DEVELOPMENT OF NOVEL THERAPEUTIC ANTI-TAU ANTIBODIES

神经退行性疾病是一种神经退行性疾病，定义为相关微管的堆积。 不溶性淀粉样蛋白聚集体中的tau蛋白。所有这些都是坚持不懈的进步。新出现的研究表明 进展是基于聚集体的跨细胞传播，在这种方式下，聚集体中的纤维 聚集体在一个细胞中形成，释放到细胞外空间，然后进入附近的细胞自然腐烂 折叠蛋白质。这一假说表明，有可能通过 适当的抗体。事实上，我们实验室最近的工作表明，使用细胞 在体内选择具有强大活性的抗体的聚合播种模型。这项提案旨在开发一种 对抗体机制的深入了解，并开发下一代治疗性抗人 Tau抗体，并在体内测试最有希望的候选者。这项工作涉及的两个PI有一个 在体内开发和评估治疗性抗体的高效合作的历史。具体的 该项目的目标是1：在体外鉴定现有的抗tau抗体。我们将使用各种单元格，并在 体外检测优先考虑已经生产的单抗。2：从变态反应中净化播种活动 用于表征大脑和产生新的抗体。以前的抗体都是针对 预先设想的表位可能与跨细胞繁殖相关，也可能与跨细胞繁殖无关。我们将利用我们的能力 从脑组织中提纯种子活性以产生针对来自于 人类紧张症患者的大脑。3：体内抗体的检测机制和效果。我们将使用已建立的 评价候选抗体对神经细胞摄取tau聚集体的影响的实验室方法 胶质细胞、间质tau水平和tau总清除量。此外，我们将确定他们的治疗方法 对P301S小鼠牵张症模型的疗效。这项拨款建议的工作对 美国人的健康，因为它寻求开发基于抗体的新疗法 由tau蓄积引起的神经退行性疾病。这一努力的成功将直接关系到对 开发治疗由其他蛋白质淀粉样蛋白引起的神经退行性疾病的类似策略。

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 laboratoris 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 cell 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 tissues 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.