Epitope-Specific Targeting of Tau Aggregates

目前有10种tau免疫疗法正在进行临床试验。研究最多的tau表位之一 临床前，包括在我们最初的报告中，磷酸丝氨酸396,404是其中两个试验的靶点。 我们已经产生了几种针对它的抗体，它们与这两种磷酸化蛋白具有独特的结合特性。 在预防tau毒性和促进tau清除方面，有不同的部位和不同的效果。目前尚不清楚为什么这种微妙的 该区域内的表位差异会极大地影响抗体的效力。另一个重要的问题是 探索在临床试验中选择哪种抗体亚型。到目前为止，这些国家要么强大，要么有限。 效应器在促进tau抗体复合体的小胶质细胞吞噬方面的作用，但这一关键 同种类型的有效性/安全性问题还没有在倒立疗法模型中得到很好的检验。关于它的几个报道不同之处在于 他们的结论。第三个需要进一步研究的问题与哪里针对病理性tau有关， 细胞内和/或细胞外。大多数公司都专注于细胞外清除，但由于几乎所有的 病理性tau驻留在细胞内(&gt；99%)，除了细胞外，针对它的应该更多 有效，正如我们多年来所倡导的那样。具体地说，我们已经证明了神经元对tau的摄取 抗体及其清除tau和预防其毒性的有效性受到其电学性质的影响 充电。在癌症领域，抗体电荷和疗效之间的关系已经得到了很好的研究，但 在tau领域几乎没有受到关注。最后，目前还不清楚哪些形式的tau毒性最大，应该 理想情况下，应以治疗为靶点。我们最近的初步数据表明，我们已经能够稳定 Tau的毒性构象。我们希望澄清这一现象，这可能对 了解tau的发病机制和开发治疗方法。解决这些相关问题非常重要 我们建议澄清的问题：1)细微的表位差异和抗体同型对 Tau抗体的效力；2)亲和力和电荷对抗体效力的强烈影响； 3)为什么设计有效的单域tau抗体(SdAb)来对抗全长抗体(Fc-(SdAb)2)使其 毒性，而相同的修饰对不同有效的tau sdAb没有影响。这些问题的科学前提 AIMS得到了我们出版物和初步数据的高度支持，该方法是非常可行的，基于 这一基础和对我们实验室中成熟技术的使用，反映了强大的严谨性 和再现性。总而言之，这些研究的结果可能会指导tau的进一步发展。 免疫治疗为了解tau在阿尔茨海默病及相关疾病中的发病机制提供了有价值的见解 这可能适用于各种蛋白质聚集性疾病的其他靶点。

Ten tau immunotherapies are currently in clinical trials. One of the most studied tau epitopes preclinically, including in our original reports, phospho-serine 396,404, is being targeted in two of these trials. We have generated several antibodies against it, which have unique binding profiles to these two phospho- sites and varying efficacy in preventing tau toxicity and promoting tau clearance. It is not clear why the subtle epitope differences within this region can greatly influence antibody efficacy. Another important issue to explore is which antibody isotype to choose for clinical trials. To date, these have either strong or limited effector function with regard to promoting microglial phagocytosis of the tau-antibody complex, but this key isotype efficacy/safety issue has not been well examined in tauopathy models. The few reports on it differ in their conclusion. A third matter that needs to be studied further has to do with where to target pathological tau, intra- and/or extracellularly. Most companies have focused on extracellular clearance but since almost all of pathological tau resides intracellularly (>99%), targeting it there in addition to extracellularly should be more efficacious, as we have advocated over the years. Specifically, we have shown that neuronal uptake of tau antibodies and thereby their efficacy in clearing tau and preventing its toxicity is influenced by their electrical charge. The relationship between antibody charge and efficacy has been well studied in the cancer field but has received little attention in the tau field. Finally, it is not clear which forms of tau are most toxic and should ideally be targeted with therapies. Our recent preliminary data indicates that we have been able to stabilize a toxic conformation of tau. We would like to clarify this phenomenon, which may have major implications for understanding tau pathogenesis and for development of therapies. To address these related very important issues we propose to clarify: 1) the pronounced influence of subtle epitope differences and antibody isotype on the efficacy of tau antibodies; 2) the robust influence of affinity and electrical charge on antibody efficacy, and; 3) why engineering an effective single domain tau antibody (sdAb) to a full size antibody (Fc-(sdAb)2 renders it toxic, whereas the same modification for a different effective tau sdAb does not. The scientific premise of these aims is highly supported by our publications and preliminary data, and the approach is very feasible based on this foundation and the use of technologies that are well established in our laboratories, reflecting strong rigor and reproducibility. Together, the outcome of these studies is likely to guide further development of tau immunotherapies and provide valuable insight into tau pathogenesis in Alzheimer's disease and related tauopathies that may be applicable to other targets in various protein aggregation diseases.