Development of an Alzheimer's disease specific antibody biomarker for a tau oligomer fragment

开发 tau 寡聚体片段的阿尔茨海默病特异性抗体生物标志物

• 批准号: 9409478
• 负责人: JAMES G. MOE
• 金额: $ 30.21万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409478
• 关键词: Alzheimer disease detection; Alzheimer' s Disease; Antibodies; Biological; Biological Assay; Biological Markers; Biological Sciences; Blood; Brain; Brain Diseases; Businesses; Cerebrospinal Fluid; Cleaved cell; Clinical; Collaborations; Competence; Cost of Illness; Development; Diagnostic; Diagnostic tests; Direct Costs; Disease; Disease Progression; Employee Strikes; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Goals; Hybridomas; Immunoblotting; Immunohistochemistry; Immunotherapeutic agent; Impairment; Laboratories; Legal patent; Liquid substance; Memory Loss; Methods; N-terminal; Pathologic; Pathology; Patient Recruitments; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phase; Plasma; Prevalence; Production; Proteins; Recombinants; Reproducibility; Research; Role; Signal Transduction; Site; Small Business Innovation Research Grant; Specificity; Specimen; Staging; Structure; Surrogate Markers; Therapeutic; Therapeutic Studies; Therapeutic Uses; aging population; assay development; base; blood-based biomarker; brain tissue; commercialization; cost; drug development; drug discovery; early detection biomarkers; effective therapy; experience; extracellular; in vivo; loss of function; minimally invasive; noninvasive diagnosis; notch protein; novel; phase 1 study; polyclonal antibody; prevent; programs; small molecule therapeutics; success; synaptic function; tau Proteins; tau aggregation

PROJECT SUMMARY - Phase I SBIR (PA-16-302) Title - Development of an Alzheimer’s disease specific antibody biomarker for a tau oligomer fragment The prevalence of Alzheimer’s disease (AD) is increasing worldwide due to demographic shifts and an aging population and currently there are no disease-modifying drugs. It is the most costly disease in the US with a financial burden of over $236 billion annually in direct costs that is estimated to increase to $1 trillion by 2050. There is an urgent unmet need for the development of blood biomarkers for the early detection and staging of AD. The lack of accurate, sensitive, and well-validated biomarkers for AD is a rate limiting factor for identifying effective treatments. Tau protein, and in particular tau oligomers, have become a high priority target for AD due to 1) their high correlation with diseased regions within the brain of AD patients, 2) their newly discovered extracellular activity that is believed to result in the impairment of synaptic function and loss of memory and 3) their role in the spread of pathology. Oligomerix has developed novel methods to highly purify tau oligomers and has discovered that they undergo autoproteolytic fragmentation at specific sites creating neo-epitopes at the cut ends. Polyclonal antibodies (pAbs) to the neo-epitopes were generated, and one pAb showed a striking specificity for AD specimens. In Aims 1 and 2, monoclonal Abs (mAbs) will be generated that have specificity for this fragment end and specificity for the uncut site. Aim 3 will be to characterize the mAbs and perform a proof-of-concept biomarker study. The overall goal of this project is to produce a blood-based, non-invasive diagnostic test as a biomarker for tau fragment levels from biological specimens for AD. These mAbs can also be used to understand the role of tau autoproteolytic fragmentation in AD, and the ratio of cut to uncut tau at this site may provide greater sensitivity in determining AD stage. Additionally, the tau fragment specific mAb that will be developed under the proposed program could have tremendous commercial utility for any therapeutic program, immuno- or small molecule therapeutics seeking to reduce tau accumulation, enhance clearance, or prevent the formation of tau oligomers. The global CNS biomarker market is projected to reach $5.1 billion by 2020 from $3.1 billion in 2015. The proposed study will be enabling for Oligomerix’s internal drug discovery programs, and the Company will make these assays available by commercializing them via collaboration with a diagnostic or life sciences company. Thus the proposed program, if successful, will have significant commercial potential and impact. The strong management and scientific team will ensure competencies in mAb production and characterization, as well as assay development and commercialization. Furthermore, the presence of Dr. Peter Davies and Dr. Steven Jacobsen on the Scientific Advisory Board provide top notch scientific and business experience to the Company.

项目摘要-第一阶段SBIR(PA-16-302) 开发一种针对tau寡聚体片段的阿尔茨海默病特异性抗体生物标记物 由于人口结构的变化和老龄化，阿尔茨海默病(AD)的患病率在全球范围内呈上升趋势 而且目前还没有治疗疾病的药物。它是美国最昂贵的疾病，具有 每年直接成本超过2360亿美元的财务负担，预计到2050年将增加到1万亿美元。 目前迫切需要开发血液生物标记物，用于早期检测和分期 广告。缺乏准确、敏感和经过充分验证的AD生物标志物是识别AD的一个速度限制因素 有效的治疗方法。Tau蛋白，特别是tau寡聚体，已成为AD的高度优先靶点 1)与AD患者脑内病变区域高度相关，2)他们的新发现 被认为会导致突触功能受损和记忆丧失的细胞外活动和3) 它们在病理学传播中的作用。低聚物已开发出高度纯化tau寡聚体的新方法 并发现它们在特定的位置经历了自我蛋白分解的碎裂，从而在 割伤结束了。产生了针对新表位的多克隆抗体(Pab)，其中一种Pab显示了惊人的 AD标本的特异性。在AIMS 1和AIMS 2中，将产生具有特异性的单抗 该片段的末端和未切割部位的特异性。目标3将是表征mAbs并执行 概念验证生物标记物研究。该项目的总体目标是生产一种基于血液的、非侵入性的 作为AD生物标本中tau片段水平的生物标志物的诊断试验。这些单抗还可以 被用来理解tau自身蛋白分解在AD中的作用，以及tau在 此部位在判断AD分期方面可能提供更高的敏感性。此外，tau片段特异性mAb 将在拟议的计划下开发的技术可能会对任何 治疗方案，免疫或小分子疗法寻求减少tau积聚，增强 清除，或防止形成tau齐聚物。全球CNS生物标记物市场预计将达到 到2020年，从2015年的31亿美元增加到51亿美元。这项拟议的研究将使寡核苷酸的内部药物成为可能 发现计划，该公司将通过以下方式将这些检测商业化 与诊断或生命科学公司合作。因此，拟议的计划，如果成功，将有 巨大的商业潜力和影响力。强大的管理和科学的团队将确保 在单抗生产和鉴定以及分析开发和商业化方面的能力。 此外，彼得·戴维斯博士和史蒂文·雅各布森博士在科学咨询委员会的存在 为公司提供一流的科学和商业经验。