Nonetheless, results from these high-throughput screens go beyond mere antibody affinity for GP to correlate with experimental protection in the mouse model. to be the main driver of protection after exposure and mirrors observations in vaccination studies. Continued analysis of antibodies that achieve protection partially or wholly through Fc-mediated functions, the precise functions required, the intersection with specificity and the importance of these functions in different animal models is needed to identify and begin to capitalize on Fc-mediated protection in vaccines and therapeutics alike. == Introduction == Monoclonal antibody (mAb) therapeutics represent one of the fastest growing classes of clinically licensed drugs due to their exquisite specificity and tunable precision. Although immunotherapies for oncology and autoimmune disorders are well-established1, there are fewer clinical applications of immunotherapy for infectious diseases2,3. However, due to their rapid discovery process, as well as their remarkable specificity and low toxicity, immunotherapeutics might be particularly valuable for emerging infectious diseases for which no other therapy is yet available47. An antibody molecule links two hypervariable, antigen-binding domains (Fab fragments) VL285 via a flexible hinge to a constant region (Fc). After anchoring to a foreign antigen, Fab fragments can mechanically neutralize pathogens by physically inactivating the viral entry machinery through blocking receptor binding, preventing necessary cleavage events, or obstructing conformational changes that drive fusion of the pathogen and host membrane. Following Fab binding, the Fc domain links the target to the innate immune system to signal the presence of a threat and to mediate destruction of the foreign body or unhealthy cell. In the design of an immunotherapeutic agent, both ends of the antibody can be tailored to enhance antigen recognition by the Fab and to drive Fc-mediated immune responses in different directions, from dampened immunopathology (silent Fc) to enhanced target clearance (active Fc). Characterization of Fab-mediated protection can be straightforward through the use measurements of binding stoichiometry and neutralization of authentic viruses or pseudoviruses. Structural analysis of the VL285 binding of Fab domains to an antigen can define specific contacts that contribute to antigen recognition and antibody function. In contrast, measurement and visualization of Fc-mediated mechanisms is complex. Different functions can be orchestrated by Fc receptors (FcRs) expressed on different cells of the immune system, with each cell type able to deploy a unique set of anti-pathogen functions such as cellular cytotoxicity, phagocytosis, direct pathogen killing, and modulation/stimulation of innate and adaptive immunity, which can be further influenced by the tissues or compartments in which they are activated. Indeed, FcRs marshal an incredible variety of anti-pathogen responses810. Further, these immune-stimulating, FcFcR interactions have lower affinity than that of the often nanomolar Fab-antigen binding events, or are more transient than the latter and instead rely on avidity to reach a threshold at which the identified target is marked for destruction. These avid interactions require that antibodies of different subclasses and isotypes compete for immune complex occupancy to collectively regulate binding and activation. Thus polyclonal responses, rather than monoclonal responses, act in synergy to drive interactions involving larger complexes of proteins and cells that result in tiered signaling events that are difficult to directly observe using structural and biophysical techniques, although evolving methods such as correlation light electron microscopy could provide additional visual insights in the future11,12. Despite the challenges that accompany study of immune effector function, several examples from oncology and infectious disease have highlighted the importance of Fc activity by showing that the ability of an antibody to affect disease in animal models is dependent on Fc-mediated functions1320. For many infectious disease targets, however, Fc-mediated clearance is or has been overshadowed by VL285 Fab-mediated neutralization, which is often the primary means for selecting mAb candidates for immunotherapy. Thus, fewer non-neutralizing, cell-targeting mAbs have been described or evaluated in animal models. Conflicting results in studies concerning filoviruses, which include ebolaviruses and marburgviruses, led us to critically examine the array of other antibody features and variables that together with neutralization correlate within vivoprotection. Our recently completed several-year, multidisciplinary analysis of antibodies against Ebola BMP6 virus glycoprotein (GP) generated results that highlight the importance of Fc-mediated effector functions in post-exposure protection from filovirus infection in animal models. Here, we first describe the historical context in which the study began.