Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base
- Author
- Sieglinde De Cae (UGent) , Inge Van Molle, Loes van Schie (UGent) , Sophie R. Shoemaker, Julie Deckers (UGent) , Nincy Debeuf (UGent) , Sahine Lameire (UGent) , Wim Nerinckx (UGent) , Kenny Roose (UGent) , Daria Fijalkowska (UGent) , Simon Devos (UGent) , Anne-Sophie De Smet (UGent) , Jackeline Cecilia Zavala Marchan (UGent) , Toon Venneman, Koen Sedeyn (UGent) , Lejla Mujanovic, Marlies Ballegeer (UGent) , Manon Vanheerswynghels (UGent) , Caroline De Wolf (UGent) , Hans Demol (UGent) , Jasper Zuallaert (UGent) , Pieter Vanhaverbeke (UGent) , Gholamreza Hassanzadeh Ghassabeh, Chiara Lonigro, Viki Bockstal, Manuela Rinaldi, Rana Abdelnabi, Johan Neyts, Susan Marqusee, Bart Lambrecht (UGent) , Nico Callewaert (UGent) , Han Remaut, Xavier Saelens (UGent) and Bert Schepens (UGent)
- Organization
- Project
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- Generation of potent, broadly betacoronavirus neutralizing antibody constructs
- Viral interference with RNA sensing and processing
- Prepared for SARS-CoV-3: advancing our understanding of SARS coronavirus antigenic and pathogenic evolution
- Antiviral mechanism and visualization of the interferon induced protein Mx1
- Prophylaxis of at risks persons with an ultrapotent SARS-CoV-2-neutralizing antibody
- Development and use of relevant hamster and mouse SARS-COV-2 infection models to aid in the design of therapeutic and prophylactic options for COVID-19
- 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.
- Keywords
- SARS-COV-2, AUTOPROC, EXCHANGE, REGION, SITES, HR2
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01K0Y9XR7PYRG04KSAN7CACSKA
- MLA
- De Cae, Sieglinde, et al. “Ultrapotent SARS Coronavirus-Neutralizing Single-Domain Antibodies That Clamp the Spike at Its Base.” NATURE COMMUNICATIONS, vol. 16, no. 1, 2025, doi:10.1038/s41467-025-60250-1.
- APA
- De Cae, S., Van Molle, I., van Schie, L., Shoemaker, S. R., Deckers, J., Debeuf, N., … Schepens, B. (2025). Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base. NATURE COMMUNICATIONS, 16(1). https://doi.org/10.1038/s41467-025-60250-1
- Chicago author-date
- De Cae, Sieglinde, Inge Van Molle, Loes van Schie, Sophie R. Shoemaker, Julie Deckers, Nincy Debeuf, Sahine Lameire, et al. 2025. “Ultrapotent SARS Coronavirus-Neutralizing Single-Domain Antibodies That Clamp the Spike at Its Base.” NATURE COMMUNICATIONS 16 (1). https://doi.org/10.1038/s41467-025-60250-1.
- Chicago author-date (all authors)
- De Cae, Sieglinde, 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 Lambrecht, Nico Callewaert, Han Remaut, Xavier Saelens, and Bert Schepens. 2025. “Ultrapotent SARS Coronavirus-Neutralizing Single-Domain Antibodies That Clamp the Spike at Its Base.” NATURE COMMUNICATIONS 16 (1). doi:10.1038/s41467-025-60250-1.
- Vancouver
- 1.De Cae S, Van Molle I, van Schie L, Shoemaker SR, Deckers J, Debeuf N, et al. Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base. NATURE COMMUNICATIONS. 2025;16(1).
- IEEE
- [1]S. De Cae et al., “Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base,” NATURE COMMUNICATIONS, vol. 16, no. 1, 2025.
@article{01K0Y9XR7PYRG04KSAN7CACSKA,
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.}},
articleno = {{5040}},
author = {{De Cae, Sieglinde and Van Molle, Inge and van Schie, Loes and Shoemaker, Sophie R. and Deckers, Julie and Debeuf, Nincy and Lameire, Sahine and Nerinckx, Wim and Roose, Kenny and Fijalkowska, Daria and Devos, Simon and De Smet, Anne-Sophie and Zavala Marchan, Jackeline Cecilia and Venneman, Toon and Sedeyn, Koen and Mujanovic, Lejla and Ballegeer, Marlies and Vanheerswynghels, Manon and De Wolf, Caroline and Demol, Hans and Zuallaert, Jasper and Vanhaverbeke, Pieter and Ghassabeh, Gholamreza Hassanzadeh and Lonigro, Chiara and Bockstal, Viki and Rinaldi, Manuela and Abdelnabi, Rana and Neyts, Johan and Marqusee, Susan and Lambrecht, Bart and Callewaert, Nico and Remaut, Han and Saelens, Xavier and Schepens, Bert}},
issn = {{2041-1723}},
journal = {{NATURE COMMUNICATIONS}},
keywords = {{SARS-COV-2,AUTOPROC,EXCHANGE,REGION,SITES,HR2}},
language = {{eng}},
number = {{1}},
pages = {{22}},
title = {{Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base}},
url = {{http://doi.org/10.1038/s41467-025-60250-1}},
volume = {{16}},
year = {{2025}},
}
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