A Novel Monoclonal Antibody Targeting a Large Surface of the Receptor Binding Motif Shows Pan-neutralizing SARS-CoV-2 Activity Including BQ.1.1 Variant

de Campos-Mata, L.; Trinite, B.; Modrego, A.; Tejedor Vaquero, S.; Pradenas, E.; Rodrigo Melero, N.; Carlero, D.; Marfil, S.; Pons-Grifols, A.; Bueno-Carrasco, M. T.; Santiago, C.; Tarres-Freixas, F.; Urrea, V.; Izquierdo, N.; Riveira-Munoz, E.; Ballana, E.; Perez, M.; Vergara-Alert, J.; Segales, J.; Carolis, C.; Arranz, R.; Blanco, J.; Magri, G.

doi:10.1101/2023.01.20.524748

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bioRxiv · 10.1101/2023.01.20.524748

A Novel Monoclonal Antibody Targeting a Large Surface of the Receptor Binding Motif Shows Pan-neutralizing SARS-CoV-2 Activity Including BQ.1.1 Variant

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Abstract

In the present study we report the functional and structural characterization of 17T2, a new highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody (mAb) isolated from a convalescent COVID-19 individual infected during the first wave of the COVID-19 pandemic. 17T2 is a class 1 VH1-58/{kappa}3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA memory B cell and developed as a human recombinant IgG1. Functional characterization revealed that 17T2 mAb has a high and exceptionally broad neutralizing activity against all SARS-CoV-2 spike variants tested, including BQ.1.1. Moreover, 17T2 mAb has in vivo prophylactic activity against Omicron BA.1.1 infection in K18-hACE2 transgenic mice. 3D reconstruction from cryogenic-electron microscopy (cryo-EM) showed that 17T2 binds the Omicron BA.1 spike protein with the RBD domains in "up" position and recognizes an epitope overlapping with the receptor binding motif, as it is the case for other structurally similar neutralizing mAbs, including S2E12. Yet, unlike S2E12, 17T2 retained its high neutralizing activity against all Omicron sublineages tested, probably due to a larger contact area with the RBD, which could confer a higher resilience to spike mutations. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 mAb as a potential candidate for future therapeutic and prophylactic interventions.

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de Campos-Mata, L., Trinite, B., Modrego, A., Tejedor Vaquero, S., Pradenas, E., Rodrigo Melero, N., Carlero, D., Marfil, S., Pons-Grifols, A., Bueno-Carrasco, M. T., Santiago, C., Tarres-Freixas, F., Urrea, V., Izquierdo, N., Riveira-Munoz, E., Ballana, E., Perez, M., Vergara-Alert, J., Segales, J., Carolis, C., Arranz, R., Blanco, J., Magri, G.. 2023-01-23. A Novel Monoclonal Antibody Targeting a Large Surface of the Receptor Binding Motif Shows Pan-neutralizing SARS-CoV-2 Activity Including BQ.1.1 Variant. https://doi.org/10.1101/2023.01.20.524748

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