Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that bind a conserved membrane proximal epitope of the spike
De Cae, S.; Van Molle, I.; van Schie, L.; Shoemaker, S. R.; Deckers, J.; Debeuf, N.; Lameire, S.; Nerinckx, W.; Roose, K.; Fijalkowska, D.; Devos, S.; Desmet, A.-S.; Zavala Marchan, J. C.; Venneman, T.; Ghassabeh, G. H.; Sedeyn, K.; Ballegeer, M.; Vanheerswynghels, M.; De Wolf, C.; Demol, H.; Vanhaverbeke, P.; Lonigro, C.; Bockstal, V.; Rinaldi, M.; Abdelnabi, R.; Neyts, J.; Marqusee, S.; Lambrecht, B. N.; Callewaert, N.; Remaut, H.; Saelens, X.; Schepens, B.
Show abstract
Currently circulating SARS-CoV-2 variants have gained complete or significant resistance to all SARS-CoV-2-neutralizing antibodies that have been used in the clinic. Such antibodies can prevent severe disease in SARS-CoV-2 exposed patients for whom vaccines may not provide optimal protection. Here, we describe single-domain antibodies (VHHs), also known as nanobodies, that can broadly neutralize SARS-CoV-2 with unusually high potency. Structural analysis revealed their binding to a unique, highly conserved, membrane proximal, quaternary epitope in the S2 subunit of the spike. Furthermore, a VHH-human IgG1 Fc fusion, efficiently expressed in Chinese hamster ovary cells as a stable antibody construct, protected hamsters against SARS-CoV-2 replication in a therapeutic setting when administered systemically at low dose. This VHH-based antibody represents a new candidate anti-COVID-19 biologic that targets the Achilles heel of the viral spike.
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