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) 标题 - 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 由于人口结构变化和老龄化，阿尔茨海默病 (AD) 的患病率在全球范围内不断增加 人口，目前没有缓解疾病的药物，这是美国最昂贵的疾病。 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。 开发用于早期检测和分期的血液生物标记物的迫切需求尚未得到满足 AD 缺乏准确、灵敏且经过充分验证的生物标志物是识别 AD 的速率限制因素。 Tau 蛋白，特别是 tau 寡聚物，已成为 AD 的高度优先目标。 1) 它们与 AD 患者大脑内的患病区域高度相关，2) 他们新发现的 细胞外活动被认为会导致突触功能受损和记忆丧失；3) Oligomerix 开发了高度纯化 tau 寡聚物的新方法。 并发现它们在特定位点进行自蛋白水解断裂，在以下位置产生新表位 产生了针对新表位的多克隆抗体 (pAb)，其中一种 pAb 显示出惊人的结果。 AD 样本的特异性 在目标 1 和 2 中，将生成具有特异性的单克隆抗体 (mAb)。 对于该片段末端和未切割位点的特异性，目标 3 将是表征 mAb 并进行分析。 该项目的总体目标是进行基于血液的非侵入性生物标志物研究。 这些 mAb 还可以作为 AD 生物样本中 tau 片段水平的生物标志物进行诊断测试。 用于了解 tau 自蛋白水解片段在 AD 中的作用，以及切割与未切割 tau 的比率 此外，tau 片段特异性 mAb 可以在确定 AD 阶段时提供更高的灵敏度。 将根据拟议计划开发的技术可能对任何人都具有巨大的商业效用 治疗计划、免疫或小分子疗法寻求减少 tau 积累、增强 清除，或防止 tau 寡聚体的形成，全球 CNS 生物标志物市场预计将达到 到 2020 年，将从 2015 年的 31 亿美元增至 51 亿美元。拟议的研究将为 Oligomerix 的内服药物提供支持 发现计划，公司将通过以下方式将这些检测方法商业化 因此，如果拟议的计划成功，将与诊断或生命科学公司合作。 强大的管理和科学团队将确保巨大的商业潜力和影响力。 mAb 生产和表征以及检测开发和商业化方面的能力。 此外，Peter Davies 博士和 Steven Jacobsen 博士也加入了科学顾问委员会 为公司提供一流的科学和商业经验。