Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

Rubio, A. A.; Baharani, V. A.; Dadonaite, B.; Parada, M.; Abernathy, M. E.; Wang, Z.; Lee, Y. E.; Eso, M.; Phung, J.; Ramos, I.; Chen, T.; El Nesr, G.; Bloom, J. D.; Bieniasz, P. D.; Nussenzweig, M. C.; Barnes, C. O.

doi:10.1101/2024.05.05.592584

bioRxiv · 10.1101/2024.05.05.592584

Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

Rubio, A. A.·Baharani, V. A.·Dadonaite, B.·Parada, M.·Abernathy, M. E.·Wang, Z.·Lee, Y. E.·Eso, M.·Phung, J.·Ramos, I.·Chen, T.·El Nesr, G.·Bloom, J. D.·Bieniasz, P. D.·Nussenzweig, M. C.·Barnes, C. O.

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Abstract

The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596s favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs. One Sentence SummaryBispecific antibodies with a highly cross-reactive NTD antibody demonstrate resilience to SARS-CoV-2 variants of concern.

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Rubio, A. A., Baharani, V. A., Dadonaite, B., Parada, M., Abernathy, M. E., Wang, Z., Lee, Y. E., Eso, M., Phung, J., Ramos, I., Chen, T., El Nesr, G., Bloom, J. D., Bieniasz, P. D., Nussenzweig, M. C., Barnes, C. O.. 2024-05-06. Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern. https://doi.org/10.1101/2024.05.05.592584

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