Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies

Wang, Y.; Zhang, X.; Liu, J.; Zhan, W.; Liu, M.; Zhang, M.; Wang, Q.; Liu, Q.; Zhu, T.-Y.; Wen, Y.; Chen, Z.; Zhao, J.; Wu, F.; Sun, L.; Huang, J.

doi:10.1101/2022.01.30.478305

bioRxiv · 10.1101/2022.01.30.478305

Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies

Wang, Y.·Zhang, X.·Liu, J.·Zhan, W.·Liu, M.·Zhang, M.·Wang, Q.·Liu, Q.·Zhu, T.-Y.·Wen, Y.·Chen, Z.·Zhao, J.·Wu, F.·Sun, L.·Huang, J.

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Abstract

The highly mutated and transmissible Omicron variant has provoked serious concerns over its decreased sensitivity to the current coronavirus disease 2019 (COVID-19) vaccines and evasion from most anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs). In this study, we explored the possibility of combatting the Omicron variant by constructing bispecific antibodies based on non-Omicron NAbs. We engineered ten IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, eight out of ten bispecific antibodies showed high binding affinity to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron, as well as authentic Omicron(+R346K) variants. Six bispecific antibodies containing the cross-NAb GW01 neutralized Omicron variant and retained their abilities to neutralize other sarbecoviruses. Bispecific antibodies inhibited Omicron infection by binding to the ACE2 binding site. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody FD01 in complex with the Omicron spike (S) revealed 5 distinct trimers and one unique bi-trimer conformation. The structure and mapping analyses of 34 Omicron S variant single mutants elucidated that two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3-RBD-up conformation, enlarged the interface area, accommodated the S371L mutation, improved the affinity between a single IgG and the Omicron RBD, and hindered ACE2 binding by forming bi-trimer conformation. Our study offers an important foundation for anti-Omicron NAb design. Engineering bispecific antibodies based on non-Omicron NAbs may provide an efficient solution to combat the Omicron variant.

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Wang, Y., Zhang, X., Liu, J., Zhan, W., Liu, M., Zhang, M., Wang, Q., Liu, Q., Zhu, T.-Y., Wen, Y., Chen, Z., Zhao, J., Wu, F., Sun, L., Huang, J.. 2022-01-31. Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies. https://doi.org/10.1101/2022.01.30.478305

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