Development of a brain penetrating single-chain antibody selectively targeting three repeat tau protein as a new treatment for frontotemporal dementia

开发选择性靶向三个重复 tau 蛋白的脑穿透单链抗体作为额颞叶痴呆的新治疗方法

• 批准号: 10383261
• 负责人: Erin Saito
• 金额: $ 43.34万
• 依托单位: 3RT INNOVATIONS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383261
• 关键词: Achievement; Address; Affect; Age of Onset; Age-Years; Alternative Splicing; Alzheimer' s disease patient; Animals; Antibodies; Attention; Behavioral; Binding; Biological; Biological Assay; Biotechnology; Blood - brain barrier anatomy; Brain; Cause of Death; Characteristics; Clinical Trials; Cost of Illness; Data; Dementia; Dendrites; Development; Diagnosis; Disease; Dose; Drug Kinetics; Economics; Empathy; Enzyme-Linked Immunosorbent Assay; Excision; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Goals; Hallucinations; Hippocampus (Brain); Hour; Human; Immune response; Impaired cognition; Incidence; Investments; Literature; Malignant Neoplasms; Measures; Metabolic Clearance Rate; Monoclonal Antibodies; Mus; Mutation; Neocortex; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Patients; Personality; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pick body; Preclinical Testing; Protein Isoforms; Psychoses; Public Health; Quality of life; Recombinants; Reporting; Risk; Safety; Signal Transduction; Small Business Innovation Research Grant; Symptoms; Tauopathies; Technology; Testing; Therapeutic; Time; Transgenic Mice; Treatment Efficacy; Wild Type Mouse; World Health Organization; astrogliosis; base; behavior test; behavioral variant frontotemporal dementia; commercialization; cost; differential expression; efficacy study; executive function; habituation; immunogenicity; immunoreactivity; improved; inhibitor; innovation; lifetime risk; neuron loss; neuropsychiatry; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; prepulse inhibition; prevent; serotonin receptor; social; success; symptom management; tau Proteins; tau aggregation; tau-1; uptake

PROJECT SUMMARY Frontotemporal dementia (FTD) is the most common form of dementia in people less than 60 years of age, and the lifetime risk of developing FTD is 1 in 742. The overall disruption and accompanying economic and social costs of this disease are catastrophic, with estimated direct and indirect annual costs per patient totaling $119,654—nearly two times higher than costs reported for Alzheimer’s Disease patients. Symptoms of FTD include severe and unusual behavioral disturbances, neuropsychiatric issues including apathy, lack of empathy, hallucinations and psychosis, changes in personality, and decreases in executive control. Given the extensive public health burden, the lack of any approved, effective disease modifying treatment for FTD represents a critical unmet need. Abnormal accumulation of tau proteins in the brain is a defining characteristic of primary tauopathies such as FTD, and alternative splicing of tau proteins can generate six tau isoforms that are differentially expressed in frontolobar degeneration (FTLD) subtypes. For example, behavioral variant FTD (bvFTD) primarily expresses the three-repeat tau (3R tau) isoform. The removal of tau pathology to treat primary tauopathies has gained increased attention in recent years; however, the majority of anti-tau therapies have focused on non- specific tau targets, which to date have not proven successful. To address this gap in the market, the antibody to be developed through this SBIR Phase I application, 3RT-085653, is a brain and neuronal penetrating single chain antibody that selectively targets and binds to the 3R tau protein predominantly expressed in bvFTD. Preclinical studies have demonstrated that 3RT-085653 crosses the blood brain barrier, selectively binds to 3R tau, reduces levels of 3R tau in the neocortex and hippocampus without significantly affecting levels of total tau, and transports 3R tau to the endosomal compartment for lysosomal degradation. Treatment with the antibody also showed reduced loss of neuronal cells including NeuN positive neurons and MAP2 immunoreactive dendrites, as well as amelioration of behavioral deficits in both pre-pulse inhibition and novel habituation. This Phase I SBIR proposal will build upon these encouraging preliminary findings by pursuing two Specific Aims to de-risk and develop 3RT-085653 to inform and plan for an IND application. In Aim 1, we will perform detailed pharmacokinetic and efficacy studies to determine the relevant biologic characterization of 3RT-085653. In Aim 2, we will assess immunogenicity and the potential for the formation of anti-drug antibodies (ADAs). Successful achievement of these Aims will determine if further investment in this technology is warranted, and enable continued development during Phase II, in which detailed IND-enabling non-rodent animal studies will be performed. Following Phase II, we will seek partnerships with pharmaceutical and/or biotechnology companies to allow the antibody to progress into human trials and then the eventual full commercialization of the product. Overall, we hope to improve the quality of life for patients with FTD and other neurodegenerative disorders by developing a new therapeutic that targets this currently untreatable condition.

项目摘要 额颞痴呆（FTD）是不到60岁的人中最常见的痴呆形式， 终生发展FTD的风险是742分之一。总体破坏和参与经济和社会 这种疾病的成本是灾难性的，估计的直接和间接年度每名患者总计 $ 119,654 - 几乎是阿尔茨海默氏病患者报告的成本的两倍。 FTD的症状 包括严重和异常的行为灾难，神经精神科问题，包括冷漠，缺乏同理心， 幻觉和精神病，人格变化以及执行控制的减少。给定广泛的 公共卫生伯恩（Burnen），缺乏对FTD的任何有效的，有效修改治疗的有效疾病，这是一个关键 未满足的需求。 tau蛋白在大脑中的异常积累是原发性tauopathies的定义特征 例如ftd和tau蛋白的替代剪接可以产生六个tau同工型，它们是差异的 以额叶变性（FTLD）亚型表示。例如，行为变体FTD（BVFTD）主要 表达三重tau（3r tau）同工型。去除tau病理以治疗原发性tauopathies 近年来，人们受到越来越多的关注；但是，大多数抗TAU疗法都集中在非 - 迄今为止尚未证明成功的特定tau目标。为了解决市场差距，抗体 通过此SBIR I期应用程序开发，即3RT-085653，是大脑和神经元穿透的单个 链抗体有选择地靶向并与BVFTD中主要表达的3R TAU蛋白结合。 临床前研究表明，3RT-085653越过血脑屏障，有选择地结合3R tau，在新皮层和海马中降低了3R tau的水平，而不会显着影响总tau水平， 并将3R TAU运输到内体室以进行溶酶体降解。用抗体治疗 还显示了包括NEUN阳性神经元和MAP2免疫反应性的神经元细胞损失减少 树突以及行为缺陷前脉冲抑制和新颖习惯中的行为缺陷的隔离。这 第一阶段SBIR提案将通过追求两个具体的目标来建立在这些令人鼓舞的初步发现的基础上 脱离风险并开发3RT-085653，以告知和计划IND申请。在AIM 1中，我们将执行详细 药代动力学和有效研究，以确定3RT-085653的相关生物学表征。目标 2，我们将评估免疫原性和形成抗药物抗体（ADA）的潜力。成功的 实现这些目标将确定是否有必要对该技术进行进一步的投资，并启用 在第二阶段的持续发展，其中详细的非统治动物研究将是 执行。在第二阶段之后，我们将与药物和/或生物技术公司建立合作伙伴关系 为了使抗体进入人体试验，然后最终对产品进行全面商业化。 总体而言，我们希望改善FTD患者和其他神经退行性疾病的生活质量 开发一种针对这种目前不可治疗的条件的新理论。