Molecular approaches for understanding and advancing tau immunotherapies

项目摘要/摘要 使用单抗(MAbs)的免疫疗法已被证明在治疗多种疾病和 目前正在调查导致痴呆症的最常见原因-阿尔茨海默病(AD)。 细胞外斑块，含有淀粉样β蛋白(Aβ)，以及神经元内神经原纤维缠结，由 过度磷酸化的tau，是AD的病理特征。β累积开始于显著的tau之前 病理、脑萎缩和痴呆的发病，但降低淀粉样蛋白的治疗，包括抗A-β 抗体，并没有导致认知的好处，轻至中度痴呆症患者由于AD。而当 这些治疗在AD的早期临床前阶段重新评估，在广泛的Aβ病理和 在认知症状方面，tau正在成为另一个有希望的治疗靶点。Tau矿床在中国的存在 在AD和其他神经退行性疾病中，特定的大脑区域与认知能力下降相关，称为 Tauopathy，其中tau包裹体本身就足以导致退化。霍尔兹曼实验室和其他机构 已经表明，用抗tau单抗被动免疫可以减少小鼠模型中tau相关的病理改变 紧张症的症状。因此，这项提案的总体目标是研究理想的tau方法。 免疫疗法。被动免疫的一个主要限制是需要长期高剂量的单抗 当只有一小部分人通过血脑屏障时，达到脑内的治疗水平。本提案使用 重组腺相关病毒在牛磺酸脑病脑内表达全长嵌合抗tau单抗 老鼠模型。我们假设，通过基因转移将抗tau单抗直接输送到大脑将刺激长时间的- TERM在宿主细胞中的表达将减少tau相关的病理改变。此外，我们还设计了反 Tau片段抗原结合(Fab)结构域和全长嵌合单抗，其中 重链被表现出差异的免疫球蛋白G(Ig G)片段结晶(FC)变体所取代 与Fcγ受体结合。免疫球蛋白Fc结构域与Fcγ受体结合，主要表达于小胶质细胞。 可能介导细胞外tau的清除，但也可以导致促炎反应，可能 加剧了退化过程。我们将检验消除Ig G结构域和Fc的假设 抗tau单抗的效应功能在提供神经保护的同时避免不良的促炎作用 通过直接给予抗tau Fab或全长Ig G Fc变异体来隔离细胞外tau 坐位疗法小鼠模型的大脑。因此，这项提议使用分子方法来研究 抗tau免疫治疗机制及提高mAb脑内递送效率的研究 推进脑源性抗原的被动免疫，如tau，并可能导致治疗方案的选择 数以百万计的人患有阿尔茨海默病和相关的焦虑症。

Project Summary/Abstract Immunotherapy using monoclonal antibodies (mAbs) has proven successful in treating numerous diseases and is currently under investigation for the most common cause of dementia, Alzheimer's disease (AD). Extracellular plaques, containing amyloid beta (Aβ), and intraneuronal neurofibrillary tangles, composed of hyperphosphorylated tau, characterize AD pathology. Aβ accumulation begins prior to significant tau pathology, cerebral atrophy and the onset of dementia, yet amyloid-lowering treatments, including anti-Aβ antibodies, have not resulted in cognitive benefits for patients with mild to moderate dementia due to AD. While these treatments are re-evaluated in the earlier “pre-clinical” stage of AD, before extensive Aβ pathology and cognitive symptoms, tau is emerging as another promising therapeutic target. The presence of tau deposits in specific brain regions correlates with cognitive decline in AD and in other neurodegenerative diseases, termed tauopathies, where tau inclusions alone are sufficient to cause degeneration. The Holtzman lab and others have shown that passive immunization with anti-tau mAbs reduces tau-associated pathology in murine models of tauopathy. Therefore, the overall objective of this proposal is to investigate ideal approaches to tau immunotherapy. A major limitation of passive immunization is the chronic high doses of mAbs required to reach therapeutic levels in the brain as only a small fraction cross the blood brain barrier. This proposal uses recombinant adeno-associated virus to express a chimeric full-length anti-tau mAb in the brain of a tauopathy mouse model. We hypothesize direct delivery of anti-tau mAbs to the brain by gene transfer will stimulate long- term expression in host cells that will reduce tau-associated pathology. Additionally, we have engineered anti- tau fragment antigen binding (Fab) domains and full-length chimeric mAbs in which the constant region of the heavy chain is replaced with immunoglobulin G (IgG) fragment crystallible (Fc) variants that exhibit differential binding to Fcγ receptors. The IgG Fc domain binds to Fcγ receptors primarily expressed on microglia in the brain and may mediate extracellular tau clearance, but can also lead to pro-inflammatory responses that may exacerbate the degenerative process. We will test the hypothesis that eliminating the IgG domain and Fc effector function of anti-tau mAbs avoids adverse pro-inflammatory effects while still providing neuroprotection by sequestering extracellular tau through direct administration of anti-tau Fab or full-length IgG Fc variants into the brain of a tauopathy mouse model. Thus, this proposal uses molecular approaches to investigate mechanisms of anti-tau immunotherapy and improve the efficiency of mAb delivery to the brain in order to advance passive immunization for brain derived antigens, like tau, and potentially lead to treatment options for the millions of people suffering from AD and related tauopathies.