Differential requirements for FcγR engagement by protective antibodies against Ebola virus

Abstract

Ebola virus (EBOV) continues to pose significant threats to global public health, requiring ongoing development of multiple strategies for disease control. To date, numerous monoclonal antibodies (mAbs) that target the EBOV glycoprotein (GP) have demonstrated potent protective activity in animal disease models and are thus promising candidates for the control of EBOV. However, recent work in a variety of virus diseases has highlighted the importance of coupling Fab neutralization with Fc effector activity for effective antibody-mediated protection. To determine the contribution of Fc effector activity to the protective function of mAbs to EBOV GP, we selected anti-GP mAbs targeting representative, protective epitopes and characterized their Fc receptor (FcγR) dependence in vivo in FcγR humanized mouse challenge models of EBOV disease. In contrast to previous studies, we find that anti-GP mAbs exhibited differential requirements for FcγR engagement in mediating their protective activity independent of their distance from the viral membrane. Anti-GP mAbs targeting membrane proximal epitopes or the GP mucin domain do not rely on Fc–FcγR interactions to confer activity, whereas antibodies against the GP chalice bowl and the fusion loop require FcγR engagement for optimal in vivo antiviral activity. This complexity of antibody-mediated protection from EBOV disease highlights the structural constraints of FcγR binding for specific viral epitopes and has important implications for the development of mAb-based immunotherapeutics with optimal potency and efficacy.

The role of IgG Fc receptors in antibody-dependent enhancement

“…The studies described above highlight how the balance of activating and inhibitory FcγRs regulates macrophage polarization and dendritic cell maturation and function, and has important biological effects on innate effector responses and adaptive immunity. A large body of evidence from in vivo experimental systems and genetic association studies shows that a major component of the antiviral activity of IgG antibodies is attributed to their capacity to engage and activate specific FcγR pathways on specific immune cell populations that are critical for mediating Fc effector functions 67,73,[77][78][79][80][81][82][83][84] . Indeed, there are numerous instances where even the most potent neutralizing mAbs are significantly compromised in their ability to confer antiviral protection in vivo when Fc-FcγR interactions are abrogated; conversely, mAbs with poor neutralizing activity in in vitro assays can provide robust antiviral protection in vivo, suggesting that antiviral protection of these mAbs is dependent on activating FcγR engagement 67,73,[77][78][79][80][81][82]84 .…”

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

“…How close antigens are to each other, as well as their individual size and shape, could influence how Fc domains are presented as well as the level of avidity experienced ( Figure 11A). There is some evidence to suggest that where an antibody binds on antigen may influence innate effector activity for HIV (261), influenza (262,263) and Ebola viruses (104,264), among other examples, but there is not yet convincing molecular data to provide a general model that ties these observations together.…”

Ebola Virus Disease Survivors Show More Efficient Antibody Immunity than Vaccinees Despite Similar Levels of Circulating Immunoglobulins

“…In this regard, anti-EBOV GP antibodies exhibit a different capacity of FcγR function engagement which depends on the epitope to which they bind. Anti-GP mAbs targeting membrane proximal epitopes or the GP mucin domain do not rely on Fc-FcγR interactions to confer activity, whereas antibodies against the GP chalice bowl and the fusion loop require FcγR engagement for optimal in vivo antiviral activity [48]. Further experiments in adequate animal models would be very valuable in determining how acute EBOV infection shapes subsequent antibody responses.…”