Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Wu, J.; Chen, Z.; Gao, Y.; Wang, Z.; Wang, J.; Chiang, B.-Y.; Zhou, Y.; Han, Y.; Zhan, W.; Xie, M.; Jiang, W.; Zhang, X.; Hao, A.; Xia, A.; He, J.; Xue, S.; Mayer, C. T.; Wu, F.; Wang, B.; Zhang, L.; Sun, L.; Wang, Q.

doi:10.1101/2022.12.12.520172

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bioRxiv · 10.1101/2022.12.12.520172

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

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Abstract

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

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Wu, J., Chen, Z., Gao, Y., Wang, Z., Wang, J., Chiang, B.-Y., Zhou, Y., Han, Y., Zhan, W., Xie, M., Jiang, W., Zhang, X., Hao, A., Xia, A., He, J., Xue, S., Mayer, C. T., Wu, F., Wang, B., Zhang, L., Sun, L., Wang, Q.. 2022-12-13. Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants. https://doi.org/10.1101/2022.12.12.520172

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