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

• Published in: Science translational medicine Vol. 13; no. 621; p. eabi7826
• Main Authors: Schepens, Bert, van Schie, Loes, Nerinckx, Wim, Roose, Kenny, Van Breedam, Wander, Fijalkowska, Daria, Devos, Simon, Weyts, Wannes, De Cae, Sieglinde, Vanmarcke, Sandrine, Lonigro, Chiara, Eeckhaut, Hannah, Van Herpe, Dries, Borloo, Jimmy, Oliveira, Ana Filipa, Catani, João Paulo Portela, Creytens, Sarah, De Vlieger, Dorien, Michielsen, Gitte, Marchan, Jackeline Cecilia Zavala, Moschonas, George D, Rossey, Iebe, Sedeyn, Koen, Van Hecke, Annelies, Zhang, Xin, Langendries, Lana, Jacobs, Sofie, Ter Horst, Sebastiaan, Seldeslachts, Laura, Liesenborghs, Laurens, Boudewijns, Robbert, Thibaut, Hendrik Jan, Dallmeier, Kai, Velde, Greetje Vande, Weynand, Birgit, Beer, Julius, Schnepf, Daniel, Ohnemus, Annette, Remory, Isabel, Foo, Caroline S, Abdelnabi, Rana, Maes, Piet, Kaptein, Suzanne J F, Rocha-Pereira, Joana, Jochmans, Dirk, Delang, Leen, Peelman, Frank, Staeheli, Peter, Schwemmle, Martin, Devoogdt, Nick, Tersago, Dominique, Germani, Massimiliano, Heads, James, Henry, Alistair, Popplewell, Andrew, Ellis, Mark, Brady, Kevin, Turner, Alison, Dombrecht, Bruno, Stortelers, Catelijne, Neyts, Johan, Callewaert, Nico, Saelens, Xavier
• Format: Journal Article
• Language: English
• Published: United States 24-11-2021
• Subjects: Animals; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; Humans; Models, Animal; SARS-CoV-2; Spike Glycoprotein, Coronavirus
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abi7826

Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody-based therapeutics are also essential for pandemic preparedness against future
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.