EBioMedicine (Feb 2024)
Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline: caution is warrantedResearch in context
- Delphine Diana Acar,
- Wojciech Witkowski,
- Magdalena Wejda,
- Ruifang Wei,
- Tim Desmet,
- Bert Schepens,
- Sieglinde De Cae,
- Koen Sedeyn,
- Hannah Eeckhaut,
- Daria Fijalkowska,
- Kenny Roose,
- Sandrine Vanmarcke,
- Anne Poupon,
- Dirk Jochmans,
- Xin Zhang,
- Rana Abdelnabi,
- Caroline S. Foo,
- Birgit Weynand,
- Dirk Reiter,
- Nico Callewaert,
- Han Remaut,
- Johan Neyts,
- Xavier Saelens,
- Sarah Gerlo,
- Linos Vandekerckhove
Affiliations
- Delphine Diana Acar
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- Wojciech Witkowski
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- Magdalena Wejda
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- Ruifang Wei
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- Tim Desmet
- Department of Basic and Applied Medical Sciences, Ghent University, Ghent 9000, Belgium
- Bert Schepens
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Sieglinde De Cae
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Koen Sedeyn
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Hannah Eeckhaut
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Daria Fijalkowska
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Kenny Roose
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Sandrine Vanmarcke
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Anne Poupon
- MAbSilico, Tours 37000, France
- Dirk Jochmans
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
- Xin Zhang
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
- Rana Abdelnabi
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
- Caroline S. Foo
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
- Birgit Weynand
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven 3000, Belgium
- Dirk Reiter
- Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Nico Callewaert
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Han Remaut
- Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels 1050, Belgium; VIB-VUB Center for Structural Biology, VIB, Brussels 1050, Belgium
- Johan Neyts
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium
- Xavier Saelens
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent 9052, Belgium
- Sarah Gerlo
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium
- Linos Vandekerckhove
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent 9000, Belgium; Corresponding author.
- Journal volume & issue
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Vol. 100
p. 104960
Abstract
Summary: Background: SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This underscored the imperative to develop nAB cocktails targeting non-overlapping epitopes. Methods: Undertaking a nAB discovery program, we employed a classical workflow, while integrating artificial intelligence (AI)-based prediction to select non-competing nABs very early in the pipeline. We identified and in vivo validated (in female Syrian hamsters) two highly potent nABs. Findings: Despite the promising results, in depth cryo-EM structural analysis demonstrated that the AI-based prediction employed with the intention to ensure non-overlapping epitopes was inaccurate. The two nABs in fact bound to the same receptor-binding epitope in a remarkably similar manner. Interpretation: Our findings indicate that, even in the Alphafold era, AI-based predictions of paratope-epitope interactions are rough and experimental validation of epitopes remains an essential cornerstone of a successful nAB lead selection. Funding: Full list of funders is provided at the end of the manuscript.
