Epitope-Specific Targeting of Tau Aggregates.

描述（由申请人提供）：利用免疫系统靶向病理性tau蛋白最近成为阿尔茨海默病（AD）和相关tau病的潜在治疗方法。我们之前的研究表明，针对疾病相关的磷酸化tau表位的主动免疫可减少体内脑tau聚集并减缓缠结相关行为表型的进展。tau免疫疗法的前景现在已经被其他研究小组证实。最近有报道称细胞外tau蛋白对tau病理的解剖扩散很重要，并加强了清除病理性tau蛋白的可行性。虽然主动免疫在许多方面对于慢性疾病如阿尔茨海默病是理想的，但它可能固有地导致自身免疫不良反应，而被动免疫可以避免这种不良反应。正如我们的初步研究结果所表明的那样，是否单独使用tau单克隆抗体（mab）可以获得类似的治疗效果，还有待彻底评估。然后，这些单克隆应该进行人源化，用于临床试验。特异性目的1是确定tau单克隆抗体的有效性、安全性和作用机制是否依赖于表位。我们假设抗体清除tau聚集物的功效可能取决于所靶向的表位和tau病理阶段。单克隆抗各种tau表位的能力，以防止或逆转tau聚集，以及相关的毒性和认知障碍将在一个新的缠结小鼠模型中进行评估，该模型是理想的。同时，将在活体动物和脑切片培养中阐明抗体介导的病理性tau清除的机制和安全性。预防或逆转tau聚集和/或下游病理可能依赖于表位。某些tau表位在tau聚集的早期阶段更明显地被检测到，而其他表位在疾病的后期阶段产生和/或变得可用于抗体结合。同样可以想象的是，靶向tau蛋白的某些区域可能具有毒性作用。这些研究可能会产生广泛的影响。它们可能阐明tau蛋白病理过程中的一系列事件，并确定tau蛋白的哪个区域是免疫治疗的最佳靶点，这也可能适用于其他治疗方法。此外，这些实验应该确定临床试验的候选单克隆。特异性目标2是对其人源化的先导治疗性tau单抗的结构表征。这个过程是必要的，以降低抗体的免疫原性，从而使其对人类使用更安全。它需要对其结合位点进行结构表征，然后可以用人类序列替换对抗原结合不重要的区域。重要的结构信息也可以促进用于治疗或诊断用途的小分子模拟物的发展。总之，这些目标可能会导致一种新的治疗阿尔茨海默病和相关的牛头病。

DESCRIPTION (provided by applicant): Harnessing the immune system to target pathological tau protein has recently become attractive as a potential therapy for Alzheimer's disease (AD) and related tauopathies. We previously showed that active immunization targeting a disease-related phospho-tau epitope reduces cerebral tau aggregates in vivo and slows progression of the tangle-related behavioral phenotype. The promise of tau immunotherapy has now been confirmed by other groups. Recent reports that extracellular tau is important for the anatomical spread of tau pathology strengthen as well the feasibility of clearing pathological tau. While the active approach is in many ways ideal for a chronic disease such as AD, it can inherently lead to autoimmune adverse reactions that may be avoided with passive immunization. It also remains to be thoroughly assessed if a similar therapeutic effect can be obtained with tau monoclonal antibodies (mAbs) alone, as our preliminary findings indicate. These monoclonals should then be humanized for clinical trials. Specific Aim 1 is to determine if the efficacy, safety and mechanism of action of tau mAbs is epitope- dependent. We hypothesize that antibody efficacy in clearing tau aggregates may depend on the epitope being targeted and the stage of tau pathology. The ability of monoclonals against various tau epitopes to prevent or reverse tau aggregation, and associated toxicity and cognitive impairments will be assessed in a novel tangle mouse model that is ideal for this purpose. Concurrently, the mechanism and safety of antibody-mediated clearance of pathological tau will be clarified in live animals and brain slice cultures. Prevention or reversal of tau aggregation and/or downstream pathology may be epitope dependent. Certain tau epitopes are more prominently detected in the early stages of tau aggregation whereas other are generated and/or become accessible for antibody-binding in the later stages of the disease. It is also conceivable that targeting some regions of tau may have toxic effects. These studies are likely to have broad implications. They may clarify sequence of events involved in tau pathology, and identify which regions of the tau protein is best to target for immunotherapy, which may apply to other therapies as well. Furthermore, these experiments should identify a candidate monoclonal for clinical trials. Specific Aim 2 is structural characterization of the lead therapeutic tau mAb for its humanization. This procedure is necessary to reduce the immunogenicity of the antibody, and thereby render it safer for human use. It requires structural characterization of its binding site, and regions not critical for antigen binding can then be replaced with human sequences. The important structural information can also facilitate development of small molecule mimetics for therapeutic or diagnostic use. Together, these aims may lead to a novel therapy for AD and related tauopathies. PUBLIC HEALTH RELEVANCE: The Aims are to determine if the efficacy, safety and mechanism of action of tau monoclonals is dependent on which region of the tau molecule in tauopathies is being targeted. Subsequently, the structure of the lead antibody will be characterized so that it can in future studies be humanized for clinical trials in individuals with Alzheimer's disease or other tauopathies. Hence, this research is very relevant to public health.