PT  - JOURNAL ARTICLE
AU  - Claudia A. Jette
AU  - Alexander A. Cohen
AU  - Priyanthi N.P. Gnanapragasam
AU  - Frauke Muecksch
AU  - Yu E. Lee
AU  - Kathryn E. Huey-Tubman
AU  - Fabian Schmidt
AU  - Theodora Hatziioannou
AU  - Paul D. Bieniasz
AU  - Michel C. Nussenzweig
AU  - Anthony P. West, Jr.
AU  - Jennifer R. Keeffe
AU  - Pamela J. Bjorkman
AU  - Christopher O. Barnes
TI  - Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies
AID  - 10.1101/2021.04.23.441195
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.23.441195
4099  - http://biorxiv.org/content/early/2021/04/26/2021.04.23.441195.short
4100  - http://biorxiv.org/content/early/2021/04/26/2021.04.23.441195.full
AB  - 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 β-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.Competing Interest StatementThe Rockefeller University has filed provisional patent applications in connection with this work on which M.C.N. (US patent 63/021,387) is listed as an inventor.