TY - JOUR
T1 - SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape
AU - Starr, Tyler N.
AU - Czudnochowski, Nadine
AU - Liu, Zhuoming
AU - Zatta, Fabrizia
AU - Park, Young Jun
AU - Addetia, Amin
AU - Pinto, Dora
AU - Beltramello, Martina
AU - Hernandez, Patrick
AU - Greaney, Allison J.
AU - Marzi, Roberta
AU - Glass, William G.
AU - Zhang, Ivy
AU - Dingens, Adam S.
AU - Bowen, John E.
AU - Tortorici, M. Alejandra
AU - Walls, Alexandra C.
AU - Wojcechowskyj, Jason A.
AU - De Marco, Anna
AU - Rosen, Laura E.
AU - Zhou, Jiayi
AU - Montiel-Ruiz, Martin
AU - Kaiser, Hannah
AU - Dillen, Josh R.
AU - Tucker, Heather
AU - Bassi, Jessica
AU - Silacci-Fregni, Chiara
AU - Housley, Michael P.
AU - di Iulio, Julia
AU - Lombardo, Gloria
AU - Agostini, Maria
AU - Sprugasci, Nicole
AU - Culap, Katja
AU - Jaconi, Stefano
AU - Meury, Marcel
AU - Dellota, Exequiel
AU - Abdelnabi, Rana
AU - Foo, Shi Yan Caroline
AU - Cameroni, Elisabetta
AU - Stumpf, Spencer
AU - Croll, Tristan I.
AU - Nix, Jay C.
AU - Havenar-Daughton, Colin
AU - Piccoli, Luca
AU - Benigni, Fabio
AU - Neyts, Johan
AU - Telenti, Amalio
AU - Lempp, Florian A.
AU - Pizzuto, Matteo S.
AU - Chodera, John D.
AU - Hebner, Christy M.
AU - Virgin, Herbert W.
AU - Whelan, Sean P.J.
AU - Veesler, David
AU - Corti, Davide
AU - Bloom, Jesse D.
AU - Snell, Gyorgy
N1 - Funding Information:
Competing interests N.C., F.Z., D.P., M.B., P.H., R.M., J.A.W., A.D.M., L.E.R., J.Z., M.M.-R., H.K., J.R.D., H.T., J.B., C.S.-F., M.P.H., J.d.I., G.L., M.A., N.S., K.C., S.J., M.M., E.D.Jr, E.C., C.H.-D., L.P., F.B., A.T., F.A.L., M.S.P., C.M.H., H.W.V., D.C. and G.S. are or were employees of Vir Biotechnology and may hold shares in Vir Biotechnology. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. After the submission of the initial version of this study, J.D.B. began consulting for Moderna on viral evolution and epidemiology. J.D.B. has the potential to receive a share of IP revenue as an inventor on a Fred Hutchinson Cancer Research Center-optioned technology/patent (application WO2020006494) related to deep mutational scanning of viral proteins. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work nor is performing related work. J.C.N., T.I.C. and D.V. are consultants for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. J.D.C. 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 Institute 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.
Funding Information:
Acknowledgements We thank I. Hoffman for assistance in refinement of crystal structures, G. R. Bowman, J. Coffland and P. K. Eastman for developing and maintaining the Folding@ home infrastructure, Amazon Web Services for Folding@home infrastructure support, the Folding@home volunteers who contributed their computational resources to this project (FAH Project 17336-17340), R. P. Wiewiora and S. Singh for their assistance with Folding@home, and A. M. Harbison and E. Fadda for assistance in glycan modeling. This work was supported by the Fred Hutch Flow Cytometry and Genomics facilities, the Fred Hutch Scientific Computing group supported by ORIP grant S10OD028685, and the University of Washington Arnold and Mabel Beckman Cryo-EM Center. This work was supported by the NIH/NIAID (R01AI127893 and R01AI141707 to J.D.B., DP1AI158186 and HHSN272201700059C to D.V. and T32AI083203 to A.J.G.), the NIH/NIGMS (R01GM120553 to D.V., and grant R01GM121505 and R01GM132386 to J.D.C.), the NIH/NCI (P30CA008748 to J.D.C.), the National Science Foundation (NSF CHI-1904822 to J.D.C.), the Damon Runyon Cancer Research Foundation (T.N.S.), the Gates Foundation (INV-004949 to J.D.B.), a Pew Biomedical Scholars Award (D.V.), Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (J.D.B. and D.V.), the Wellcome Trust (209407/Z/17/Z to T.I.C.), Fast Grants (D.V.), Bayer (W.G.G.) and the Molecular Sciences Software Institute (I.Z.). J.D.B. is an Investigator of the Howard Hughes Medical Institute. The Molecular Biology Consortium beamline 4.2.2 of the Advanced Light Source, a US DOE Office of Science User Facility under contract no. DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the NIH/NIGMS (P30GM124169-01). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH/NIGMS (P30GM133894).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/9/2
Y1 - 2021/9/2
N2 - An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse sarbecoviruses4–7, 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 the development of therapeutic antibodies 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). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
AB - An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse sarbecoviruses4–7, 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 the development of therapeutic antibodies 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). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
UR - http://www.scopus.com/inward/record.url?scp=85112516276&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03807-6
DO - 10.1038/s41586-021-03807-6
M3 - Article
C2 - 34261126
AN - SCOPUS:85112516276
VL - 597
SP - 97
EP - 102
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7874
ER -