Humanized antibody potently neutralizes all SARS-CoV-2 variants by a novel mechanism

Luo, S.; Zhang, J.; Kreutzberger, A. J. B.; Eaton, A.; Edwards, R. J.; Jing, C.; Dai, H.-Q.; Sempowski, G. D.; Cronin, K.; Parks, R.; Ye, A. Y.; Mansouri, K.; Barr, M.; Pishesha, N.; Williams, A. C.; Francisco, L. V.; Saminathan, A.; Peng, H.; Batra, H.; Bellusci, L.; Khurana, S.; Alam, S. M.; Montefiori, D. C.; Saunders, K. O.; Tian, M.; Ploegh, H.; Kirchhausen, T.; Chen, B.; Haynes, B. F.; Alt, F. W.

doi:10.1101/2022.06.26.497634

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bioRxiv · 10.1101/2022.06.26.497634

Humanized antibody potently neutralizes all SARS-CoV-2 variants by a novel mechanism

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Abstract

SARS-CoV-2 Omicron variants have generated a world-wide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of antibodies induced by vaccination. Here, we describe the SARS-CoV-2 neutralizing SP1-77 antibody that was generated from a humanized mouse model with a single human VH1-2 and V{kappa}1-33-associated with immensely diverse complementarity-determining-region-3 (CDR3) sequences. SP1-77 potently and broadly neutralizes SARS-CoV-2 variants of concern and binds the SARS-CoV-2 spike protein receptor-binding-domain (RBD) via a novel-CDR3-based mode. SP1-77 does not block RBD-binding to the ACE2-receptor or endocytosis step of viral entry, but rather blocks membrane fusion. Our findings provide the first mechanistic insight into how a non-ACE2 blocking antibody potently neutralizes SARS-CoV-2, which may inform strategies for designing vaccines that robustly neutralize current and future SARS-CoV-2 variants.

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Luo, S., Zhang, J., Kreutzberger, A. J. B., Eaton, A., Edwards, R. J., Jing, C., Dai, H.-Q., Sempowski, G. D., Cronin, K., Parks, R., Ye, A. Y., Mansouri, K., Barr, M., Pishesha, N., Williams, A. C., Francisco, L. V., Saminathan, A., Peng, H., Batra, H., Bellusci, L., Khurana, S., Alam, S. M., Montefiori, D. C., Saunders, K. O., Tian, M., Ploegh, H., Kirchhausen, T., Chen, B., Haynes, B. F., Alt, F. W.. 2022-06-26. Humanized antibody potently neutralizes all SARS-CoV-2 variants by a novel mechanism. https://doi.org/10.1101/2022.06.26.497634

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