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

项目总结-第I阶段SBIR（PA-16-302） 标题-tau寡聚体片段的阿尔茨海默病特异性抗体生物标志物的开发 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不断增加 目前还没有治疗疾病的药物。它是美国最昂贵的疾病， 每年的直接费用超过2 360亿美元，估计到2050年将增加到1万亿美元。 目前迫切需要开发用于早期检测和分期的血液生物标志物， AD.缺乏准确、敏感和有效的AD生物标志物是鉴别AD的一个限速因素。 有效的治疗。Tau蛋白，特别是Tau寡聚体，已经成为AD的高优先级靶标，这是由于 1）它们与AD患者脑内患病区域的高度相关性，2）它们的新发现 细胞外活性，其被认为导致突触功能受损和记忆丧失，以及3） 他们在病理学传播中的作用Oligomerix开发了高度纯化tau寡聚体的新方法 并发现它们在特定位点发生自身蛋白水解片段化， 切割结束。产生了针对新表位的多克隆抗体（pAb），并且一种pAb显示出显著的特异性。 AD标本的特异性。在目的1和2中，将生成具有特异性的单克隆抗体（mAb） 和对未切割位点的特异性。目标3将是表征mAb并进行 概念验证生物标志物研究。该项目的总体目标是生产一种基于血液的非侵入性 诊断测试作为来自AD的生物样本的tau片段水平的生物标志物。这些mAb还可以 用于理解tau蛋白自身蛋白水解片段化在AD中的作用，以及在AD中切割的tau蛋白与未切割的tau蛋白的比率。 该位点可在确定AD分期中提供更高的灵敏度。此外，tau片段特异性mAb 根据拟议的计划，将开发的任何可能有巨大的商业用途， 治疗方案、免疫或小分子治疗剂，其寻求减少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 从2015年的31亿美元到2020年的51亿美元。拟议的研究将使Oligomerix的内部药物 发现计划，公司将通过商业化这些检测方法， 与诊断或生命科学公司合作。因此，拟议的方案，如果成功，将有 巨大的商业潜力和影响。强大的管理和科学团队将确保 在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博士在科学顾问委员会的存在 为公司提供一流的科学和商业经验。

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.