@article{26848f05a34649c1a7ae77eca7d5d8f2,
title = "Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein",
abstract = "Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.",
keywords = "N-terminal domain, SARS-CoV-2, coronavirus, monoclonal antibodies, neutralizing antibodies, viral antibodies",
author = "Naveenchandra Suryadevara and Swathi Shrihari and Pavlo Gilchuk and VanBlargan, {Laura A.} and Elad Binshtein and Zost, {Seth J.} and Nargi, {Rachel S.} and Sutton, {Rachel E.} and Winkler, {Emma S.} and Chen, {Elaine C.} and Fouch, {Mallorie E.} and Edgar Davidson and Doranz, {Benjamin J.} and Chen, {Rita E.} and Shi, {Pei Yong} and Carnahan, {Robert H.} and Thackray, {Larissa B.} and Diamond, {Michael S.} and Crowe, {James E.}",
note = "Funding Information: We thank Ryan Irving at Vanderbilt University Medical Center for laboratory management support and Merissa Mayo and Norma Suazo Galeano for human subjects support. EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at Vanderbilt University. This work was supported by the NIAID/NIH grants T32 AI095202 (S.J.Z.), T32 AI007163 (E.S.W.), and R01 AI157155 (M.S.D. and J.E.C.), HHSN contracts 75N93019C00074 (J.E.C.) and 75N93019C00073 (B.J.D.), and DARPA HR0011-18-2-0001 (J.E.C.); the Dolly Parton COVID-19 Research Fund at Vanderbilt University Medical Center (J.E.C.); and Fast Grants, Mercatus Center, George Mason University (J.E.C.). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA. The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. Conceived of the project, N.S. P.G. S.J.Z. R.H.C. L.B.T. M.S.D. and J.E.C.; obtained funding, M.S.D. and J.E.C.; performed laboratory experiments, N.S. S.S. P.G. L.A.V. E.B. S.J.Z. R.S.N. R.E.S. E.S.W. M.E.F. R.E.C. and L.B.T.; performed computational work, E.C.C.; supervised research, R.H.C. L.B.T. E.D. B.J.D. M.S.D. and J.E.C.; provided reagent, P.-Y.S.; wrote the first draft of the paper, N.S. P.G. S.S. L.B.T. M.S.D. and J.E.C.; all authors reviewed and approved the final manuscript. M.E.F. E.D. and B.J.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome, and the Diamond laboratory at Washington University School of Medicine has received sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from IDBiologics and AstraZeneca. Funding Information: We thank Ryan Irving at Vanderbilt University Medical Center for laboratory management support and Merissa Mayo and Norma Suazo Galeano for human subjects support. EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at Vanderbilt University. This work was supported by the NIAID /NIH grants T32 AI095202 (S.J.Z.), T32 AI007163 (E.S.W.), and R01 AI157155 (M.S.D. and J.E.C.), HHSN contracts 75N93019C00074 (J.E.C.) and 75N93019C00073 (B.J.D.), and DARPA HR0011-18-2-0001 (J.E.C.); the Dolly Parton COVID-19 Research Fund at Vanderbilt University Medical Center (J.E.C.); and Fast Grants, Mercatus Center, George Mason University (J.E.C.). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA . The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "29",
doi = "10.1016/j.cell.2021.03.029",
language = "English (US)",
volume = "184",
pages = "2316--2331.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "9",
}