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

Acta Neuropathologica Communications

Jürgen Götz¹  Rinie Bajracharya¹  David Brici¹  Liviu-Gabriel Bodea¹  Rebecca M. Nisbet²  Phillip W. Janowicz³ 

[1] Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, University of Queensland, 4072, St Lucia, Brisbane, QLD, Australia;Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, University of Queensland, 4072, St Lucia, Brisbane, QLD, Australia;Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, 3052, Melbourne Victoria, Australia;Translational Research Institute, The University of Queensland, 4072, St Lucia, Brisbane, QLD, Australia;

关键词: Tau;    Antibody;    Immunotherapy;    Microglia;    Alzheimer’s disease;   

DOI  :  10.1186/s40478-021-01147-0

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY