An affinity-enhanced, broadly neutralizing heavy chain–only antibody protects against SARS-CoV-2 infection in animal models

• DOI: 10.1126/scitranslmed.abi7826
• Publication Date: 2021-10-18T02:13:31Z
• Authors: Bert Schepens; Loes van Schie; Wim Nerinckx; Kenny Roose; Wander Van Breedam; Daria Fijalkowska; Simon Devos; Wannes Weyts; Sieglinde De Cae; Sandrine Vanmarcke; Chiara Lonigro; Hannah Eeckhaut; Dries Van Herpe; Jimmy Borloo; Ana Filipa Oliveira; João Paulo Portel...; Sarah Creytens; Dorien De Vlieger; Gitte Michielsen; Jackeline Cecilia...; George D. Moschonas; Iebe Rossey; Koen Sedeyn; Annelies Van Hecke; Xin Zhang; Lana Langendries; Sofie Jacobs; Sebastiaan ter Horst; Laura Seldeslachts; Laurens Liesenborghs; Robbert Boudewijns; Hendrik Jan Thibaut; Kai Dallmeier; Greetje Vande Velde; Birgit Weynand; Julius Beer; Daniel Schnepf; Annette Ohnemus; Isabel Remory; Caroline S. Foo; Rana Abdelnabi; Piet Maes; Suzanne J. F. Kap...; Joana Rocha-Pereira; Dirk Jochmans; Leen Delang; Frank Peelman; Peter Staeheli; Martin Schwemmle; Nick Devoogdt; Dominique Tersago; Massimiliano Germani; James Heads; Alistair Henry; Andrew Popplewell; Mark Ellis; Kevin Brady; Alison Turner; Bruno Dombrecht; Catelijne Stortelers; Johan Neyts; Nico Callewaert; Xavier Saelens
• Keywords: Coronavirus; Vero cell

Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Antibody-based therapeutics also essential pandemic preparedness against future Sarbecovirus outbreaks. Camelid-derived single domain (VHHs) exhibit potent antimicrobial activity and being developed as SARS-CoV-2–neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 SARS-CoV-2, including now circulating variants. We observed the bound to a highly conserved epitope in receptor binding of viral spike protein is difficult access human antibodies. Structure-guided molecular modeling, combined rapid yeast-based prototyping, resulted affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule subnanomolar activity. This VHH-Fc protein, produced purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication prophylactic therapeutic settings mice expressing angiotensin converting enzyme hamsters infected SARS-CoV-2. These data led affinity-enhanced selection VHH, XVR011, stable anti–COVID-19 biologic evaluated clinic.