Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection

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. [Display omitted] •Cocktail of two human mAbs affording pan-ebolavirus neutralization was selected•Cocktail outperforms single antibody in protecting against EBOV infection in guinea pigs•Second-generation cocktail with optimized Fc effector functions enhances protection•Single low dose of optimized cocktail protects guinea pigs against two ebolaviruses Broadly protective therapies against filoviruses are urgently needed. Wec et al. advance a cocktail of two human mAbs as a candidate pan-ebolavirus therapeutic. The mAbs were selected for antiviral potency and breadth, engineered to enhance breadth and Fc effector functions, and tested against multiple ebolaviruses in guinea pig models of lethal challenge.