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-I阶段SBIR（PA-16-302） 标题 - tau低聚物片段的阿尔茨海默氏病特异性抗体生物标志物的开发 由于人口变化和衰老 人口，目前没有改良疾病的药物。它是美国最昂贵的疾病 直接成本每年的财务烧毁超过2360亿美元，到2050年估计将增加到1万亿美元。 迫切需要开发血液生物标志物，以便早期发现和分期 广告。缺乏准确，敏感和良好的AD生物标志物是识别的速率限制因素 有效的治疗方法。 tau蛋白，尤其是tau低聚物，已成为AD的高优先级目标 到1）它们与AD患者大脑内的疏散区域的高相关性，2）他们新发现 细胞外活动被认为会导致突触功能障碍和记忆力丧失，而3） 它们在病理传播中的作用。寡聚物已开发出新的方法来高度净化tau低聚物 并发现他们在特定地点进行自溶解碎片，从而在 切割末端。产生了对新epitopes的多克隆抗体（PAB），一个PAB显示出罢工 广告标本的特异性。在目标1和2中，将产生具有特异性的单克隆ABS（mAb） 对于该片段的末端和未切割位点的特异性。 AIM 3将是表征mabs并执行 概念验证生物标志物研究。该项目的总体目标是产生基于血液的，无创的 诊断测试是AD生物标本的Tau片段水平的生物标志物。这些mab也可以 用于了解AD中Tau自传溶解碎片的作用，以及切割与未切割Tau的比率 该站点在确定AD阶段时可能会提供更大的敏感性。此外，tau碎片特异性mab 这将根据拟议的计划开发 治疗程序，免疫或小分子疗法寻求减少tau积累，增强 清除或防止Tau低聚物的形成。全球CNS生物标志物市场预计将达到 到2020年，2015年的31亿美元到2020年。拟议的研究将使寡聚的内部药物启用 发现计划，该公司将通过通过商业化来使这些测定可用 与诊断或生命科学公司合作。拟议的计划（如果成功的话）将拥有 巨大的商业潜力和影响。强大的管理和科学团队将确保 MAB生产和表征以及测定开发和商业化的能力。 此外，彼得·戴维斯（Peter Davies）博士和史蒂文·雅各布森（Steven Jacobsen）博士在科学顾问委员会中的存在 为公司提供一流的科学和业务经验。