Magnus, Clara Luzia and Hiergeist, Andreas and Schuster, Philipp and Rohrhofer, Anette and Medenbach, Jan and Gessner, Andre and Peterhoff, David and Schmidt, Barbara (2022) Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab. FRONTIERS IN IMMUNOLOGY, 13: 966236. ISSN 1664-3224,
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Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of the viral receptor-binding domain with angiotensin-converting enzyme 2 (ACE2), while class 3 antibodies target a highly conserved epitope outside the ACE2 binding site. We aimed to investigate the plasticity of the spike protein by propagating wild-type SARS-CoV-2 in the presence of class 3 antibody S309. After 12 weeks, we obtained a viral strain that was completely resistant to inhibition by S309, due to successively evolving amino acid exchanges R346S and P337L located in the paratope of S309. The antibody lost affinity to receptor-binding domains carrying P337L or both amino acid exchanges, while ACE2 binding was not affected. The resistant strain replicated efficiently in human CaCo-2 cells and was more susceptible to inhibition of fusion than the original strain. Overall, SARS-CoV-2 escaped inhibition by class 3 antibody S309 through a slow, but targeted evolution enabling immune escape and altering cell entry. This immune-driven enhancement of infectivity and pathogenicity could play an important role in the future evolution of SARS-CoV-2, which is under increasing immunological pressure from vaccination and previous infections.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; SARS-CoV-2; receptor-binding domain; monoclonal antibody; sotrovimab; immune escape; entry; endocytosis; fusion |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Oct 2023 05:54 |
| Last Modified: | 17 Oct 2023 05:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/56467 |
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