Epitope-Specific Targeting of Tau Aggregates

Tau 聚集体的表位特异性靶向

• 批准号: 10594553
• 负责人: Einar M Sigurdsson
• 金额: $ 67.73万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594553
• 关键词: Active Immunization; Acute; Address; Advocate; Affect; Affinity; Alzheimer' s Disease; Amino Acids; Antibodies; Antigen-Antibody Complex; Antigens; Attention; Binding; Binding Sites; Biochemical; Biological Assay; Calcium; Charge; Chimera organism; Clinical Trials; Complex; Crystallization; Data; Development; Disease; Engineering; Epitope Mapping; Epitopes; Foundations; Human; IgG1; IgG3; IgG4; Image; Immunoglobulin G; Immunotherapy; In Vitro; Laboratories; Malignant Neoplasms; Measurement; Microglia; Modeling; Modification; Mus; Neurons; Outcome; Outcome Study; Passive Immunization; Pathogenesis; Pathologic; Penetration; Phagocytosis; Phosphoserine; Property; Protein Conformation; Public Health; Publications; Publishing; Reporting; Reproducibility; Research; Safety; Structure; Tauopathies; Technology; Therapeutic; Tissues; Toxic effect; Vaccines; arm; clinical candidate; confocal imaging; experimental study; extracellular; fly; follow-up; in vivo; in vivo Model; insight; nanobodies; novel; novel therapeutics; pre-clinical; prevent; protein aggregation; prototype; tau Proteins; tau aggregation; tau conformation; tau function; therapy development; uptake

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.

目前有十种 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，包括我们最初的报告中，磷酸丝氨酸 396,404 是其中两项试验的目标。 我们已经产生了几种针对它的抗体，它们对这两种磷酸化具有独特的结合特征。 预防 tau 毒性和促进 tau 清除的作用位点和不同功效。目前还不清楚为什么微妙 该区域内的表位差异可以极大地影响抗体功效。另一个重要问题 探索选择哪种抗体同种型进行临床试验。迄今为止，这些措施的效果要么很强，要么有限。 效应器功能与促进小胶质细胞吞噬 tau 抗体复合物有关，但这关键 同型功效/安全性问题尚未在 tau 蛋白病模型中得到充分研究。关于它的几篇报道的不同之处在于 他们的结论。需要进一步研究的第三个问题与病理性 tau 蛋白的靶向位置有关， 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 病理性 tau 存在于细胞内（>99%），除了细胞外以外，还应更多地将其靶向那里 有效，正如我们多年来所倡导的那样。具体来说，我们已经证明神经元对 tau 蛋白的摄取 抗体及其清除 tau 蛋白和防止其毒性的功效受到其电学的影响 收费。抗体电荷与功效之间的关系在癌症领域已得到充分研究，但 在 tau 领域很少受到关注。最后，尚不清楚哪种形式的 tau 蛋白毒性最强，应该 理想情况下是有针对性的治疗。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。我们想澄清这一现象，这可能会对 了解 tau 发病机制并开发治疗方法。解决这些相关问题非常重要 我们建议澄清的问题：1）微妙的表位差异和抗体同种型的显着影响 tau 抗体的功效； 2) 亲和力和电荷对抗体功效的强烈影响； 3) 为什么将有效的单域 tau 抗体 (sdAb) 改造为全尺寸抗体 (Fc-(sdAb)2) 有毒，而不同有效 tau sdAb 的相同修饰却没有毒性。这些的科学前提 我们的出版物和初步数据高度支持目标，并且该方法基于 这一基础以及我们实验室成熟技术的使用体现了高度的严谨性 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 免疫疗法并为阿尔茨海默病及相关疾病的 tau 发病机制提供有价值的见解 tau蛋白病可能适用于各种蛋白质聚集疾病中的其他靶标。