Journal: J Infect Dis / Year: 2018 Title: Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates. Authors: Kristen E Pascal / Drew Dudgeon / John C Trefry / Manu Anantpadma / Yasuteru Sakurai / Charles D Murin / Hannah L Turner / Jeanette Fairhurst / Marcela Torres / Ashique Rafique / Ying Yan / ...Authors: Kristen E Pascal / Drew Dudgeon / John C Trefry / Manu Anantpadma / Yasuteru Sakurai / Charles D Murin / Hannah L Turner / Jeanette Fairhurst / Marcela Torres / Ashique Rafique / Ying Yan / Ashok Badithe / Kevin Yu / Terra Potocky / Sandra L Bixler / Taylor B Chance / William D Pratt / Franco D Rossi / Joshua D Shamblin / Suzanne E Wollen / Justine M Zelko / Ricardo Carrion / Gabriella Worwa / Hilary M Staples / Darya Burakov / Robert Babb / Gang Chen / Joel Martin / Tammy T Huang / Karl Erlandson / Melissa S Willis / Kimberly Armstrong / Thomas M Dreier / Andrew B Ward / Robert A Davey / Margaret L M Pitt / Leah Lipsich / Peter Mason / William Olson / Neil Stahl / Christos A Kyratsous / Abstract: BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, ...BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing ...METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected ...RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in ...CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
History
Deposition
May 23, 2018
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Header (metadata) release
Jun 13, 2018
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Map release
Jun 13, 2018
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Update
Dec 12, 2018
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Current status
Dec 12, 2018
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : REGN3479 antibody Fab in complex with Ebola virus GP
Entire
Name: REGN3479 antibody Fab in complex with Ebola virus GP
Components
Complex: REGN3479 antibody Fab in complex with Ebola virus GP
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Supramolecule #1: REGN3479 antibody Fab in complex with Ebola virus GP
Supramolecule
Name: REGN3479 antibody Fab in complex with Ebola virus GP / type: complex / ID: 1 / Parent: 0 Details: Fab fragment generated by proteolytic cleavage of IgG antibody with papain.
Details: Solution was made from 10x concentration stock.
Staining
Type: NEGATIVE / Material: uranyl formate Details: Stained using 2% uranyl formate on carbon-coated grids.
Grid
Model: Homemade / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
Details
This sample was monodisperse.
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Electron microscopy
Microscope
FEI TECNAI SPIRIT
Image recording
Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 92 / Average exposure time: 0.5 sec. / Average electron dose: 30.0 e/Å2
Electron beam
Acceleration voltage: 120 kV / Electron source: LAB6
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
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