Clearance and In Vivo Detection of Tau Pathology

描述（由申请人提供）：阿尔茨海默病（AD）中的β淀粉样蛋白（Aβ）是几项临床试验的目标，其中许多是免疫疗法。迄今为止的研究结果表明，Aβ斑块清除不会减缓痴呆的进展，强调需要替代靶点，最近III期Aβ抗体试验的失败进一步支持了这一点。显然，tau病理是AD中的另一个重要靶点，并且是其他tau病变中的主要靶点。病理性tau蛋白的存在与痴呆程度的相关性比Aβ沉积更好。因此，一旦认知障碍明显，清除tau可能比去除Aβ更有效，理想情况下，AD的这两个标志最终应该一起靶向治疗。在诊断方面，单链可变抗体片段（scFv）作为检测AD或其他tau病变中的tau病变的成像配体是有吸引力的。衍生自β折叠结合染料的Aβ斑块成像探针已经在临床上使用，并且一些这样的tau结合染料正在动物和人类中进行评估。抗体衍生的探针可能为检测tau病变提供更高的特异性。此外，tract-tracing manganese-enhanced magnetic resonance imaging（tt-MEMRI）是一种独特的技术，可用于研究tau病理学如何损害活体动物的神经元转运，并用于纵向监测相关疗法的疗效。具体目的1是鉴定转基因tau蛋白病小鼠中最有效的主动tau免疫方法。我们已经评估了各种磷酸化tau免疫原的功效，其中最有效的一种包括P-Ser 396，404表位。假设靶向多个表位将增强功效。如果没有，那么用单一表位免疫在临床上会更安全，因为这些表位不太可能导致不利的T细胞增殖。 细胞激活理想情况下，这应该在临床试验之前澄清。具体目标2是评估我们使用噬菌体展示技术产生的各种tau抗体片段的治疗和诊断效用。我们假设，由于其较小的尺寸，scFv作为tau病理学的治疗或诊断PET标志物将比抗体更有效。我们已经鉴定了几种在体外和体内显示出前景的靶向tau的scFv。具体目标3是确定tau免疫疗法是否可以在体内急性改善神经元转运，和/或逆转这种损伤。此外，将阐明这种改善是否与病理性可溶性和/或不溶性tau的清除相关。我们已经用tt-MEMRI表明，随着tau病理学的进展，神经元转运减少，并且预防性主动tau免疫改善了这种转运。我们现在寻求评估tau抗体与这种成像的急性和长期益处。我们假设这两种方法（急性，逆转）将改善神经元转运，但只有后者将与不溶性tau的清除相关，这表明可溶性tau是一个有效的治疗靶点。总的来说，这三个目标 可能导致AD和相关tau蛋白病的新疗法和诊断标志物。

DESCRIPTION (provided by applicant): Amyloid-β (Aβ) in Alzheimer's disease (AD) is being targeted in several clinical trials, with many being immunotherapies. Findings to date indicate that Aβ plaque clearance does not slow progression of dementia, emphasizing the need for alternative targets, further supported by the recent failures of Phase III Aβ antibody trials. Obviously, tau pathology is another important target in AD, and the primary one in other tauopathies. Presence of pathological tau correlates much better with the degree of dementia than Aβ deposition. Hence, clearing tau may be more effective than removing Aβ once cognitive impairments are evident, and ideally both these hallmarks of AD should eventually be targeted together prophylactically. On the diagnostic front, single chain variable antibody fragments (scFv's) are attractive as imaging ligands to detect tau lesions in AD or other tauopathies. Aβ plaque imaging probes derived from β-sheet binding dyes are already in clinical use, and a few such tau-binding dyes are being evaluated in animals and humans. Antibody-derived probes are likely to provide greater specificity for detecting tau lesions. Furthermore, tract-tracing manganese-enhanced magnetic resonance imaging (tt-MEMRI) is a unique technique to study how tau pathology impairs neuronal transport in live animals, and for monitoring longitudinally the efficacy of related therapies. Specific Aim 1 is to identify the most efficacious active tau immunization approach in transgenic tauopathy mice. We have assessed the efficacy of various phospho-tau immunogens, with the most efficacious one encompassing the P-Ser396, 404 epitope. It is hypothesized that targeting multiple epitopes will enhance efficacy. If not, it woul be clinically safer to immunize with a single epitope as those are less likely to lead to adverse T cell activation. Ideally, this should be clarified prior to clinical trials. Specific Aim 2 is to asess the therapeutic and diagnostic utility of various tau antibody fragments that we have generated using phage display technology. We hypothesize that because of their smaller size, scFv's will be more efficacious than antibodies as therapy or diagnostic PET markers for tau pathology. We have already identified several tau-targeting scFv's that show promise in vitro and in vivo. Specific Aim 3 is to determine if tau immunotherapy can acutely improve neuronal transport in vivo, and/or reverse such impairments. Furthermore, it will be clarified if such improvements correlate with clearance of pathological soluble and/or insoluble tau. We have shown with tt-MEMRI that neuronal transport decreases as tau pathology advances, and that prophylactic active tau immunization improves such transport. We now seek to assess acute and long term benefits of tau antibodies with such imaging. We hypothesize that both approaches (acute, reversal) will improve neuronal transport but only the latter will correlate with clearance of insoluble tau, suggesting that soluble tau is a valid therapeutic target. Overall, these three aims may lead to novel therapies and diagnostic markers for AD and related tauopathies.