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Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies.
<div class='caption-title'>C118 and C022 show diverse binding and neutralization of sarbecoviruses</div>
<div class='caption-title'>Crystal structures of C022 and C118 Fabs bound to RBDs reveal class 4-like RBD binding</div>
Jette CA, Cohen AA, Gnanapragasam PNP, Muecksch F, Lee YE, Huey-Tubman KE, Schmidt F, Hatziioannou T, Bieniasz PD, Nussenzweig MC, West AP, Keeffe JR, Bjorkman PJ, Barnes CO
OpenAccess logo Cell Rep 36 109760 (2021)
Related entries: 7rks, 7rku

Cited: 62 times
EuropePMC logo PMID: 34534459

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.

Reviews - 7rkv mentioned but not cited (1)

  1. Emerging mutations in the SARS-CoV-2 variants and their role in antibody escape to small molecule-based therapeutic resistance. Chakraborty C, Bhattacharya M, Sharma AR. Curr Opin Pharmacol 62 64-73 (2022)

Articles - 7rkv mentioned but not cited (8)

  1. Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models. Cohen AA, van Doremalen N, Greaney AJ, Andersen H, Sharma A, Starr TN, Keeffe JR, Fan C, Schulz JE, Gnanapragasam PNP, Kakutani LM, West AP, Saturday G, Lee YE, Gao H, Jette CA, Lewis MG, Tan TK, Townsend AR, Bloom JD, Munster VJ, Bjorkman PJ. Science 377 eabq0839 (2022)
  2. Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies. Jette CA, Cohen AA, Gnanapragasam PNP, Muecksch F, Lee YE, Huey-Tubman KE, Schmidt F, Hatziioannou T, Bieniasz PD, Nussenzweig MC, West AP, Keeffe JR, Bjorkman PJ, Barnes CO. Cell Rep 36 109760 (2021)
  3. Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes. Fan C, Cohen AA, Park M, Hung AF, Keeffe JR, Gnanapragasam PNP, Lee YE, Gao H, Kakutani LM, Wu Z, Kleanthous H, Malecek KE, Williams JC, Bjorkman PJ. Immunity 55 2419-2435.e10 (2022)
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  6. Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals. Cohen AA, Keeffe JR, Schiepers A, Dross SE, Greaney AJ, Rorick AV, Gao H, Gnanapragasam PNP, Fan C, West AP, Ramsingh AI, Erasmus JH, Pata JD, Muramatsu H, Pardi N, Lin PJC, Baxter S, Cruz R, Quintanar-Audelo M, Robb E, Serrano-Amatriain C, Magneschi L, Fotheringham IG, Fuller DH, Victora GD, Bjorkman PJ. bioRxiv 2024.02.08.576722 (2024)
  7. research-article SARS-CoV-2 spike glycosylation affects function and neutralization sensitivity. Zhang F, Schmidt F, Muecksch F, Wang Z, Gazumyan A, Nussenzweig MC, Gaebler C, Caskey M, Hatziioannou T, Bieniasz PD. bioRxiv 2023.06.30.547241 (2023)
  8. SARS-CoV-2 spike glycosylation affects function and neutralization sensitivity. Zhang F, Schmidt F, Muecksch F, Wang Z, Gazumyan A, Nussenzweig MC, Gaebler C, Caskey M, Hatziioannou T, Bieniasz PD. mBio 15 e0167223 (2024)


Reviews citing this publication (11)

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Articles citing this publication (42)

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