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.
【저자키워드】 neutralizing antibody, SARS-CoV-2, coronavirus, Receptor-binding domain, cryo-EM, Spike trimer: structural biology, sarbecovirus, virology: X-ray crystallography., 【초록키워드】 COVID-19, coronavirus disease, neutralizing antibody, Structure, Coronavirus disease 2019, ACE2, coronavirus, Virology, Neutralizing antibodies, spike, structural biology, antibody, neutralization, Vaccine design, X-ray crystallography, anti-SARS-CoV-2, angiotensin-converting enzyme 2, variants, binding site, sensitivity, Epitopes, Viral, Receptor-binding domain, SARS-CoV-2 variants, RBD, Neutralizing, cryo-EM, avidity, respiratory, epitope, potent, Donor, breadth, sarbecovirus, Angiotensin-converting enzyme, angiotensin, RBDs, ACE2 binding, Anti-RBD antibody, changes, acute respiratory syndrome, acute respiratory syndrome coronavirus, Anti-RBD antibodies, trimer, class, viral spike, Zoonotic coronavirus, crosslinking, cryo, zoonotic coronaviruses, spike trimer, CDRH3, facilitate, recognize, reducing, reveal, H-bond interaction, occlude, RBD-binding antibody, zoonotic sarbecovirus, 【제목키워드】 COVID-19, cross-reactivity, exhibited, subset,