Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Jacob C. Milligan; Carl W. Davis; Xiaoying Yu; Philipp A. Ilinykh; Kai Huang; Peter J. Halfmann; Robert W. Cross; Viktoriya Borisevich; Krystle N. Agans; Joan B. Geisbert; Chakravarthy Chennareddy; Arthur J. Goff; Ashley E. Piper; Sean Hui; Kelly C.L. Shaffer; Tierra Buck; Megan L. Heinrich; Luis M. Branco; Ian Crozier; Michael R. Holbrook; Jens H. Kuhn; Yoshihiro Kawaoka; Pamela J. Glass; Alexander Bukreyev; Thomas W. Geisbert; Gabriella Worwa; Rafi Ahmed; Erica Ollmann Saphire

doi:10.1016/j.cell.2022.02.023

Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Jacob C. Milligan, Carl W. Davis, Xiaoying Yu, Philipp A. Ilinykh, Kai Huang, Peter J. Halfmann, Robert W. Cross, Viktoriya Borisevich, Krystle N. Agans, Joan B. Geisbert, Chakravarthy Chennareddy, Arthur J. Goff, Ashley E. Piper, Sean Hui, Kelly C.L. Shaffer, Tierra Buck, Megan L. Heinrich, Luis M. Branco, Ian Crozier, Michael R. HolbrookJens H. Kuhn, Yoshihiro Kawaoka, Pamela J. Glass, Alexander Bukreyev, Thomas W. Geisbert, Gabriella Worwa, Rafi Ahmed, Erica Ollmann Saphire

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

Original language	English (US)
Pages (from-to)	995-1007.e18
Journal	Cell
Volume	185
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2022.02.023
State	Published - Mar 17 2022

Keywords

Bundibugyo virus
Ebola virus
Sudan virus
antibody therapeutic
cryo-EM
ebolavirus
medical countermeasure
monoclonal antibody
nonhuman primate

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2022.02.023

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Milligan, J. C., Davis, C. W., Yu, X., Ilinykh, P. A., Huang, K., Halfmann, P. J., Cross, R. W., Borisevich, V., Agans, K. N., Geisbert, J. B., Chennareddy, C., Goff, A. J., Piper, A. E., Hui, S., Shaffer, K. C. L., Buck, T., Heinrich, M. L., Branco, L. M., Crozier, I., ... Saphire, E. O. (2022). Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses. Cell, 185(6), 995-1007.e18. https://doi.org/10.1016/j.cell.2022.02.023

Milligan, JC, Davis, CW, Yu, X, Ilinykh, PA, Huang, K, Halfmann, PJ, Cross, RW, Borisevich, V, Agans, KN, Geisbert, JB, Chennareddy, C, Goff, AJ, Piper, AE, Hui, S, Shaffer, KCL, Buck, T, Heinrich, ML, Branco, LM, Crozier, I, Holbrook, MR, Kuhn, JH, Kawaoka, Y, Glass, PJ, Bukreyev, A , Geisbert, TW, Worwa, G, Ahmed, R & Saphire, EO 2022, 'Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses', Cell, vol. 185, no. 6, pp. 995-1007.e18. https://doi.org/10.1016/j.cell.2022.02.023

@article{70bff4b1888d4564906053e75555ff5e,

title = "Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses",

abstract = "Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.",

keywords = "Bundibugyo virus, Ebola virus, Sudan virus, antibody therapeutic, cryo-EM, ebolavirus, medical countermeasure, monoclonal antibody, nonhuman primate",

author = "Milligan, {Jacob C.} and Davis, {Carl W.} and Xiaoying Yu and Ilinykh, {Philipp A.} and Kai Huang and Halfmann, {Peter J.} and Cross, {Robert W.} and Viktoriya Borisevich and Agans, {Krystle N.} and Geisbert, {Joan B.} and Chakravarthy Chennareddy and Goff, {Arthur J.} and Piper, {Ashley E.} and Sean Hui and Shaffer, {Kelly C.L.} and Tierra Buck and Heinrich, {Megan L.} and Branco, {Luis M.} and Ian Crozier and Holbrook, {Michael R.} and Kuhn, {Jens H.} and Yoshihiro Kawaoka and Glass, {Pamela J.} and Alexander Bukreyev and Geisbert, {Thomas W.} and Gabriella Worwa and Rafi Ahmed and Saphire, {Erica Ollmann}",

note = "Funding Information: We thank the University of Texas Medical Branch (UTMB) Animal Resource Center for husbandry support of laboratory animals and Daniel Deer and Kevin Melody for assistance with the animal studies. This study was supported in part by the U.S. Department of Health and Human Services, NIH grant UC7AI094660 to the UTMB for BSL-4 operations in support of the Galveston National Laboratory. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the UTMB. Funding Information: We thank Sharon Schendel for editing the manuscript, and Dawid Zyla and Haoyang Li for help with model validation. We gratefully acknowledge our funding from National Institute of Allergy and Infectious Diseases (NIAID) U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S. C.W.D.), DARPA contract W31P4Q-14-1-0010 (C.W.D.), and U19AI109762 (T.W.G). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. 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 National Institutes of Health, National Institute of General Medical Sciences (P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. We thank all the staff of the National Institutes of Health (NIH) NIAID Division of Clinical Research (DCR) Integrated Research Facility at Fort Detrick (IRF-Frederick), Frederick, MD, USA, who supported this study?in particular, Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St. Claire, and Lisa Hensley. This work was supported in part through Laulima Government Solutions, LLC, prime contract and Battelle Memorial Institute prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272201800013C and No. HHSN272200700016I, respectively (M.R.H. G.W.). J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC under Contract No. HHSN272201800013C. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I, Task Order No. HHSN26100043 and Contract No. 75N91019D00024, Task Order No. 75N91019F00130 (I.C.). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors. The study protocol was reviewed and approved by the NIH NIAID DCR IRF-Frederick Animal Care and Use Committee in compliance with all applicable federal regulations governing the protection of animals and research. We thank Anya Crane (NIH NIAID DCR IRF-Frederick) for critically editing the manuscript and Jiro Wada (NIH NIAID DCR IRF-Frederick) for helping with figure preparation. We thank the University of Texas Medical Branch (UTMB) Animal Resource Center for husbandry support of laboratory animals and Daniel Deer and Kevin Melody for assistance with the animal studies. This study was supported in part by the U.S. Department of Health and Human Services, NIH grant UC7AI094660 to the UTMB for BSL-4 operations in support of the Galveston National Laboratory. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the UTMB. Conceptualization, J.C.M. C.W.D. X.Y. R.A. E.O.S.; Methodology, J.C.M. C.W.D. X.Y. P.A.I. P.J.H. T.W.G. P.J.G, A.B. G.W. R.A. E.O.S.; Investigation, J.C.M. C.W.D. X.Y. P.A.I. K.H. P.J.H. R.W.C. V.B. K.N.A. J.B.G. C.C. A.J.G. A.E.P. S.H. K.C.L.S. T.B. M.L.H. M.R.H.; Formal analysis, J.C.M. C.W.D. X,Y. P.A.I. P.J.H. R.W.C. T.W.G. I.C. P.J.G. G.W. R.A. E.O.S.; Writing ? original draft, J.C.M. C.W.D. X.Y. E.O.S.; Writing ? review & editing, C.W.D. X,Y. P.A.I. J.H.K. I.C. G.W. E.O.S.; Visualization, J.C.M. C.W.D. X.Y. P.A.I. P.J.G. G.W.; Supervision, T.W.G. A.B. Y.K. P.J.G. G.W. R.A. E.O.S.; Resources, L.M.B. Y.K. P.J.G. A.B. T.W.G. G.W. R.A. E.O.S.; Funding Acquisition, C.W.D. Y.K. P.J.G. A.B. T.W.G. G.W. R.A. E.O.S. R.A. C.D. and E.O.S. are inventors on a patent relating to the antibodies described in this work. All other authors declare no competing interests. Funding Information: We thank all the staff of the National Institutes of Health (NIH) NIAID Division of Clinical Research (DCR) Integrated Research Facility at Fort Detrick (IRF-Frederick), Frederick, MD, USA, who supported this study—in particular, Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St. Claire, and Lisa Hensley. This work was supported in part through Laulima Government Solutions, LLC , prime contract and Battelle Memorial Institute prime contract with the U.S. National Institute of Allergy and Infectious Diseases ( NIAID ) under Contract No. HHSN272201800013C and No. HHSN272200700016I , respectively (M.R.H., G.W.,). J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC under Contract No. HHSN272201800013C . This project has been funded in whole or in part with federal funds from the National Cancer Institute , National Institutes of Health , under Contract No. HHSN261201500003I , Task Order No. HHSN26100043 and Contract No. 75N91019D00024 , Task Order No. 75N91019F00130 (I.C.). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors. The study protocol was reviewed and approved by the NIH NIAID DCR IRF-Frederick Animal Care and Use Committee in compliance with all applicable federal regulations governing the protection of animals and research. We thank Anya Crane (NIH NIAID DCR IRF-Frederick) for critically editing the manuscript and Jiro Wada (NIH NIAID DCR IRF-Frederick) for helping with figure preparation. Funding Information: We thank Sharon Schendel for editing the manuscript, and Dawid Zyla and Haoyang Li for help with model validation. We gratefully acknowledge our funding from National Institute of Allergy and Infectious Diseases ( NIAID ) U19 AI142790 , Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S., C.W.D.), DARPA contract W31P4Q-14-1-0010 (C.W.D.), and U19AI109762 (T.W.G). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. 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 National Institutes of Health , National Institute of General Medical Sciences ( P30GM133894 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = mar,

day = "17",

doi = "10.1016/j.cell.2022.02.023",

language = "English (US)",

volume = "185",

pages = "995--1007.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

AU - Milligan, Jacob C.

AU - Davis, Carl W.

AU - Yu, Xiaoying

AU - Ilinykh, Philipp A.

AU - Huang, Kai

AU - Halfmann, Peter J.

AU - Cross, Robert W.

AU - Borisevich, Viktoriya

AU - Agans, Krystle N.

AU - Geisbert, Joan B.

AU - Chennareddy, Chakravarthy

AU - Goff, Arthur J.

AU - Piper, Ashley E.

AU - Hui, Sean

AU - Shaffer, Kelly C.L.

AU - Buck, Tierra

AU - Heinrich, Megan L.

AU - Branco, Luis M.

AU - Crozier, Ian

AU - Holbrook, Michael R.

AU - Kuhn, Jens H.

AU - Kawaoka, Yoshihiro

AU - Glass, Pamela J.

AU - Bukreyev, Alexander

AU - Geisbert, Thomas W.

AU - Worwa, Gabriella

AU - Ahmed, Rafi

AU - Saphire, Erica Ollmann

N1 - Funding Information: We thank the University of Texas Medical Branch (UTMB) Animal Resource Center for husbandry support of laboratory animals and Daniel Deer and Kevin Melody for assistance with the animal studies. This study was supported in part by the U.S. Department of Health and Human Services, NIH grant UC7AI094660 to the UTMB for BSL-4 operations in support of the Galveston National Laboratory. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the UTMB. Funding Information: We thank Sharon Schendel for editing the manuscript, and Dawid Zyla and Haoyang Li for help with model validation. We gratefully acknowledge our funding from National Institute of Allergy and Infectious Diseases (NIAID) U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S. C.W.D.), DARPA contract W31P4Q-14-1-0010 (C.W.D.), and U19AI109762 (T.W.G). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. 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 National Institutes of Health, National Institute of General Medical Sciences (P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. We thank all the staff of the National Institutes of Health (NIH) NIAID Division of Clinical Research (DCR) Integrated Research Facility at Fort Detrick (IRF-Frederick), Frederick, MD, USA, who supported this study?in particular, Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St. Claire, and Lisa Hensley. This work was supported in part through Laulima Government Solutions, LLC, prime contract and Battelle Memorial Institute prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272201800013C and No. HHSN272200700016I, respectively (M.R.H. G.W.). J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC under Contract No. HHSN272201800013C. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I, Task Order No. HHSN26100043 and Contract No. 75N91019D00024, Task Order No. 75N91019F00130 (I.C.). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors. The study protocol was reviewed and approved by the NIH NIAID DCR IRF-Frederick Animal Care and Use Committee in compliance with all applicable federal regulations governing the protection of animals and research. We thank Anya Crane (NIH NIAID DCR IRF-Frederick) for critically editing the manuscript and Jiro Wada (NIH NIAID DCR IRF-Frederick) for helping with figure preparation. We thank the University of Texas Medical Branch (UTMB) Animal Resource Center for husbandry support of laboratory animals and Daniel Deer and Kevin Melody for assistance with the animal studies. This study was supported in part by the U.S. Department of Health and Human Services, NIH grant UC7AI094660 to the UTMB for BSL-4 operations in support of the Galveston National Laboratory. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the UTMB. Conceptualization, J.C.M. C.W.D. X.Y. R.A. E.O.S.; Methodology, J.C.M. C.W.D. X.Y. P.A.I. P.J.H. T.W.G. P.J.G, A.B. G.W. R.A. E.O.S.; Investigation, J.C.M. C.W.D. X.Y. P.A.I. K.H. P.J.H. R.W.C. V.B. K.N.A. J.B.G. C.C. A.J.G. A.E.P. S.H. K.C.L.S. T.B. M.L.H. M.R.H.; Formal analysis, J.C.M. C.W.D. X,Y. P.A.I. P.J.H. R.W.C. T.W.G. I.C. P.J.G. G.W. R.A. E.O.S.; Writing ? original draft, J.C.M. C.W.D. X.Y. E.O.S.; Writing ? review & editing, C.W.D. X,Y. P.A.I. J.H.K. I.C. G.W. E.O.S.; Visualization, J.C.M. C.W.D. X.Y. P.A.I. P.J.G. G.W.; Supervision, T.W.G. A.B. Y.K. P.J.G. G.W. R.A. E.O.S.; Resources, L.M.B. Y.K. P.J.G. A.B. T.W.G. G.W. R.A. E.O.S.; Funding Acquisition, C.W.D. Y.K. P.J.G. A.B. T.W.G. G.W. R.A. E.O.S. R.A. C.D. and E.O.S. are inventors on a patent relating to the antibodies described in this work. All other authors declare no competing interests. Funding Information: We thank all the staff of the National Institutes of Health (NIH) NIAID Division of Clinical Research (DCR) Integrated Research Facility at Fort Detrick (IRF-Frederick), Frederick, MD, USA, who supported this study—in particular, Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St. Claire, and Lisa Hensley. This work was supported in part through Laulima Government Solutions, LLC , prime contract and Battelle Memorial Institute prime contract with the U.S. National Institute of Allergy and Infectious Diseases ( NIAID ) under Contract No. HHSN272201800013C and No. HHSN272200700016I , respectively (M.R.H., G.W.,). J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC under Contract No. HHSN272201800013C . This project has been funded in whole or in part with federal funds from the National Cancer Institute , National Institutes of Health , under Contract No. HHSN261201500003I , Task Order No. HHSN26100043 and Contract No. 75N91019D00024 , Task Order No. 75N91019F00130 (I.C.). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the U.S. Department of Health and Human Services or of the institutions and companies affiliated with the authors. The study protocol was reviewed and approved by the NIH NIAID DCR IRF-Frederick Animal Care and Use Committee in compliance with all applicable federal regulations governing the protection of animals and research. We thank Anya Crane (NIH NIAID DCR IRF-Frederick) for critically editing the manuscript and Jiro Wada (NIH NIAID DCR IRF-Frederick) for helping with figure preparation. Funding Information: We thank Sharon Schendel for editing the manuscript, and Dawid Zyla and Haoyang Li for help with model validation. We gratefully acknowledge our funding from National Institute of Allergy and Infectious Diseases ( NIAID ) U19 AI142790 , Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S., C.W.D.), DARPA contract W31P4Q-14-1-0010 (C.W.D.), and U19AI109762 (T.W.G). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. 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 National Institutes of Health , National Institute of General Medical Sciences ( P30GM133894 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/3/17

Y1 - 2022/3/17

N2 - Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

AB - Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

KW - Bundibugyo virus

KW - Ebola virus

KW - Sudan virus

KW - antibody therapeutic

KW - cryo-EM

KW - ebolavirus

KW - medical countermeasure

KW - monoclonal antibody

KW - nonhuman primate

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UR - http://www.scopus.com/inward/citedby.url?scp=85126273580&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.02.023

DO - 10.1016/j.cell.2022.02.023

M3 - Article

C2 - 35303429

AN - SCOPUS:85126273580

SN - 0092-8674

VL - 185

SP - 995-1007.e18

JO - Cell

JF - Cell

IS - 6

ER -

Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

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