Abstract
An ideal anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse SARS-related coronaviruses4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S3094, the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 in vitro neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.
Competing Interest Statement
NC, FZ, DP, MB, PH, RM, JAW, ADM, LER, JZ, MMR, HK, HT, MPH, JDI, GL, MA, NS, KC, SJ, MM, ED, EC, CHD, AT, FAL, MSP, CMH, HWV, DC and GS are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. DC is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. HWV is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. JCN, TIC, and DV are consultants for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. JDC is a current member of the Scientific Advisory Boards of OpenEye Scientific Software, Interline Therapeutics, and Redesign Science. The Chodera laboratory receives or has received funding from the National Institutes of Health, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, XtalPi, Interline Therapeutics, and the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding. The other authors declare no competing interests.
