Epitope-Specific Targeting of Tau Aggregates.

Tau 聚集体的表位特异性靶向。

基本信息

批准号：
8464819
负责人：
Einar M Sigurdsson
金额：
$ 35.67万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464819
关键词：
Active Immunization Adverse effects Adverse reactions Affinity Age Alzheimer&apos s Disease Amyloid Animal Model Animals Antibodies Antigens Autoimmune Process Autopsy Behavioral Binding Binding Sites Brain Cerebrum Chronic Disease Clinical Research Clinical Trials Cognition Cognitive Dementia Deposition Development Diagnostic Disease Encephalitis Epitopes Event Excision Fab Immunoglobulins Future Human Immune system Immunization Immunotherapy Impaired cognition Individual Knock-out Knowledge Lead Life Mediating Modeling Monoclonal Antibodies Mus Neurofibrillary Tangles Neurons Passive Immunization Pathology Patients Phenotype Prevention Procedures Public Health Publishing Reporting Research Resolution Rodent Safety Slice Specificity Staging Structure T-Lymphocyte Tauopathies Testing Therapeutic Therapeutic Effect Toxic effect alpha synuclein antigen binding base extracellular functional disability hTau Mice immunogenicity immunoregulation improved in vivo mimetics mouse model novel prevent research study small molecule tau Proteins tau aggregation tau-1 three dimensional structure uptake

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：利用免疫系统来靶向病理性 tau 蛋白作为治疗阿尔茨海默氏病 (AD) 和相关 tau 病的潜在疗法，最近已变得颇具吸引力。我们之前表明，针对疾病相关磷酸 tau 表位的主动免疫可减少体内 tau 蛋白聚集，并减缓缠结相关行为表型的进展。 tau 免疫疗法的前景现已得到其他研究小组的证实。最近的报道表明，细胞外 tau 对 tau 病理学的解剖学扩散很重要，这也增强了清除病理性 tau 的可行性。虽然主动方法在许多方面对于 AD 等慢性疾病来说是理想的选择，但它本质上会导致自身免疫不良反应，而被动免疫可以避免这种不良反应。正如我们的初步研究结果所示，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。然后应将这些单克隆抗体进行人源化以用于临床试验。具体目标 1 是确定 tau mAb 的功效、安全性和作用机制是否具有表位依赖性。我们假设抗体清除 tau 聚集物的功效可能取决于靶向表位和 tau 病理阶段。将在一种理想的新型缠结小鼠模型中评估单克隆抗体针对各种 tau 表位预防或逆转 tau 聚集的能力，以及相关的毒性和认知障碍。同时，抗体介导的病理性 tau 蛋白清除的机制和安全性将在活体动物和脑切片培养物中得到阐明。 tau 聚集和/或下游病理学的预防或逆转可能是表位依赖性的。某些 tau 表位在 tau 聚集的早期阶段更显着地被检测到，而其他表位则在疾病的后期阶段产生和/或变得易于与抗体结合。还可以想象，针对 tau 蛋白的某些区域可能会产生毒性作用。这些研究可能会产生广泛的影响。他们可能会阐明 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免疫治疗，这也可能适用于其他疗法。此外，这些实验应该确定用于临床试验的候选单克隆抗体。具体目标 2 是对主要治疗性 tau mAb 进行人源化的结构表征。该过程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。它需要对其结合位点进行结构表征，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，这些目标可能会带来一种治疗 AD 和相关 tau蛋白病的新疗法。