tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Inge Van Molle[SUP] 3 4 [/SUP], Loes van Schie[SUP] 1 2 [/SUP], Sophie R Shoemaker[SUP] 5 [/SUP], Julie Deckers[SUP] 6 7 [/SUP], Nincy Debeuf[SUP] 6 7 [/SUP], Sahine Lameire[SUP] 6 7 [/SUP], Wim Nerinckx[SUP] 1 2 [/SUP], Kenny Roose[SUP] 1 2 [/SUP], Daria Fijalkowska[SUP] 1 2 [/SUP], Simon Devos[SUP] 1 2 [/SUP], Anne-Sophie De Smet[SUP] 1 2 [/SUP], Jackeline Cecilia Zavala Marchan[SUP] 1 2 [/SUP], Toon Venneman[SUP] 8 [/SUP], Koen Sedeyn[SUP] 1 2 [/SUP], Lejla Mujanovic[SUP] 1 2 [/SUP], Marlies Ballegeer[SUP] 1 2 [/SUP], Manon Vanheerswynghels[SUP] 6 7 [/SUP], Caroline De Wolf[SUP] 6 7 [/SUP], Hans Demol[SUP] 1 2 [/SUP], Jasper Zuallaert[SUP] 1 2 [/SUP], Pieter Vanhaverbeke[SUP] 1 2 [/SUP], Gholamreza Hassanzadeh Ghassabeh[SUP] 9 [/SUP], Chiara Lonigro[SUP] 8 [/SUP], Viki Bockstal[SUP] 8 [/SUP], Manuela Rinaldi[SUP] 8 [/SUP], Rana Abdelnabi[SUP] 10 11 [/SUP], Johan Neyts[SUP] 10 11 12 13 [/SUP], Susan Marqusee[SUP] 5 14 [/SUP], Bart N Lambrecht[SUP] 6 7 15 [/SUP], Nico Callewaert[SUP] 1 2 [/SUP], Han Remaut[SUP] 3 4 [/SUP], Xavier Saelens[SUP] 16 17 [/SUP], Bert Schepens[SUP] 18 19 [/SUP]
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[SUP] 1 2 [/SUP], Inge Van Molle[SUP] 3 4 [/SUP], Loes van Schie[SUP] 1 2 [/SUP], Sophie R Shoemaker[SUP] 5 [/SUP], Julie Deckers[SUP] 6 7 [/SUP], Nincy Debeuf[SUP] 6 7 [/SUP], Sahine Lameire[SUP] 6 7 [/SUP], Wim Nerinckx[SUP] 1 2 [/SUP], Kenny Roose[SUP] 1 2 [/SUP], Daria Fijalkowska[SUP] 1 2 [/SUP], Simon Devos[SUP] 1 2 [/SUP], Anne-Sophie De Smet[SUP] 1 2 [/SUP], Jackeline Cecilia Zavala Marchan[SUP] 1 2 [/SUP], Toon Venneman[SUP] 8 [/SUP], Koen Sedeyn[SUP] 1 2 [/SUP], Lejla Mujanovic[SUP] 1 2 [/SUP], Marlies Ballegeer[SUP] 1 2 [/SUP], Manon Vanheerswynghels[SUP] 6 7 [/SUP], Caroline De Wolf[SUP] 6 7 [/SUP], Hans Demol[SUP] 1 2 [/SUP], Jasper Zuallaert[SUP] 1 2 [/SUP], Pieter Vanhaverbeke[SUP] 1 2 [/SUP], Gholamreza Hassanzadeh Ghassabeh[SUP] 9 [/SUP], Chiara Lonigro[SUP] 8 [/SUP], Viki Bockstal[SUP] 8 [/SUP], Manuela Rinaldi[SUP] 8 [/SUP], Rana Abdelnabi[SUP] 10 11 [/SUP], Johan Neyts[SUP] 10 11 12 13 [/SUP], Susan Marqusee[SUP] 5 14 [/SUP], Bart N Lambrecht[SUP] 6 7 15 [/SUP], Nico Callewaert[SUP] 1 2 [/SUP], Han Remaut[SUP] 3 4 [/SUP], Xavier Saelens[SUP] 16 17 [/SUP], Bert Schepens[SUP] 18 19 [/SUP]
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.