Structural and functional analysis of cooperativity in a potent human antibody cocktail against Ebola virus

Abstract

Abstract Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus (EBOV). Systematic analysis of antibody repertoire in the human survivors identified a pair of potently neutralizing mAbs that cooperatively bind to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb/GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. MAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated high levels of effectiveness against EBOV in nonhuman primates. These data illuminate structural principles of antibody cooperativity with implications for the design and development of antiviral immunotherapeutics.