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（由适用提供）：tauopathies是由微管相关蛋白tau在不溶性淀粉样蛋白聚集体中的累积所定义的神经退行性疾病。所有人都是无情的进步。新兴的研究表明，进展是基于聚集体的跨细胞传播，其中一个细胞中的原纤维聚集体形式被释放到细胞外空间中，并进入附近的细胞以损坏折叠的本质上折叠的蛋白质。该假设表明，有可能靶向具有适当抗体的细胞外物种。实际上，我们实验室的最新工作表明，可以使用骨料播种的细胞模型来选择具有潜在活性的抗体。该建议旨在发展对抗体机制的复杂理解，并开发下一代的治疗性抗TAU抗体，并在体内测试最有希望的候选者。参与这项工作的两个PI具有高生产力的合作历史，可以在体内开发和评估治疗性抗体。该项目的具体目的是1：在体外表征现有的抗TAU抗体。我们将使用各种ELL和体外测定方法来确定已经产生的单克隆抗体。 2：纯化的播种活性，来自tauopathy的大脑，以表征和新型抗体产生。先前的抗体已针对可能与跨细胞传播有关的先入为主的表位。我们将利用我们的能力从脑组织纯化播种活性，以产生针对源自人tauopathy大脑的种子的单克隆抗体。 3：体内抗体的测试机制和有效性。我们将使用既定的实验室方法来评估候选抗体对TAU聚集物摄入神经元和神经胶质，间质TAU水平以及TAU骨料清除的影响。此外，我们将确定它们在Tauopathy的P301S小鼠模型中的治疗效率。这项赠款中提出的工作对美国人群的健康具有重要意义，因为它试图开发基于TAU的累积导致神经退行性疾病的新型抗体疗法。这项工作的成功将直接取决于使用类似策略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。