Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation

Abstract

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro. Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies. The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.

Alzheimer’s Risk Gene TREM2 Determines Functional Properties of New Type of Human iPSC-Derived Microglia

“…Moreover, microglia are reported to have different regional abundance and activity states during aging, brain activity and neurodegenerative processes ( 58 , 70 – 72 ). In addition, accessing microglia in the human brain is in the majority of cases only possible in postmortem tissue ( 73 ).…”

The engagement of microglia in tau-targeted immunotherapy in Alzheimer’s disease

“…Assuming that an effective therapeutic antibody should eliminate pathological tau proteins from the diseased brain, the effector function of such antibody becomes desirable. Our preclinical data with therapeutic anti-tau antibody AX004 indicate that IgG1 antibodies (with effector function) are more effective in facilitating the uptake of extracellular abnormal tau by adult human microglia than the IgG4 isotype (Zilkova et al 2020). Moreover, no safety signals have been observed throughout the course of the AADvac1 phase 1 and phase 2 clinical trials, although AADvac1 vaccination generated predominantly IgG1 antibody response in AD patients (Novak et al 2018).…”

“…This approach eliminates potential unfavourable effect of microglia activation but at the same time desirable tau clearing properties. In summary, tau-targeting vaccines recognize different tau species and have been suggested to act through various mechanisms: by preventing tau aggregation and cell-to-cell spreading (Theunis et al 2013;Albayram et al 2017;Courade et al 2018;Novak et al 2018;Albert et al 2019;Weisova et al 2019), by facilitating tau uptake by microglia (Zilkova et al 2020) and endo-lysosomal degradation of tau in microglia (Andersson et al 2019) or proteasomal degradation of tau seeds in neurons (McEwan et al 2017).…”

“…Compelling body of evidence suggest that microglia engulf and degrade tau aggregates more efficiently in a complex with anti-tau antibody, which is an important underlying mechanism of action for the tau-targeted immunotherapy research. Various in vitro studies demonstrated how anti-tau antibodies significantly potentiate uptake and degradation of pathological tau via an Fc-dependent manner in BV2 microglia-like cells (Funk et al 2015), primary mouse microglia (Luo et al 2015;Andersson et al 2019) or primary human microglia (Zilkova et al 2020). Fc effector function is essential for the antibody-enhanced internalization and degradation of tau by microglia (Fig.…”

Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

“…When delivered with SUS +MB , RNF5 was only internalised into degenerating neurons and this is in line with other publications that have shown that antibodies are not readily internalised into neurons [25] or are only detected in dying neurons [27] which presents the possibility that RNF5 is acting in the extracellular space. Since we did not detect any increase in the phagocytic activity of the microglia in the RNF5-treated mice, we speculate that microglial phagocytosis may not be playing a significant role in tau clearance, despite being one of the well-documented mechanisms of action following passive immunotherapy with tau antibodies [20,21,28,29]. Alternatively, it may be possible that RNF5 is acting in the extracellular space to prevent the internalisation of tau seeds in the K3 mice, thus preventing the formation of insoluble tau species.…”