DEVELOPMENT OF NOVEL THERAPEUTIC ANTI-TAU ANTIBODIES

新型治疗性抗 TAU 抗体的开发

基本信息

批准号：
8884754
负责人：
MARC I DIAMOND
金额：
$ 59.3万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884754
关键词：
Accounting Acute Affinity Alzheimer&apos s Disease Amyloid Amyloid Proteins Antibodies Antibody Formation Antigens Astrocytes Binding Biological Assay Brain Cell model Cell surface Cells Cellular Assay Collaborations Development Diamond Disease Effectiveness Epitopes Extracellular Space Frontotemporal Dementia Grant Health Human Image In Vitro Injection of therapeutic agent Intercellular Fluid Laboratories MAPT gene Maps Mass Spectrum Analysis Methods Microdialysis Microglia Modeling Molecular Molecular Sieve Chromatography Monoclonal Antibodies Morphology Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathology Peripheral Population Post-Translational Protein Processing Progressive Supranuclear Palsy Proteins Recombinants Recording of previous events Relative (related person)Research Seeds Societies Structure Tauopathies Testing Therapeutic Trials Therapeutic antibodies Treatment Efficacy Ursidae Family Vaccination Work base cost extracellular in vitro Assay in vitro activity in vivo interstitial monoclonal antibody production mouse model novel novel therapeutics pre-clinical prion-like protein degradation protein folding public health relevance response skills social success tau Proteins tau aggregation therapy development uptake

项目摘要

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.

描述（由申请人提供）：tau蛋白病是一种神经退行性疾病，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，所有这些疾病都是不断进展的，其进展是基于朊病毒中聚集体的跨细胞传播。以类似的方式，纤维状聚集体在一个细胞中形成，被释放到细胞外空间，并进入附近的细胞以破坏天然折叠的蛋白质。表明可能有可能用适当的抗体靶向细胞外物种。事实上，我们实验室最近的工作表明，可以使用聚集接种的细胞模型来选择具有体内有效活性的抗体。抗体机制，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抗体。参与这项工作的两位 PI 在开发和评估体内治疗性抗体方面有着高效的合作历史。该项目的具体目标是1：在体外表征现有的抗 tau 抗体。我们将使用各种细胞和体外测定来优先考虑已产生的单克隆抗体。 2：纯化来自 tau 病大脑的接种活性，以进行表征和新型抗体的生产。我们将利用我们从脑抗体中纯化种子活性的能力来创建针对源自人类的种子的单克隆抗体。 3：体内抗体的测试机制和功效我们将使用现有的实验室方法来评估候选抗体对神经元和神经胶质细胞摄取 tau 蛋白、间质 tau 蛋白水平和 tau 蛋白聚集物清除的影响。确定它们在 P301S tau 蛋白病小鼠模型中的治疗效果这项资助中提出的工作对美国人口的健康具有重要意义，因为它寻求开发新的基于抗体的疗法。这项工作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。