Abstract
Monoclonal antibodies (mAbs) have proven effective for the treatment of ebolavirus infection in humans, with two mAb-based drugs Inmazeb™ and Ebanga™ receiving FDA approval in 2020. While these drugs represent a major advance in the field of filoviral therapeutics, they are composed of antibodies with single-species specificity for Zaire ebolavirus. The Ebolavirus genus includes five additional species, two of which, Bundibugyo ebolavirus and Sudan ebolavirus, have caused severe disease and significant outbreaks in the past. There are several recently identified broadly neutralizing ebolavirus antibodies, including some in the clinical development pipeline, that have demonstrated broad protection in preclinical studies. In this review, we describe how structural biology has illuminated the molecular basis of broad ebolavirus neutralization, including details of common antigenic sites of vulnerability on the glycoprotein surface. We begin with a discussion outlining the history of monoclonal antibody therapeutics for ebolaviruses, with an emphasis on how structural biology has contributed to these efforts. Next, we highlight key structural studies that have advanced our understanding of ebolavirus glycoprotein structures and mechanisms of antibody-mediated neutralization. Finally, we offer examples of how structural biology has contributed to advances in anti-viral medicines and discuss what opportunities the future holds, including rationally designed next-generation therapeutics with increased potency, breadth, and specificity against ebolaviruses.
Highlights
Ebolaviruses are the genus from the family of Filoviridae that includes six distinct viral species: Zaire ebolavirus [represented by Ebola virus (EBOV)], Bundibugyo ebolavirus [(Bundibugyo virus (BDBV)], Sudan ebolavirus [Sudan virus (SUDV)], Taï Forest ebolavirus [Taï Forest virus (TAFV)], Bombali ebolavirus [Bombali virus (BOMV)], and Reston ebolavirus [Reston virus (RESTV)]
The approval of antibody therapeutics in humans was accelerated due to an unprecedented pandemic that occurred from 2013-2016, when more than 30,000 humans were infected by a novel variant of EBOV (Makona)
Structural biology has been a valuable tool for the development of these and other antibody therapeutics, both by defining sites of vulnerability and by providing atomic level details of antibody mechanisms-of-action
Summary
Ebolaviruses are the genus from the family of Filoviridae that includes six distinct viral species: Zaire ebolavirus [represented by Ebola virus (EBOV)], Bundibugyo ebolavirus [(Bundibugyo virus (BDBV)], Sudan ebolavirus [Sudan virus (SUDV)], Taï Forest ebolavirus [Taï Forest virus (TAFV)], Bombali ebolavirus [Bombali virus (BOMV)], and Reston ebolavirus [Reston virus (RESTV)]. EbangaTM and InmazebTM were derived from B cells of human survivors or vaccinated, humanized mice, respectively Both treatments provided significant protection from death and severe disease over the standard of care, according to the results of clinical trials completed during an outbreak that occurred in 2018 [8]. We discuss how structural biology has provided insight into the molecular basis of antibody therapeutic efficacy for ebolaviruses, through low-resolution epitope mapping and high-resolution structures of mono-specific or broadly reactive antibodies These approaches have jointly provided valuable insights into how antibody therapeutics can be improved to develop pan-ebolavirus drugs
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