Epitope-Specific Targeting of Tau Aggregates.

利用免疫系统靶向病理性tau蛋白最近已成为有吸引力的阿尔茨海默病（AD）和相关tau蛋白病的潜在疗法。我们先前表明，针对疾病相关磷酸化tau表位的主动免疫减少了体内脑tau聚集体，并减缓了缠结相关行为表型的进展。tau免疫疗法的前景现在已经得到了其他研究小组的证实。细胞外tau对于tau病理学的解剖学扩散是重要的最近报道也加强了清除病理性tau的可行性。虽然主动方法在许多方面对于慢性疾病如AD是理想的，但它可能固有地导致可以通过被动免疫避免的自身免疫不良反应。正如我们的初步研究结果所表明的那样，单独使用tau单克隆抗体（mAb）是否可以获得类似的治疗效果还有待彻底评估。然后，这些单克隆抗体应该被人源化用于临床试验。 具体目的1是确定tau mAb的功效、安全性和作用机制是否是表位依赖性的。我们假设抗体清除tau聚集体的功效可能取决于靶向的表位和tau病理学的阶段。针对各种tau表位的单克隆抗体预防或逆转tau聚集的能力，以及相关的毒性和认知障碍将在一种新的缠结小鼠模型中进行评估，该模型对于该目的是理想的。同时，将在活体动物和脑切片培养物中阐明抗体介导的病理性tau清除的机制和安全性。tau聚集和/或下游病理的预防或逆转可以是表位依赖性的。某些tau表位在tau聚集的早期阶段被更显著地检测到，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。也可以想象，靶向tau的某些区域可能具有毒性作用。这些研究可能具有广泛的影响。它们可以阐明tau病理学中涉及的事件序列，并确定tau蛋白的哪些区域最适合用于免疫治疗，这也可以应用于其他疗法。此外，这些实验应确定用于临床试验的候选单克隆抗体。 具体目标2是用于其人源化的主要治疗性tau mAb的结构表征。该程序对于降低抗体的免疫原性是必要的，从而使其对人类使用更安全。它需要其结合位点的结构表征，然后可以用人类序列替换对抗原结合不重要的区域。重要的结构信息还可以促进用于治疗或诊断用途的小分子模拟物的开发。 总之，这些目标可能导致AD和相关tau蛋白病的新疗法。

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.