An affinity-enhanced, broadly neutralizing heavy chain–only antibody protects against SARS-CoV-2 infection in animal models
Bert Schepens, Loes van Schie, Wim Nerinckx, Kenny Roose, Wander Van Breedam, Daria Fijałkowska, Simon Devos, Wannes Weyts, Sieglinde De, Sandrine Vanmarcke, Chiara Lonigro, Hannah Eeckhaut, Dries Van Herpe, Jimmy Borloo, ANDREZA ESTEFANY DA SILVA OLIVEIRA, João Paulo Portela Catani, Sarah Creytens, Dorien De Vlieger, Gitte Michielsen, Jackeline Cecilia Zavala Marchan, 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. Kaptein, Joana Rocha‐Pereira, Dirk Jochmans, Leen Delang, Frank Peelman, Peter Staeheli, Martin Schwemmle, Nick Devoogdt, Dominique Tersago, Massimiliano Germani, James T. Heads, Alistair J. Henry, Andrew G. Popplewell, Mark Ellis, Kevin Brady, Alison Turner, Bruno Dombrecht, Catelijne Stortelers, Johan Neyts, Nico Callewaert, Xavier Saelens
Abstract
outbreaks. Camelid-derived single domain antibodies (VHHs) exhibit potent antimicrobial activity and are being developed as SARS-CoV-2–neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 and SARS-CoV-2, including now circulating variants. We observed that the VHHs bound to a highly conserved epitope in the receptor binding domain of the viral spike protein that is difficult to access for human antibodies. Structure-guided molecular modeling, combined with rapid yeast-based prototyping, resulted in an affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule with subnanomolar neutralizing activity. This VHH-Fc fusion protein, produced in and purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication in prophylactic and therapeutic settings in mice expressing human angiotensin converting enzyme 2 and in hamsters infected with SARS-CoV-2. These data led to affinity-enhanced selection of the VHH, XVR011, a stable anti–COVID-19 biologic that is now being evaluated in the clinic.