Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Jette, C. A.; Cohen, A. A.; Gnanapragasam, P. N. P.; Muecksch, F.; Lee, Y. E.; Huey-Tubman, K. E.; Schmidt, F.; Hatziioannou, T.; Bieniasz, P. D.; Nussenzweig, M. C.; West, A. P.; Keeffe, J. R.; Bjorkman, P.; Barnes, C. O.

doi:10.1101/2021.04.23.441195

bioRxiv · 10.1101/2021.04.23.441195

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

Jette, C. A.·Cohen, A. A.·Gnanapragasam, P. N. P.·Muecksch, F.·Lee, Y. E.·Huey-Tubman, K. E.·Schmidt, F.·Hatziioannou, T.·Bieniasz, P. D.·Nussenzweig, M. C.·West, A. P.·Keeffe, J. R.·Bjorkman, P.·Barnes, C. O.

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Abstract

Many anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). The most potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. We characterized two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibited broad recognition and potent neutralization of zoonotic coronavirus and SARS-CoV-2 variants. C118-RBD and C022-RBD structures revealed CDRH3 mainchain H-bond interactions that extended an RBD {beta}-sheet, thus reducing sensitivity to RBD sidechain changes, and epitopes that extended from the cryptic epitope to occlude ACE2 binding. A C118-spike trimer structure revealed rotated RBDs to allow cryptic epitope access and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.

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Jette, C. A., Cohen, A. A., Gnanapragasam, P. N. P., Muecksch, F., Lee, Y. E., Huey-Tubman, K. E., Schmidt, F., Hatziioannou, T., Bieniasz, P. D., Nussenzweig, M. C., West, A. P., Keeffe, J. R., Bjorkman, P., Barnes, C. O.. 2021-04-26. Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies. https://doi.org/10.1101/2021.04.23.441195

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