title: Structures of protective antibodies reveal sites of vulnerability on Ebola virus.
abstract: Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre- and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.
authors.affiliation: Department of Integrative Structural and Computational Biology, Department of Immunology and Microbial Science, and.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Murin
authors.affiliation: Department of Immunology and Microbial Science, and.
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Fusco
authors.affiliation: Department of Immunology and Microbial Science, and.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Bornholdt
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada R3E 3R2;
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.affiliation: National Institute of Allergy and Infectious Diseases/Integrated Research Facility, National Institutes of Health, Frederick, MD 21702;
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.affiliation: Mapp Biopharmaceutical, San Diego, CA 92121;
authors.forename: Larry
authors.initials: L
authors.lastname: Zeitlin
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada R3E 3R2; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada R3E 0J9; and Department of Immunology, University of Manitoba, Winnipeg, MB, Canada R3E 0T5.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
authors.affiliation: Department of Integrative Structural and Computational Biology, abward@scripps.edu erica@scripps.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Immunology and Microbial Science, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; abward@scripps.edu erica@scripps.edu.
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology; D002460:Cell Line; D029043:Ebolavirus / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000821:virology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008854:Microscopy, Electron; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D014764:Viral Proteins
keywords: EM; Ebola; ZMapp; antibodies