The effectiveness of SARS-CoV-2 therapeutic antibodies targeting the spike (S) receptor-binding domain (RBD) has been hampered by the emergence of variants of concern (VOCs), which have acquired mutations to escape neutralizing antibodies (nAbs). These mutations are not evenly distributed on the RBD surface but cluster on several distinct surfaces, suggesting an influence of the targeted epitope on the capacity to neutralize a broad range of VOCs. Here, we identified a potent nAb from convalescent patients targeting the receptor-binding domain of a broad range of SARS-CoV-2 VOCs. Except for the Lambda and BA.2.86 variants, this nAb efficiently inhibited the entry of most tested VOCs, including Omicron subvariants BA.1, BA.2, XBB.1.5, and EG.5.1 and to a limited extent also BA.4/5, BA.4.6, and BQ.1.1. It bound recombinant S protein with picomolar affinity, reduced the viral load in the lung of infected hamsters, and prevented the severe lung pathology typical for SARS-CoV-2 infections. An X-ray structure of the nAb-RBD complex revealed an epitope that does not fall into any of the conventional classes and provided insights into its broad neutralization properties. Our findings highlight a conserved epitope within the SARS-CoV-2 RBD that should be preferably targeted by therapeutic antibodies and inform rational vaccine development.
A human monoclonal antibody neutralizing SARS-CoV-2 Omicron variants containing the L452R mutation / Stein, S. C.; Hansen, G.; Ssebyatika, G.; Stroh, L. J.; Ochulor, O.; Herold, E.; Schwarzloh, B.; Mutschall, D.; Zischke, J.; Cordes, A. K.; Schneider, T.; Hinrichs, I.; Blasczyk, R.; Kleine-Weber, H.; Hoffmann, M.; Klein, F.; Kaiser, F. K.; Gonzalez-Hernandez, M.; Armando, F.; Ciurkiewicz, M.; Beythien, G.; Pohlmann, S.; Baumgartner, W.; Osterhaus, A.; Schulz, T. F.; Krey, T.. - In: JOURNAL OF VIROLOGY. - ISSN 0022-538X. - 98:12(2024). [10.1128/jvi.01223-24]
A human monoclonal antibody neutralizing SARS-CoV-2 Omicron variants containing the L452R mutation
Armando F.;
2024-01-01
Abstract
The effectiveness of SARS-CoV-2 therapeutic antibodies targeting the spike (S) receptor-binding domain (RBD) has been hampered by the emergence of variants of concern (VOCs), which have acquired mutations to escape neutralizing antibodies (nAbs). These mutations are not evenly distributed on the RBD surface but cluster on several distinct surfaces, suggesting an influence of the targeted epitope on the capacity to neutralize a broad range of VOCs. Here, we identified a potent nAb from convalescent patients targeting the receptor-binding domain of a broad range of SARS-CoV-2 VOCs. Except for the Lambda and BA.2.86 variants, this nAb efficiently inhibited the entry of most tested VOCs, including Omicron subvariants BA.1, BA.2, XBB.1.5, and EG.5.1 and to a limited extent also BA.4/5, BA.4.6, and BQ.1.1. It bound recombinant S protein with picomolar affinity, reduced the viral load in the lung of infected hamsters, and prevented the severe lung pathology typical for SARS-CoV-2 infections. An X-ray structure of the nAb-RBD complex revealed an epitope that does not fall into any of the conventional classes and provided insights into its broad neutralization properties. Our findings highlight a conserved epitope within the SARS-CoV-2 RBD that should be preferably targeted by therapeutic antibodies and inform rational vaccine development.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.