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Cell Rep. 2016 May 17;15(7):1514-1526. doi: 10.1016/j.celrep.2016.04.026. Epub 2016 May 5.

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

Author information

1
Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
2
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
3
U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
4
Integral Molecular, Philadelphia, PA 19104, USA.
5
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
7
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
8
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
9
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10
Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
11
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
12
Mapp Biopharmaceutical, San Diego, CA 92121, USA.
13
Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA. Electronic address: javad@integratedbiotherapeutics.com.

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.

PMID:
27160900
PMCID:
PMC4871745
DOI:
10.1016/j.celrep.2016.04.026
[Indexed for MEDLINE]
Free PMC Article

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