Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement

Abstract

The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau.

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

“…Conversely, TRIM21 mRNA was detected in all cell lines at comparable levels. These findings are in agreement with data from cultured mouse neurons and transcriptomic databases, where cell surface FcγR expression in neurons is found to be very low or absent (14,26). Tau neutralization in SHSY-5Y cells occurred similarly to HEK293s.…”

“…Mechanisms that have been described include the clearance by FcγRs expressed on microglia (37), the blockade of tau assemblies from entering neurons (20), the uptake of antibodies in an FcγRII/III-dependent manner and subsequent colocalization with tau in an endolysosomal compartment (24), and the uptake of uncomplexed antibodies by neurons via unknown mechanisms and degradation of soluble tau toxic precursors via TRIM21 (13). The relevance of mechanisms in which interaction with an FcγR is required has recently been questioned by the finding that an anti-tau antibody mutated to prevent FcγR binding remains protective in mice (26). This is consistent with our in vitro findings that FcγR interactions neither promote nor inhibit tau aggregation in neuronal cell lines.…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…If the antibody is acting extracellularly, one question that is being asked is if it should have an effector function or not, to facilitate microglial phagocytosis of the antibody-tau complex. Only one report has explored this issue on antibodies with an identical Fab binding portion, indicating that an effector function is not necessary for efficacy in clearing pathological tau [72]. A prior study comparing two antibodies that recognize a similar epitope (pSer404) with comparable affinity suggested that effector function is beneficial, with an IgG2aκ isotype being effective whereas an IgG1aκ was ineffective [23].…”

“…an unidentified epitope that may be phospho-serine 409 (RO7105705) in healthy subjects and AD patients [72,90], and;…”

MultiTEP platform–based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency

“…Recently, this finding was confirmed when Lee et al . demonstrated that the effector function of an anti-tau antibody Fc fragment was not required for the reduction of pathology in vivo (Lee et al, 2016). Importantly, the authors of this elegant study showed that the antibody with an effector function not only promotes uptake of tau by microglia, but also triggers secretion of pro-inflammatory cytokines in these cells that could have harmful effects on neurons.…”