Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

Katie A. Howell; Xiangguo Qiu; Jennifer M. Brannan; Christopher Bryan; Edgar Davidson; Frederick W. Holtsberg; Anna Z. Wec; Sergey Shulenin; Julia E. Biggins; Robin Douglas; Sven G. Enterlein; Hannah L. Turner; Jesper Pallesen; Charles D. Murin; Shihua He; Andrea Kroeker; Hong Vu; Andrew S. Herbert; Marnie L. Fusco; Elisabeth K. Nyakatura; Jonathan R. Lai; Zhen Yong Keck; Steven K.H. Foung; Erica Ollmann Saphire; Larry Zeitlin; Andrew B. Ward; Kartik Chandran; Benjamin J. Doranz; Gary P. Kobinger; John M. Dye; M. Javad Aman

doi:10.1016/j.celrep.2016.04.026

Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

Katie A. Howell, Xiangguo Qiu, Jennifer M. Brannan, Christopher Bryan, Edgar Davidson, Frederick W. Holtsberg, Anna Z. Wec, Sergey Shulenin, Julia E. Biggins, Robin Douglas, Sven G. Enterlein, Hannah L. Turner, Jesper Pallesen, Charles D. Murin, Shihua He, Andrea Kroeker, Hong Vu, Andrew S. Herbert, Marnie L. Fusco, Elisabeth K. NyakaturaJonathan R. Lai, Zhen Yong Keck, Steven K.H. Foung, Erica Ollmann Saphire, Larry Zeitlin, Andrew B. Ward, Kartik Chandran, Benjamin J. Doranz, Gary P. Kobinger, John M. Dye, M. Javad Aman

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82 Scopus citations

Abstract

Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.

Original language	English (US)
Pages (from-to)	1514-1526
Number of pages	13
Journal	Cell Reports
Volume	15
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2016.04.026
State	Published - May 17 2016
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2016.04.026

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Howell, K. A., Qiu, X., Brannan, J. M., Bryan, C., Davidson, E., Holtsberg, F. W., Wec, A. Z., Shulenin, S., Biggins, J. E., Douglas, R., Enterlein, S. G., Turner, H. L., Pallesen, J., Murin, C. D., He, S., Kroeker, A., Vu, H., Herbert, A. S., Fusco, M. L., ... Aman, M. J. (2016). Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site. Cell Reports, 15(7), 1514-1526. https://doi.org/10.1016/j.celrep.2016.04.026

Howell, KA, Qiu, X, Brannan, JM, Bryan, C, Davidson, E, Holtsberg, FW, Wec, AZ, Shulenin, S, Biggins, JE, Douglas, R, Enterlein, SG, Turner, HL, Pallesen, J, Murin, CD, He, S, Kroeker, A, Vu, H, Herbert, AS, Fusco, ML, Nyakatura, EK, Lai, JR, Keck, ZY, Foung, SKH, Saphire, EO, Zeitlin, L, Ward, AB, Chandran, K, Doranz, BJ, Kobinger, GP, Dye, JM & Aman, MJ 2016, 'Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site', Cell Reports, vol. 15, no. 7, pp. 1514-1526. https://doi.org/10.1016/j.celrep.2016.04.026

@article{c96ee1eade2f41f7885fc9c30b7a47e9,

title = "Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site",

abstract = "Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp{\texttrademark} is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp{\texttrademark} components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.",

author = "Howell, \{Katie A.\} and Xiangguo Qiu and Brannan, \{Jennifer M.\} and Christopher Bryan and Edgar Davidson and Holtsberg, \{Frederick W.\} and Wec, \{Anna Z.\} and Sergey Shulenin and Biggins, \{Julia E.\} and Robin Douglas and Enterlein, \{Sven G.\} and Turner, \{Hannah L.\} and Jesper Pallesen and Murin, \{Charles D.\} and Shihua He and Andrea Kroeker and Hong Vu and Herbert, \{Andrew S.\} and Fusco, \{Marnie L.\} and Nyakatura, \{Elisabeth K.\} and Lai, \{Jonathan R.\} and Keck, \{Zhen Yong\} and Foung, \{Steven K.H.\} and Saphire, \{Erica Ollmann\} and Larry Zeitlin and Ward, \{Andrew B.\} and Kartik Chandran and Doranz, \{Benjamin J.\} and Kobinger, \{Gary P.\} and Dye, \{John M.\} and Aman, \{M. Javad\}",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = may,

day = "17",

doi = "10.1016/j.celrep.2016.04.026",

language = "English (US)",

volume = "15",

pages = "1514--1526",

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T1 - Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

AU - Howell, Katie A.

AU - Qiu, Xiangguo

AU - Brannan, Jennifer M.

AU - Bryan, Christopher

AU - Davidson, Edgar

AU - Holtsberg, Frederick W.

AU - Wec, Anna Z.

AU - Shulenin, Sergey

AU - Biggins, Julia E.

AU - Douglas, Robin

AU - Enterlein, Sven G.

AU - Turner, Hannah L.

AU - Pallesen, Jesper

AU - Murin, Charles D.

AU - He, Shihua

AU - Kroeker, Andrea

AU - Vu, Hong

AU - Herbert, Andrew S.

AU - Fusco, Marnie L.

AU - Nyakatura, Elisabeth K.

AU - Lai, Jonathan R.

AU - Keck, Zhen Yong

AU - Foung, Steven K.H.

AU - Saphire, Erica Ollmann

AU - Zeitlin, Larry

AU - Ward, Andrew B.

AU - Chandran, Kartik

AU - Doranz, Benjamin J.

AU - Kobinger, Gary P.

AU - Dye, John M.

AU - Aman, M. Javad

PY - 2016/5/17

Y1 - 2016/5/17

N2 - Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.

AB - Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.

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AN - SCOPUS:84964961843

SN - 2211-1247

VL - 15

SP - 1514

EP - 1526

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

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