Achieving cross-reactivity with pan-ebolavirus antibodies

Abstract

Filoviruses are the causative agents of highly lethal outbreaks in sub-Saharan Africa. Although an experimental vaccine and several therapeutics are being deployed in the Democratic Republic of Congo to combat the ongoing Ebola virus outbreak, these therapies are specific for only one filovirus species. There is currently significant interest in developing broadly reactive monoclonal antibodies (mAbs) with utility against the variety of ebolaviruses that may emerge. Thus far, the primary target of these mAbs has been the viral spike glycoprotein (GP). Here we present an overview of GP-targeted antibodies that exhibit broad reactivity and the structural characteristics that could confer this cross-reactivity. We also discuss how these structural features could be leveraged to design vaccine antigens that elicit cross-reactive antibodies.

Figure 1.

Overview of broadly neutralizing ebolavirus antibodies

Figure 2.

Antibody footprints. (A)

Figure 3.

Cryptic epitopes engaged by ADI-15946, ADI-15878, and CA45. (a) The N-terminal pocket (red) is shown on the surface of EBOV GP (PDB: 5JQ3 [60]) with the N-terminal tail removed. (b) The N-terminal tail engages the highly conserved N-terminal pocket directly through I504 and D506, likely impeding recognition by the immune system. (c) ADI-15878 engages the N-terminal pocket through heavy chain CDRs 1–3, most importantly with W103. (d) The 3₁₀-pocket (blue) is shown with the β17–β18 loop removed. (e) The β17–β18 loop engages the 3₁₀-pocket primarily through two hydrophobic-aromatic residues (F290 and W291). (f) ADI-15946 engages this pocket through CDR-H3, with three hydrophobic residues (W110, L111, and L112) localized in the binding pocket. (g) The DFF cavity targeted by CA45 is shown in cyan. This pocket is bound by the cathepsin cleavage loop (h) in apo-GP. CDR H3 of CA45 binds into this pocket (i) with F100a appearing to bind similarly to F194 of the cathepsin cleavage loop.