Hassanzadeh Ghassabeh: Vrije Universiteit Brussel
Chiara Lonigro: ExeVir Bio BV
Viki Bockstal: ExeVir Bio BV
Manuela Rinaldi: ExeVir Bio BV
Rana Abdelnabi: KU Leuven
Johan Neyts: KU Leuven
Susan Marqusee: University of California
Bart N. Lambrecht: VIB Center for Inflammation Research
Nico Callewaert: VIB
Han Remaut: VIB
Xavier Saelens: VIB
Bert Schepens: VIB

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60250-1

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