Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates.
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Pascal Kristen E, Dudgeon Drew, Trefry John C, Anantpadma Manu, Sakurai Yasuteru, Murin Charles D, Turner Hannah L, Fairhurst Jeanette, Torres Marcela, Rafique Ashique, Yan Ying, Badithe Ashok, Yu Kevin, Potocky Terra, Bixler Sandra L, Chance Taylor B, Pratt William D, Rossi Franco D, Shamblin Joshua D, Wollen Suzanne E, Zelko Justine M, Carrion Ricardo, Worwa Gabriella, Staples Hilary M, Burakov Darya, Babb Robert, Chen Gang, Martin Joel, Huang Tammy T, Erlandson Karl, Willis Melissa S, Armstrong Kimberly, Dreier Thomas M, Ward Andrew B, Davey Robert A, Pitt Margaret L M, Lipsich Leah, Mason Peter, Olson William, Stahl Neil, Kyratsous Christos A
Аннотация
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 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 NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.