Pan-ebolavirus protective therapy by two multifunctional human antibodies

Pavlo Gilchuk; Charles D. Murin; Robert W. Cross; Philipp A. Ilinykh; Kai Huang; Natalia Kuzmina; Viktoriya Borisevich; Krystle N. Agans; Joan B. Geisbert; Seth J. Zost; Rachel S. Nargi; Rachel E. Sutton; Naveenchandra Suryadevara; Robin G. Bombardi; Robert H. Carnahan; Alexander Bukreyev; Thomas W. Geisbert; Andrew B. Ward; James E. Crowe

doi:10.1016/j.cell.2021.09.035

Pan-ebolavirus protective therapy by two multifunctional human antibodies

Pavlo Gilchuk, Charles D. Murin, Robert W. Cross, Philipp A. Ilinykh, Kai Huang, Natalia Kuzmina, Viktoriya Borisevich, Krystle N. Agans, Joan B. Geisbert, Seth J. Zost, Rachel S. Nargi, Rachel E. Sutton, Naveenchandra Suryadevara, Robin G. Bombardi, Robert H. Carnahan, Alexander Bukreyev, Thomas W. Geisbert, Andrew B. Ward, James E. Crowe

Pathology

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

26 Scopus citations

Abstract

Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.

Original language	English (US)
Pages (from-to)	5593-5607.e18
Journal	Cell
Volume	184
Issue number	22
DOIs	https://doi.org/10.1016/j.cell.2021.09.035
State	Published - Oct 28 2021

Keywords

Ebolavirus
antibody therapeutics
ebolavirus infection
epitope mapping
glycoprotein
neutralizing antibodies
viral antibodies

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2021.09.035

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Gilchuk, P., Murin, C. D., Cross, R. W., Ilinykh, P. A., Huang, K., Kuzmina, N., Borisevich, V., Agans, K. N., Geisbert, J. B., Zost, S. J., Nargi, R. S., Sutton, R. E., Suryadevara, N., Bombardi, R. G., Carnahan, R. H., Bukreyev, A., Geisbert, T. W., Ward, A. B., & Crowe, J. E. (2021). Pan-ebolavirus protective therapy by two multifunctional human antibodies. Cell, 184(22), 5593-5607.e18. https://doi.org/10.1016/j.cell.2021.09.035

Gilchuk, P, Murin, CD, Cross, RW, Ilinykh, PA, Huang, K, Kuzmina, N, Borisevich, V, Agans, KN, Geisbert, JB, Zost, SJ, Nargi, RS, Sutton, RE, Suryadevara, N, Bombardi, RG, Carnahan, RH, Bukreyev, A , Geisbert, TW, Ward, AB & Crowe, JE 2021, 'Pan-ebolavirus protective therapy by two multifunctional human antibodies', Cell, vol. 184, no. 22, pp. 5593-5607.e18. https://doi.org/10.1016/j.cell.2021.09.035

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AU - Carnahan, Robert H.

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AU - Ward, Andrew B.

AU - Crowe, James E.

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N2 - Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.

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Pan-ebolavirus protective therapy by two multifunctional human antibodies

Abstract

Keywords

ASJC Scopus subject areas

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