1. Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.
- Author
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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, and Aman MJ
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal ultrastructure, Antibodies, Neutralizing, Antibodies, Viral chemistry, Binding Sites, Disease Models, Animal, Female, Glycoproteins chemistry, Glycoproteins genetics, Glycoproteins ultrastructure, Guinea Pigs, HEK293 Cells, Humans, Kinetics, Mice, Inbred BALB C, Models, Molecular, Mutation genetics, Negative Staining, Neutralization Tests, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Ebolavirus physiology, Epitopes immunology, Glycoproteins metabolism, Hemorrhagic Fever, Ebola immunology, Receptors, Virus metabolism
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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