Immunotherapy Targeting Tau Aggregate Polymorphs

项目摘要 微管相关蛋白tau的病理性聚集及其随后的积累， 神经纤维缠结（NFT）或其他过度磷酸化的含tau的内含物是定义性的 额颞叶变性（FTLD）和许多其他神经退行性变组织病理学特征 条件，统称为tau蛋白病，包括皮克病（PiD），进行性核上性麻痹， (PSP)皮质基底节变性（CBD）、阿尔茨海默病（AD）、路易体痴呆（DLB）， 帕金森病（PD），甚至创伤性脑损伤（TBI）。最近的研究表明， 致病性tau种类是可溶性寡聚体。我们创造了几种新的tau寡聚体特异性单克隆抗体， 特异性识别tau寡聚体但不识别功能性tau单体的抗体（TOMA克隆 在体外，这些抗体识别tau蛋白中间和C-末端部分的非连续表位。托马 克隆是有效的中和mAb，其有效且特异性地去除毒性tau寡聚体，并且具有潜在的 治疗和诊断应用。此外，我们最近建立了一种特异性和有效性， 我们的新型TOMA克隆在三种不同的小鼠模型中。 我们假设tau形成构象上不同的毒性寡聚体株/多晶型物。在此，我们将 确定四种TOMA克隆对疾病相关tau寡聚体增殖的功效 以及它们特异性靶向特定疾病相关tau菌株/多晶型物的功效 通过被动免疫疗法。此外，我们将产生人源化TOMA克隆，最终目标是 开发可以在临床环境中靶向异常tau种类的抗体。 这项研究项目的成功完成将提供非常引人注目的数据，这些数据将推动tau领域的发展 推动和促进安全、有效、个性化治疗策略的临床开发， 神经退行性tau蛋白病

Project Summary Pathological aggregation of the microtubule-associated protein tau and its subsequent accumulation into neurofibrillary tangles (NFTs) or other hyperphosphorylated tau-containing inclusions are defining histopathological features of frontotemporal lobar degeneration (FTLD) and many other neurodegenerative conditions, collectively known as tauopathies, including Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and even traumatic brain injury (TBI). Recent studies suggest that the most pathogenic tau species are soluble oligomers. We created several novel tau oligomer-specific monoclonal antibodies (TOMA clones) that specifically recognize tau oligomers but do not recognize functional tau monomer in vitro, these antibodies recognize non-continues epitopes in the middle and c-terminal part of tau protein. TOMA clones are potent neutralizing mAbs that effectively and specifically remove toxic tau oligomers and have potential therapeutic and diagnostic applications. Moreover, we recently established the specificity and efficacy of one of our novel TOMA clones in three different mouse models. We hypothesize that tau forms conformationally distinct toxic oligomeric strains/polymorphs. Herein we will determine the efficacy of four TOMA clones on the propagation of disease relevant tau oligomeric strains/polymorphs, and their efficacy to specifically targeting specific disease relevant tau strains/polymorphs through passive immunotherapy. Moreover, we will generate humanized TOMA clones with the ultimate goal of developing antibodies that can target aberrant tau species in clinical settings. The successful completion of this research project will deliver very compelling data that will move the tau field forward and facilitate the clinical development of safe, effective, personalized therapeutic strategies for neurodegenerative tauopathies.