DEVELOPMENT OF NOVEL THERAPEUTIC ANTI-TAU ANTIBODIES

 描述（由申请人提供）：tau蛋白病是神经退行性疾病，定义为微管相关蛋白tau在不溶性淀粉样蛋白聚集体中的积累。一切都在不断进步。新兴的研究表明，进展是基于以朊病毒样方式的聚集体的跨细胞传播，其中纤维状聚集体在一个细胞中形成，释放到细胞外空间，并进入附近的细胞以破坏天然折叠的蛋白质。这一假设表明，有可能用适当的抗体靶向细胞外物质。事实上，我们实验室最近的工作表明，有可能使用聚集体接种的细胞模型来选择具有体内有效活性的抗体。该提案旨在发展对抗体机制的复杂理解，并开发下一代治疗性抗tau抗体，并在体内测试最有前途的候选物。参与这项工作的两个PI在体内开发和评估治疗性抗体方面有着高效合作的历史。该项目的具体目标是1：体外表征现有的抗tau抗体。我们将使用各种细胞和体外试验来优先考虑已经产生的单克隆抗体。2：从tau蛋白病脑纯化接种活性用于表征和新抗体产生。先前的抗体已经针对可能与跨细胞传播相关或不相关的预先设想的表位。我们将利用我们从脑组织中纯化种子活性的能力来创建针对来自人类tau蛋白病大脑的种子的单克隆抗体。3：抗体在体内的测试机制和功效。我们将使用已建立的实验室方法来评估候选抗体对神经元和神经胶质摄取tau聚集体、间质tau水平和tau聚集体清除的影响。此外，我们将确定它们在tau蛋白病的P301S小鼠模型中的治疗功效。这项资助中提出的工作对美国人口的健康具有重要意义，因为它旨在为tau积累引起的神经退行性疾病开发新的基于抗体的疗法。这一努力的成功将直接关系到使用类似的策略来开发由其他蛋白质淀粉样蛋白引起的神经退行性疾病的疗法。

 DESCRIPTION (provided by applicant): The tauopathies are neurodegenerative disorders defined by the accumulation of the microtubule associated protein tau in insoluble amyloid aggregates. All are relentlessly progressive. Emerging research suggests that progression is based on trans-cellular propagation of aggregates in a prion-like manner, in which a fibrillar aggregate forms in one cell, is released into the extracellular space, and enters a nearby cell to corrupt natively folded protein. This hypothesis suggests that it might be possible to target extracellular species with appropriate antibodies. Indeed, recent work from our laboratories suggests that it is possible to use cellular models of aggregate seeding to select antibodies with potent activity in vivo. This proposal seeks to develop a sophisticated understanding of antibody mechanisms, and to develop the next generation of therapeutic anti-tau antibodies, and to test the most promising candidates in vivo. The two PIs involved in this work have a history of highly productive collaboration to develop and assess therapeutic antibodies in vivo. The Specific Aims of the project are 1: Characterize existing anti-tau antibodies in vitro. We will use a variety of ell and in vitro assays to prioritize monoclonal antibodies already produced. 2: Purify seeding activity from tauopathy brains for characterization and novel antibody production. Prior antibodies have been directed against preconceived epitopes that may or may not be relevant for trans-cellular propagation. We will use our ability to purify seeding activity from brain tissus to create monoclonal antibodies directed against seeds derived from human tauopathy brains. 3: Test mechanisms and efficacy of antibodies in vivo. We will use established laboratory methods to evaluate the effect of candidate antibodies on uptake of tau aggregates into neurons and glia, interstitial tau levels, and tau aggregate clearance. Further, we will determine their therapeutic efficacy in P301S mouse models of tauopathy. The work proposed in this grant is of great significance to the health of the U.S. population, because it seeks to develop novel antibody-based therapies for neurodegenerative diseases due to tau accumulation. Success in this effort will bear directly on the use of similar strategies to develop therapies for neurodegenerative diseases caused by other protein amyloids.