Tau antibody isotype induces differential effects following passive immunisation of tau transgenic mice

Abstract

One of the main pathological hallmarks of Alzheimer’s disease (AD) is the intraneuronal accumulation of hyperphosphorylated tau. Passive immunotherapy is a promising strategy for the treatment of AD and there are currently a number of tau-specific monoclonal antibodies in clinical trials. A proposed mechanism of action is to engage and clear extracellular, pathogenic forms of tau. This process has been shown in vitro to be facilitated by microglial phagocytosis through interactions between the antibody-tau complex and microglial Fc-receptors. As this interaction is mediated by the conformation of the antibody's Fc domain, this suggests that the antibody isotype may affect the microglial phagocytosis and clearance of tau, and hence, the overall efficacy of tau antibodies. We therefore aimed to directly compare the efficacy of the tau-specific antibody, RN2N, cloned into a murine IgG1/κ framework, which has low affinity Fc-receptor binding, to that cloned into a murine IgG2a/κ framework, which has high affinity Fc-receptor binding. Our results demonstrate, for RN2N, that although enhanced microglial activation via the IgG2a/κ isotype increased extracellular tau phagocytosis in vitro, the IgG1/κ isoform demonstrated enhanced ability to reduce tau pathology and microgliosis following passive immunisation of the P301L tau transgenic pR5 mouse model.

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

“…This suggests the dose of RNF5 delivered into the brain may have been too high and that the benefit of SUS +MB might have reached a threshold in that attempting to deliver too much antibody into the brain may then become toxic. This is especially the case because RNF5 is of a murine IgG2b isotype, and it is important to note that high concentrations of a high effector isotype antibody may ultimately be deleterious, as we have demonstrated previously [40]. By further exploring the possibility of toxicity, on top of observing acute neuronal degeneration, we also found that microglia had infiltrated the areas in the brain parenchyma into which RNF5 had extravasated.…”

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

“…In a third study, Bajracharya et al examined the efficacy of the tau antibody RN2N in isolated mouse microglia and in a mouse tauopathy model. 31 As expected, the mouse IgG2A (full effector function, comparable to human IgG1) promoted glial phagocytosis of tau more effectively in culture than the mouse IgG1 (less effector function). However, the two subclasses had a similar effect in the mice on clearing several soluble and insoluble phospho-tau epitopes as quantified on western blots, although the IgG1 subclass appeared to be more effective in clearing a particular phospho-tau epitope on immunostained brain sections.…”

“…We have previously shown that adding PHF and antibody together to cultures results in complexes of the two, 33 and other groups have shown that antibody bound tau can be cleared via microglia in an Fc-dependent manner. 19 , 20 , 31 , 54 , 55 , 56 , 57 Because phagocytosis of exogenous tau requires Fc receptor binding, it is also likely to be impacted by subclass.…”

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

“…Tau seeds immunodepleted by C10.2 are less competent at inducing tau aggregation and spread in cellular assays and in rTg4510 tau transgenic mice [ 85 ]. Specifically, the C10.2 antibody has been demonstrated to help mediate lysosomal degradation of pathogenic tau by microglia in cell culture experiments [ 181 ], and in general, antibody uptake is dependent on its isotype and other characteristics [ 193 ]. This antibody has been humanized as Lu AF87908 by H. Lundbeck company and will be tested in a Phase I clinical trial, which is expected to be completed in May of 2021 [ 194 ].…”