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

Cell Reports

Jennifer R. Keeffe¹  Michel C. Nussenzweig¹  Kathryn E. Huey-Tubman²  Yu E. Lee²  Christopher O. Barnes²  Claudia A. Jette²  Alexander A. Cohen²  Priyanthi N.P. Gnanapragasam²  Pamela J. Bjorkman²  Anthony P. West, Jr.³  Paul D. Bieniasz⁴  Fabian Schmidt⁴  Frauke Muecksch⁴  Theodora Hatziioannou⁴ 

[1] Howard Hughes Medical Institute;Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA;Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA;Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA;

关键词: cryo-EM;    coronavirus;    neutralizing antibody;    receptor-binding domain;    sarbecovirus;    SARS-CoV-2;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown