Cross-reactive neutralizing human survivor monoclonal antibody BDBV223 targets the ebolavirus stalk

Abstract

Three Ebolavirus genus viruses cause lethal disease and lack targeted therapeutics: Ebola virus, Sudan virus and Bundibugyo virus. Monoclonal antibody (mAb) cocktails against the surface glycoprotein (GP) present a potential therapeutic strategy. Here we report two crystal structures of the antibody BDBV223, alone and complexed with its GP2 stalk epitope, an interesting site for therapeutic/vaccine design due to its high sequence conservation among ebolaviruses. BDBV223, identified in a human survivor of Bundibugyo virus disease, neutralizes both Bundibugyo virus and Ebola virus, but not Sudan virus. Importantly, the structure suggests that BDBV223 binding interferes with both the trimeric bundle assembly of GP and the viral membrane by stabilizing a conformation in which the monomers are separated by GP lifting or bending. Targeted mutagenesis of BDBV223 to enhance SUDV GP recognition indicates that additional determinants of antibody binding likely lie outside the visualized interactions, and perhaps involve quaternary assembly or membrane-interacting regions.

Structural basis for broad coronavirus neutralization

“…As a result, B6 binding appears to be incompatible with adoption of the postfusion S conformation ( Figure 4F). Collectively, the data presented here suggest that B6 binding sterically interferes with S fusogenic conformational changes and likely block viral entry through inhibition of membrane fusion ( Figure 4C-F), as proposed for fusion machinerydirected mAbs against influenza virus (Corti et al, 2011), ebolavirus (King et al, 2019) or HIV (Kong et al, 2016). the B6 mAb.…”

“…Heterotypic influenza virus neutralization was also described for human cross-reactive mAbs recognizing the hemagglutinin receptor-binding site or the fusion machinery (Corti et al, 2011;Dreyfus et al, 2012;Ekiert et al, 2011;Ekiert et al, 2012;Kallewaard et al, 2016;Whittle et al, 2011). These findings were paralleled by efforts to identify broadly neutralizing Abs against respiroviruses , henipaviruses (Dang et al, 2019;Mire et al, 2019;Zhu et al, 2006), Dengue and Zika viruses (Barba-Spaeth et al, 2016;Dejnirattisai et al, 2015;Rouvinski et al, 2015) or ebolaviruses (Bornholdt et al, 2016;Flyak et al, 2018;King et al, 2019;West et al, 2018).…”

Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

“…A 40% reduction in EC50 was observed for GP∆muc-WL 2 -foldon binding to BDBV223, confirming that the C terminal extension into MPER can indeed improve the recognition of this conserved bNAb epitope at HR2-MPER (74). King et al proposed 185 two scenarios for EBOV GP to expose the BDBV223 epitope: one HR2 helix is splayed apart from the coiled-coil or the whole GP is lifted/tilted from the membrane (74). It is perhaps more plausible that EBOV GP may adopt an "open stalk" similar to the parainfluenza virus 5 (PIV5) fusion (F) protein, which has a similar long HR-B stalk (77).…”

“…The two HR2 stalk modifications led to slightly increased recognition of RBS by mAb114 and IFL by CA45, respectively, although the EC50 values only showed moderate changes. A 40% reduction in EC50 was observed for GP∆muc-WL 2 -foldon binding to BDBV223, confirming that the C terminal extension into MPER can indeed improve the recognition of this conserved bNAb epitope at HR2-MPER (74). King et al proposed 185 two scenarios for EBOV GP to expose the BDBV223 epitope: one HR2 helix is splayed apart from the coiled-coil or the whole GP is lifted/tilted from the membrane (74).…”

Evidence for distinct mechanisms of small molecule inhibitors of filovirus entry

“…A systemic screen of antibodies against EBOV showed six out eight antibodies targeting the HR2 domain conferred >60% protection, greater average protection than antibodies targeted to many other sites on GP [ 55 ]. Monoclonal antibody BDBV223 from a human survivor targeting the HR2 motif was also reported to show cross-protection against multiple filoviruses [ 56 ]. Collectively, the evidence supports the key role of the HR2 domain in mediating viral fusion and its importance as a target for filovirus therapeutics.…”