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 额颞叶痴呆症（FTD）是60岁以下人群中最常见的痴呆症形式，并且 发生FTD的终生风险为1/742。全面破坏以及随之而来的经济和社会 这种疾病的成本是灾难性的，估计每位患者的直接和间接年成本总计 119，654美元-比阿尔茨海默病患者报告的费用高出近两倍。FTD的症状 包括严重和不寻常行为障碍，神经精神问题，包括冷漠，缺乏同情心， 幻觉和精神病，人格改变，执行控制力下降。鉴于广泛的 公共卫生负担，缺乏任何批准的有效的FTD疾病缓解治疗是一个关键问题， 未满足的需求tau蛋白在脑中的异常积累是原发性tau蛋白病的定义特征 例如FTD，并且tau蛋白的可变剪接可以产生六种tau同种型， 在额叶变性（FTLD）亚型中表达。例如，行为变体FTD（bvFTD）主要 表达三重复tau（3R tau）同种型。去除tau病变以治疗原发性tau病变， 近年来获得了越来越多的关注;然而，大多数抗tau疗法都集中在非- 具体的tau靶点，迄今为止尚未证明成功。为了解决市场上的这一差距，抗体 通过SBIR第一阶段申请开发的3RT-085653是一种脑和神经元穿透性单克隆抗体， 选择性靶向并结合主要在bvFTD中表达的3R tau蛋白的链抗体。 临床前研究表明，3RT-085653可穿过血脑屏障，选择性结合3R tau，降低新皮层和海马中3R tau的水平，而不显著影响总tau的水平， 并将3R tau转运至内体区室进行溶酶体降解。以该抗体治疗 还显示减少的神经元细胞损失，包括NeuN阳性神经元和MAP 2免疫反应性神经元。 树突，以及改善行为缺陷的前脉冲抑制和新的习惯。这 第一阶段SBIR建议将以这些令人鼓舞的初步研究结果为基础，追求两个具体目标， 消除风险并开发3RT-085653，以通知和计划IND申请。在目标1中，我们将执行详细的 药代动力学和疗效研究，以确定3RT-085653的相关生物学特征。在Aim中 2，我们将评估免疫原性和形成抗药抗体（ADA）的可能性。成功 这些目标的实现将决定是否有必要对这项技术进行进一步投资， 在II期期间继续开发，其中将进行详细的IND使能非啮齿类动物研究， 执行。在第二阶段之后，我们将寻求与制药和/或生物技术公司建立伙伴关系。 让抗体进入人体试验，然后最终实现产品的全面商业化。 总体而言，我们希望通过以下方式改善FTD和其他神经退行性疾病患者的生活质量： 针对这种目前无法治愈的疾病开发一种新的治疗方法。