The continuum of antibody epitopes on the GP waist viewed from the top (left) and side (right). Site A includes the conserved hydrophobic pocket beneath the GP2 tail recognized by Adi-15878. Antibodies interacting with epitopes in Sites A-C are more likely to cross-reactive.
Only one naturally occurring human antibody, ADI-15878, is currently known that can neutralize all five ebolavirus. A paper by West et al. that appeared in mBio on September 11, 2018 describes the structural basis for this broad neutralization activity. The crystal structures of the ADI-15878 Fab domain in complex with cleaved Ebola virus (EBOV) and Bundibugyo virus (BDBV) glycoproteins (GP) revealed that the broad reactivity of this antibody can be attributed to its ability to bind to a cryptic hydrophobic pocket that lies beneath the N-terminal tail of the GP2 subunit that contains the internal fusion loop.
Although multiple other antibodies bind to the base region of Ebola virus GP, they are not cross-reactive with GP from other ebolavirus. The mono-specificity of these other base-targeted antibodies may be due their interaction with the N-terminal polypeptide of the GP2 subunit that covers the hydrophobic pocket recognized by ADI-15878. Moreover, the amino acid sequence similarly of the GP2 N-terminal region is low across the five ebolavirus, whereas the sequence of the hydrophobic pocket is highly conserved. Thus, by targeting this region ADI-15878 could bypass species-specific polymorphisms that limit cross-reactivity.
Antibodies have been previously classified into “base-binding” and fusion loop-binding epitope groups. However, the ADI-15878-GP structures together with other new structures of antibodies in complex with GP indicate that there is a continuum of antibody epitopes that ranges from base binding to fusion loop binding sites. Within this spectrum, and lying in the region termed the “waist” of GP, are sites recognized by a variety of GP-targeted antibodies, including Mab100, KZ52 and ADI-15946.
Targeting of the conserved hydrophobic pocket that lies beneath the GP2 tail could be a broadly applicable strategy to develop other antibodies that have cross-reactivity and would be effective to treat disease outbreaks caused by any of the five different ebolavirus.