Hatfield Research Laboratories, Eisai Limited, Hatfield, UK.
Reta Lila Weston Institute & Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London, UK.
Acta Neuropathol Commun. 2020 Feb 4;8(1):13. doi: 10.1186/s40478-020-0884-2.
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, IgG 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.
脑内 Tau 沉积是许多神经退行性疾病的病理标志，包括阿尔茨海默病（AD）。在这些 Tau 病中，Tau 通过突触连接的途径在大脑中传播。这种病理学的传播被认为是由含有微管结合区（MTBR）的 Tau 物种（“种子”）介导的，该 MTBR 由三重复（3R）或四重复（4R）异构体组成。Tau MTBR 也是 AD 大脑和其他 Tau 病中鉴定的神经病理学纤维的核心。目前正在采取多种方法来限制 Tau 病理学，包括使用抗 Tau 抗体进行免疫疗法。鉴于其在纤维中的关键结构作用，用治疗性抗体特异性靶向 MTBR 以抑制 Tau 种子形成和聚集可能是为 AD 和其他 Tau 病提供疾病修饰治疗的有前途的策略。因此，发起了一项单克隆抗体生成运动，重点是 MTBR。本文描述了 E2814 的临床前生成和表征，E2814 是一种针对 Tau MTBR 的人源化、高亲和力、IgG 抗体。通过表位作图揭示，E2814 和其鼠源前体 7G6 是针对 4R 的双表位抗体，针对 3R Tau 异构体的单表位抗体，因为它们结合 HVPGG 序列基序。功能上，两种抗体都抑制 Tau 体外聚集。它们还免疫耗竭了各种含有 MTBR 的 Tau 蛋白物种。在 Tau 种子形成和传播的体内模型中，还可以观察到针对抗体治疗，脑内 Sarkosyl 不溶性 Tau 沉积减少。在 AD 大脑中，E2814 如免疫金标记所示，与不同类型的 Tau 纤维结合，并通过免疫组织化学染色识别病理性 Tau 结构。与 PSP 或对照相比，AD 大脑中还发现含有 HVPGG 表位的 Tau 片段升高。总之，这里报告的数据导致 E2814 被提议用于临床开发。
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