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 Fijalkowska, Simon Devos, Wannes Weyts, Sieglinde De Cae, Sandrine Vanmarcke, Chiara Lonigro, Hannah Eeckhaut, Dries Van Herpe, Jimmy Borloo, Ana Filipa Oliveira, João Paulo Portela Catani, Sarah Creytens, Dorien De Vlieger, Gitte Michielsen, Jackeline Cecilia Zavala MarchanGeorge 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 Heads, Alistair Henry, Andrew Popplewell, Mark Ellis, Kevin Brady, Alison Turner, Bruno Dombrecht, Catelijne Stortelers, Johan Neyts, Nico Callewaert, Xavier Saelens

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Abstract

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 Sarbecovirus 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.

Original languageEnglish
Article numbereabi7826
JournalScience Translational Medicine
Volume13
Issue number621
ISSN1946-6234
DOIs
Publication statusPublished - 24-Nov-2021

Keywords

  • Animals
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19
  • Humans
  • Models, Animal
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus

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