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

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

  • Sci Transl Med. 2021 Nov 24;13(621):eabi7826. doi: 10.1126/scitranslmed.abi7826.
Bert Schepens 1 2,  Loes van Schie 1 2,  Wim Nerinckx 1 2,  Kenny Roose 1 2,  Wander Van Breedam 1 2,  Daria Fijalkowska 1 2,  Simon Devos 1 2,  Wannes Weyts 1 2,  Sieglinde De Cae 1 2,  Sandrine Vanmarcke 1 2,  Chiara Lonigro 1 2,  Hannah Eeckhaut 1 2,  Dries Van Herpe 1 2,  Jimmy Borloo 3,  Ana Filipa Oliveira 3,  João Paulo Portela Catani 1 2,  Sarah Creytens 1 2,  Dorien De Vlieger 1 2,  Gitte Michielsen 1 2,  Jackeline Cecilia Zavala Marchan 1 2,  George D Moschonas 1 2,  Iebe Rossey 1 2,  Koen Sedeyn 1 2,  Annelies Van Hecke 1 2,  Xin Zhang 4 5,  Lana Langendries 4 5,  Sofie Jacobs 4 5,  Sebastiaan Ter Horst 4 5,  Laura Seldeslachts 6,  Laurens Liesenborghs 4 5,  Robbert Boudewijns 4 5 7,  Hendrik Jan Thibaut 4 7 8,  Kai Dallmeier 4 5 7,  Greetje Vande Velde 6,  Birgit Weynand 9,  Julius Beer 10,  Daniel Schnepf 10,  Annette Ohnemus 10,  Isabel Remory 11,  Caroline S Foo 4,  Rana Abdelnabi 4 5,  Piet Maes 12,  Suzanne J F Kaptein 4 5,  Joana Rocha-Pereira 4 5,  Dirk Jochmans 4 5,  Leen Delang 4 5,  Frank Peelman 1 13,  Peter Staeheli 10 14,  Martin Schwemmle 10 14,  Nick Devoogdt 11,  Dominique Tersago 15,  Massimiliano Germani 16,  James Heads 16,  Alistair Henry 16,  Andrew Popplewell 16,  Mark Ellis 16,  Kevin Brady 16,  Alison Turner 16,  Bruno Dombrecht 3,  Catelijne Stortelers 3,  Johan Neyts 4 5 7,  Nico Callewaert 1 2,  Xavier Saelens 1 2
Affiliations

Affiliations

  • 1 VIB-UGent Center for Medical Biotechnology, VIB, Technologiepark-Zwijnaarde 75, 9052 Ghent, Belgium.
  • 2 Department of Biochemistry and Microbiology, Ghent University, Technologiepark-Zwijnaarde 75, 9052 Ghent, Belgium.
  • 3 VIB Discovery Sciences, Technologiepark-Zwijnaarde 104B, 9052 Ghent, Belgium.
  • 4 KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, 3000 Leuven, Belgium.
  • 5 GVN, Global Virus Network, Baltimore, MD 21201, USA.
  • 6 KU Leuven Department of Imaging and Pathology, Biomedical MRI and MoSAIC, 3000 Leuven, Belgium.
  • 7 KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Molecular Vaccinology and Vaccine Discovery Group, 3000 Leuven, Belgium.
  • 8 KU Leuven Department of Microbiology, Immunology and Transplantation, Translational Platform Virology and Chemotherapy (TPVC), Rega Institute, 3000 Leuven, Belgium.
  • 9 KU Leuven Department of Imaging and Pathology, Division of Translational Cell and Tissue Research, Translational Cell and Tissue Research, 3000 Leuven, Belgium.
  • 10 Institute of Virology, Medical Center University Freiburg, 79104 Freiburg, Germany.
  • 11 Department of Medical Imaging, In vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
  • 12 KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, 3000 Leuven, Belgium.
  • 13 Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
  • 14 Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany.
  • 15 ExeVir, Rijvisschestraat 120, 9052 Ghent, Belgium.
  • 16 UCB Celltech, Slough, SL1 3WE, UK.
PMID: 34609205 DOI: 10.1126/scitranslmed.abi7826
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.

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