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
  • 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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