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™ 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.
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Howell
authors.affiliation: 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.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Brannan
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bryan
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Davidson
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Anna Z
authors.initials: AZ
authors.lastname: Wec
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Shulenin
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Biggins
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Douglas
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Enterlein
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Turner
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jesper
authors.initials: J
authors.lastname: Pallesen
authors.affiliation: 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.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Murin
authors.affiliation: 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.
authors.forename: Shihua
authors.initials: S
authors.lastname: He
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kroeker
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Vu
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Herbert
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Fusco
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Nyakatura
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lai
authors.affiliation: Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Zhen-Yong
authors.initials: ZY
authors.lastname: Keck
authors.affiliation: Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Steven K H
authors.initials: SKH
authors.lastname: Foung
authors.affiliation: 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.
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
authors.affiliation: Mapp Biopharmaceutical, San Diego, CA 92121, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Zeitlin
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: 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.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA. Electronic address: javad@integratedbiotherapeutics.com.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral / Q000737:chemistry; D001665:Binding Sites; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000502:physiology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006168:Guinea Pigs; D057809:HEK293 Cells; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D016624:Negative Staining; D009500:Neutralization Tests; D011991:Receptors, Virus / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D011991:Receptors, Virus