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Nat Commun
. 2025 May 30;16(1):5040.
doi: 10.1038/s41467-025-60250-1. Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base
Sieglinde De Cae 1 2 , Inge Van Molle 3 4 , Loes van Schie 1 2 , Sophie R Shoemaker 5 , Julie Deckers 6 7 , Nincy Debeuf 6 7 , Sahine Lameire 6 7 , Wim Nerinckx 1 2 , Kenny Roose 1 2 , Daria Fijalkowska 1 2 , Simon Devos 1 2 , Anne-Sophie De Smet 1 2 , Jackeline Cecilia Zavala Marchan 1 2 , Toon Venneman 8 , Koen Sedeyn 1 2 , Lejla Mujanovic 1 2 , Marlies Ballegeer 1 2 , Manon Vanheerswynghels 6 7 , Caroline De Wolf 6 7 , Hans Demol 1 2 , Jasper Zuallaert 1 2 , Pieter Vanhaverbeke 1 2 , Gholamreza Hassanzadeh Ghassabeh 9 , Chiara Lonigro 8 , Viki Bockstal 8 , Manuela Rinaldi 8 , Rana Abdelnabi 10 11 , Johan Neyts 10 11 12 13 , Susan Marqusee 5 14 , Bart N Lambrecht 6 7 15 , Nico Callewaert 1 2 , Han Remaut 3 4 , Xavier Saelens 16 17 , Bert Schepens 18 19
Affiliations
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.
. 2025 May 30;16(1):5040.
doi: 10.1038/s41467-025-60250-1. Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base
Sieglinde De Cae 1 2 , Inge Van Molle 3 4 , Loes van Schie 1 2 , Sophie R Shoemaker 5 , Julie Deckers 6 7 , Nincy Debeuf 6 7 , Sahine Lameire 6 7 , Wim Nerinckx 1 2 , Kenny Roose 1 2 , Daria Fijalkowska 1 2 , Simon Devos 1 2 , Anne-Sophie De Smet 1 2 , Jackeline Cecilia Zavala Marchan 1 2 , Toon Venneman 8 , Koen Sedeyn 1 2 , Lejla Mujanovic 1 2 , Marlies Ballegeer 1 2 , Manon Vanheerswynghels 6 7 , Caroline De Wolf 6 7 , Hans Demol 1 2 , Jasper Zuallaert 1 2 , Pieter Vanhaverbeke 1 2 , Gholamreza Hassanzadeh Ghassabeh 9 , Chiara Lonigro 8 , Viki Bockstal 8 , Manuela Rinaldi 8 , Rana Abdelnabi 10 11 , Johan Neyts 10 11 12 13 , Susan Marqusee 5 14 , Bart N Lambrecht 6 7 15 , Nico Callewaert 1 2 , Han Remaut 3 4 , Xavier Saelens 16 17 , Bert Schepens 18 19
Affiliations
- PMID: 40447603
- PMCID: PMC12125293
- DOI: 10.1038/s41467-025-60250-1
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.