Cell host & microbe · 2019
Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод в очереди
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Wec Anna Z, Bornholdt Zachary A, He Shihua, Herbert Andrew S, Goodwin Eileen, Wirchnianski Ariel S, Gunn Bronwyn M, Zhang Zirui, Zhu Wenjun, Liu Guodong, Abelson Dafna M, Moyer Crystal L, Jangra Rohit K, James Rebekah M, Bakken Russell R, Bohorova Natasha, Bohorov Ognian, Kim Do H, Pauly Michael H, Velasco Jesus, Bortz Robert H, Whaley Kevin J, Goldstein Tracey, Anthony Simon J, Alter Galit, Walker Laura M, Dye John M, Zeitlin Larry, Qiu Xiangguo, Chandran Kartik
Аннотация
Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.