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 在临床前，包括在我们的原始报告中，磷酸丝氨酸396，404在这些试验中的两个中被靶向。 我们已经产生了几种针对它的抗体，这些抗体对这两种磷酸化- 在预防tau毒性和促进tau清除中的不同位点和不同功效。目前尚不清楚为什么微妙的 该区域内的表位差异可极大地影响抗体效力。另一个重要问题是， 探索是选择哪种抗体同种型进行临床试验。到目前为止，这些措施要么有力，要么有限。 在促进tau-抗体复合物的小胶质细胞吞噬作用方面， 同种型功效/安全性问题尚未在tau蛋白病模型中得到充分检验。关于它的少数报告在以下方面有所不同： 他们的结论。第三个需要进一步研究的问题是在哪里靶向病理性tau蛋白， 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 病理性tau蛋白存在于细胞内（>99%），除了细胞外，靶向它应该更多 这是我们多年来一直倡导的。具体地说，我们已经表明，神经元对tau蛋白的摄取 因此，它们在清除tau和防止其毒性方面的功效受到它们的电特性的影响。 消费标准.抗体电荷和功效之间的关系在癌症领域已经得到了很好的研究， 在tau领域很少受到关注。最后，目前还不清楚哪种形式的tau蛋白毒性最大， 理想情况下是治疗的目标。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。我们要澄清这一现象，它可能对以下方面产生重大影响： 了解tau发病机制和开发治疗方法。为了解决这些相关的非常重要的 我们建议澄清的问题：1）细微表位差异和抗体同种型对 tau抗体的功效; 2）亲和力和电荷对抗体功效的强烈影响，以及; 3)为什么将有效的单结构域tau抗体（sdAb）工程化为全尺寸抗体（Fc-（sdAb）2使得其 毒性，而对于不同的有效tau sdAb的相同修饰则没有。科学的前提是， aims得到了我们的出版物和初步数据的高度支持，基于以下方面，该方法非常可行： 这一基础和使用的技术是在我们的实验室建立，反映了强大的严谨性 和再现性。总之，这些研究的结果可能会指导tau蛋白的进一步发展。 并为阿尔茨海默病和相关疾病中tau发病机制提供有价值的见解 这可能适用于各种蛋白质聚集疾病中的其他靶点。

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.