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.

中文翻译：

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临床前表征E2814，一种针对tau微管结合重复结构域的高亲和力抗体，用于阿尔茨海默氏病的被动免疫治疗。

Tau在大脑中的沉积是许多神经退行性疾病（包括阿尔茨海默氏病（AD））的病理标志。在这些tauopathies的过程中，tau通过突触连接的途径在整个大脑中扩散。这种病理学传播被认为是由包含由三个重复（3R）或四个重复（4R）同工型组成的微管结合区（MTBR）的tau种（“种子”）介导的。tau MTBR还形成了在AD脑和其他颅骨病变中识别出的神经病理丝的核心。正在采取多种方法来限制tau病理，包括使用抗tau抗体进行免疫治疗。鉴于其在原纤维中的关键结构作用，用治疗性抗体特异性靶向MTBR来抑制tau种子的聚集和聚集可能是一种有前途的策略，可为AD和其他疾病提供改善疾病的治疗方法。因此，开始着重于MTBR的单克隆抗体产生运动。本文中，我们描述了可识别tau MTBR的人源化，高亲和力IgG1抗体E2814的临床前生成和表征。如表位作图所揭示的，E2814及其鼠类前体7G6是4R的双表位抗体和3R tau的亚表位抗体，因为它们与序列基序HVPGG结合。在功能上，两种抗体均在体外抑制tau聚集。他们还免疫消耗了多种含有MTBR的tau蛋白。在tau播种和传播的体内模型中，响应抗体治疗，还可以观察到大脑中沙克糖基不溶性tau沉积的减弱。在AD脑中，E2814结合不同类型的tau细丝，如免疫金标记所示，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，在AD脑中还发现含有HVPGG表位的Tau片段升高。综上所述，此处报告的数据已导致E2814被提议用于临床开发。