Details

Autor(en) / Beteiligte

• Jette, Claudia A.
• Cohen, Alexander A.
• Gnanapragasam, Priyanthi N.P.
• Muecksch, Frauke
• Lee, Yu E.
• Huey-Tubman, Kathryn E.
• Schmidt, Fabian
• Hatziioannou, Theodora
• Bieniasz, Paul D.
• Nussenzweig, Michel C.
• West, Anthony P.
• Keeffe, Jennifer R.
• Bjorkman, Pamela J.
• Barnes, Christopher O.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2021-09, Vol.36 (13), p.109760-109760, Article 109760

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Donor-derived antibodies C118 and C022 recognize a highly conserved RBD epitope•Both antibodies cross-react and neutralize sarbecoviruses and SARS-CoV-2 VOCs•C118-RBD and C022-RBD crystal structures show long CDRH3s that extend RBD β sheet•C118-S cryo-EM structure suggests intra- and inter-spike crosslinking by C118 IgG Jette et al. characterize antibodies derived from convalescent COVID-19 donors that broadly recognize sarbecoviruses and neutralize ACE2-tropic strains, including all SARS-CoV-2 variants of concern. Structures reveal binding to a highly conserved RBD epitope using long CDRH3 loops, with an orientation that inhibits ACE2 binding to the RBD and allows IgG avidity.