Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer\u2019s disease

Matthew C Roberts ,Kishan Lal Agarwala,Yoichi Imaizumi,Zhi Zhou,Madhurima Dey,Ezat Sajedi,Earl F Albone ,Kazuyuki Horie ,Ioanna Sevastou,Kate Strand,James M Staddon,Sonia Talma,Jared L Spidel ,Muneo Aoyama,Naoki Tokuhara,Hirofumi Aoyagi,Makoto Ogo,Shigeru Akasofu,Jane Gartlon,Kavita Mistry,Hiroshi Ochiai,Rohan De Silva

doi:10.1186/s40478-020-0884-2

Abstract

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

Highlights

Tauopathies are a group of diverse, age-associated neurodegenerative disorders that are neuropathologically characterised by various neuronal and glial inclusions of abnormally hyperphosphorylated, insoluble and fibrillar tau protein [31]
In support of our observation that E2814 can bind to the HVPGG epitope in pathological tau fibrils isolated from tauopathy brains, we demonstrated binding to tau aggregates in solution
We showed that E2814 effectively binds to and depletes seed-competent K18 fibrils (Fig. 6 a and b) and 7G6 recognises preformed recombinant 2N4R P301S tau fibrils (Additional file 1: Figure S11)

Summary

Introduction

Tauopathies are a group of diverse, age-associated neurodegenerative disorders that are neuropathologically characterised by various neuronal and glial inclusions of abnormally hyperphosphorylated, insoluble and fibrillar tau protein [31]. These diseases include Alzheimer’s disease (AD), the most common neurological disorder, as well as the parkinsonian primary tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Work by Braak and colleagues showed tau pathology burden and distribution better reflected disease severity, progression and cognitive decline compared with the initiating amyloid load [8]. Neuronal malfunction and death ensue, leading to clinical progression of disease [20]

Methods

Results

Discussion

Conclusion