Epitope-Specific Targeting of Tau Aggregates.

最近，利用免疫系统靶向病理性tau蛋白作为阿尔茨海默病(AD)和相关tau病的潜在治疗方法已变得有吸引力。我们之前的研究表明，以疾病相关的磷酸-tau表位为靶点的主动免疫可以减少体内的脑tau聚集体，并减缓与缠结相关的行为表型的进展。Tau免疫疗法的前景现在已经得到了其他组织的证实。最近关于细胞外tau在tau病理解剖扩散中的重要作用的报道也加强了清除病理性tau的可行性。虽然主动免疫方法在许多方面都是治疗AD等慢性疾病的理想方法，但它本身也会导致自身免疫不良反应，而被动免疫可以避免这些不良反应。正如我们的初步发现所表明的那样，单独使用tau单抗(MAbs)是否能获得类似的治疗效果还有待彻底评估。然后，这些单克隆体应该人源化，以进行临床试验。 具体目的1是确定tau单抗的有效性、安全性和作用机制是否依赖于表位。我们推测，抗体清除tau聚集体的有效性可能取决于靶标表位和tau病理阶段。针对不同tau表位的单克隆体防止或逆转tau聚集的能力，以及相关的毒性和认知损害将在一种新的理想的缠结小鼠模型中进行评估。同时，在活体动物和脑片培养中，抗体介导的病理性tau清除的机制和安全性将被阐明。防止或逆转tau聚集和/或下游病理可能依赖于表位。某些tau表位在tau聚集的早期阶段被更显著地检测到，而另一些表位则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，以tau的某些区域为目标可能会产生有毒影响。这些研究可能会产生广泛的影响。他们可能会澄清tau病理中涉及的一系列事件，并确定tau蛋白的哪些区域是免疫治疗的最佳靶点，这可能也适用于其他治疗。此外，这些实验应该确定用于临床试验的候选单抗。 具体目标2是用于人源化的先导治疗性tau单抗的结构特征。这一过程是必要的，以降低抗体的免疫原性，从而使其对人类使用更安全。它需要其结合部位的结构特征，然后可以用人类序列取代对抗原结合不关键的区域。这些重要的结构信息也有助于开发用于治疗或诊断的小分子模拟物。 总而言之，这些目标可能会导致一种治疗AD和相关肌萎缩侧索硬化症的新疗法。

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.