tetano
Editor, Senior Moderator
Cell Rep
. 2021 Sep 8;109760.
doi: 10.1016/j.celrep.2021.109760. Online ahead of print.
Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies
Claudia A Jette[SUP] 1 [/SUP], Alexander A Cohen[SUP] 1 [/SUP], Priyanthi N P Gnanapragasam[SUP] 1 [/SUP], Frauke Muecksch[SUP] 2 [/SUP], Yu E Lee[SUP] 1 [/SUP], Kathryn E Huey-Tubman[SUP] 1 [/SUP], Fabian Schmidt[SUP] 2 [/SUP], Theodora Hatziioannou[SUP] 2 [/SUP], Paul D Bieniasz[SUP] 3 [/SUP], Michel C Nussenzweig[SUP] 4 [/SUP], Anthony P West Jr[SUP] 1 [/SUP], Jennifer R Keeffe[SUP] 1 [/SUP], Pamela J Bjorkman[SUP] 5 [/SUP], Christopher O Barnes[SUP] 6 [/SUP]
Affiliations
Abstract
Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). 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 they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD β sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope 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.
Keywords: SARS-CoV-2; Spike trimer: structural biology; coronavirus; cryo-EM; neutralizing antibody; receptor-binding domain; sarbecovirus; virology: X-ray crystallography.
. 2021 Sep 8;109760.
doi: 10.1016/j.celrep.2021.109760. Online ahead of print.
Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies
Claudia A Jette[SUP] 1 [/SUP], Alexander A Cohen[SUP] 1 [/SUP], Priyanthi N P Gnanapragasam[SUP] 1 [/SUP], Frauke Muecksch[SUP] 2 [/SUP], Yu E Lee[SUP] 1 [/SUP], Kathryn E Huey-Tubman[SUP] 1 [/SUP], Fabian Schmidt[SUP] 2 [/SUP], Theodora Hatziioannou[SUP] 2 [/SUP], Paul D Bieniasz[SUP] 3 [/SUP], Michel C Nussenzweig[SUP] 4 [/SUP], Anthony P West Jr[SUP] 1 [/SUP], Jennifer R Keeffe[SUP] 1 [/SUP], Pamela J Bjorkman[SUP] 5 [/SUP], Christopher O Barnes[SUP] 6 [/SUP]
Affiliations
- PMID: 34534459
- PMCID: PMC8423902
- DOI: 10.1016/j.celrep.2021.109760
Abstract
Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). 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 they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD β sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope 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.
Keywords: SARS-CoV-2; Spike trimer: structural biology; coronavirus; cryo-EM; neutralizing antibody; receptor-binding domain; sarbecovirus; virology: X-ray crystallography.