Developing novel immunoassays specific for thyroid stimulating and TSHblocking autoantibodies

开发针对甲状腺刺激和 TSH 阻断自身抗体的新型免疫测定法

基本信息

批准号：
10263298
负责人：
Ling Tian
金额：
$ 49.51万
依托单位：
MEDIOMICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263298
关键词：
Accounting Agonist Algorithms Autoantibodies Autoimmune Diseases Autoimmunity Binding Biological Assay Blocking Antibodies Blood specimen COVID-19 Cell Culture Techniques Cells Clear Cell Clinical Clinical Trials Communicable Diseases Consumption Cyclic AMP Data Detection Development Diagnosis Diagnostic Disease Disease Management Disease Progression Disease remission Epitopes Fc Receptor Funding Goals Graves&apos Disease Hashimoto Disease Hour Human Hyperthyroidism Immunoassay Immunoglobulins Ligands Measures Methods Monitor Neonatal Outcome Patients Peptides Performance Periodicity Pharmacotherapy Phase Plasma Pregnancy Production Qualitative Methods Residual state Ribosomes Sampling Sensitivity and Specificity Serum Signal Transduction Somatotropin Specificity Sum TSH receptor antibody Testing Thyroid Gland Thyroid Hormones Thyrotropin Thyrotropin Receptor Time Training Validation Work ZIKA accurate diagnosis base commercialization cost cost effective design detection assay diagnostic assay disease diagnosis improved in-vitro diagnostics novel novel diagnostics receptor binding relapse prediction screening success tool

项目摘要

Abstract Graves’ disease (GD) is the most common cause of hyperthyroidism, accounting for 60 to 80 percent of more than 250 million cases of hyperthyroidism globally. Quantification of TSHR stimulating autoantibodies (TSAbs) can provide important guidance for the diagnosis and management of the disease, including predicting relapse or remission after initial anti-thyroid drug treatment or disease progression. However, TSHR blocking autoantibodies (TBAbs) can be also found in GD patients, complicating disease diagnosis and producing a spectrum of clinical presentations. For accurate diagnosis, assays to measure TSHR autoantibodies should be able to discriminate between TSAbs and TBAbs. Currently, TSAbs and TBAbs are measured either by cell-based bioassays or by binding assays. The cell-based bioassays can detect the total sum of functional TSAbs and TBAbs, but are time-consuming, laborious, and relatively expensive. Commercial binding assays are much simpler and faster. However, recent studies have clearly demonstrated that no commercially available binding assay can differentiate between TSAbs and TBAbs. Given the highly problematic lack of specificity of current binding assays, as well as the cost and time related drawbacks of the cell-based bioassays, there is a demonstrable need and commercial opportunity for simple, cost effective, and sensitive assays that can differentiate between TSAbs and TBAbs in patient blood samples. Developing and commercializing such assays are the goals of this project. In Phase I, we successfully used our novel epitope screening approach to identify unique peptide ligands that could differentiate between TSAbs and TBAbs. The goal of Phase II is to use these unique peptide ligands to develop, optimize and validate the novel diagnostic assays for GD, followed by testing their clinical utility. To accomplish this, we will use autoantibodies isolated from GD patient samples to identify additional peptide ligands (Aim 1) to assure high specificity and sensitivity of the assays. In Aim 2, we will use the best peptide ligands identified in Aim 1, together with those identified in Phase I, to develop specific assays with improved analytical performance. For a final validation of performance and clinical utility of the newly developed assays, we will compare the outcomes with two FDA-cleared assays on ~ 1,100 de-identified patient samples (Aim 3). Success of the Phase II project will allow Mediomics to establish our unique assays as simpler and more cost-effective alternatives to the cell-based bioassays, with a demonstrated ability to discriminate between TSAbs and TBAbs in patient samples. It will also allow Mediomics to develop rapid and cost-effective immunoassays for monitoring a range of other diseases, including infectious diseases. In Phase III, we will seek additional funding and collaborate with our corporate partners to enter clinical trials for FDA 510(k) clearance and to commercialize the assays as in vitro diagnostic immunoassays to monitor the TSAbs and TBAbs in human serum or plasma samples during the management of GD patients.

抽象的格雷夫斯病 (GD) 是甲状腺功能亢进症最常见的原因，占甲状腺功能亢进症的 60% 至 80% 全球超过 2.5 亿例甲状腺功能亢进病例。TSHR 刺激性自身抗体 (TSAb) 的定量分析。可以为疾病的诊断和治疗提供重要指导，包括预测复发或初始抗甲状腺药物治疗后缓解或疾病进展，但 TSHR 阻断。自身抗体 (TBAb) 也可在 GD 患者中发现，使疾病诊断复杂化并产生为了准确诊断，应进行 TSHR 自身抗体检测。能够区分 TSAb 和 TBAb 目前，TSAb 和 TBAb 是通过基于细胞进行测量的。生物测定或通过结合测定基于细胞的生物测定可以检测功能性 TSAb 和的总和。 TBAb 是一种耗时、费力且相对昂贵的商业结合测定方法。然而，最近的研究清楚地表明，没有商业上可用的绑定。鉴于当前缺乏特异性的严重问题，测定可以区分 TSAb 和 TBAb。结合测定，以及基于细胞的生物测定的成本和时间相关的缺点，有一个对简单、具有成本效益且灵敏的检测的明显需求和商业机会区分患者血液样本中的 TSAb 和 TBAb 开发此类检测并将其商业化。是该项目的目标，在第一阶段，我们成功地使用我们的新型表位筛选方法来识别。可以区分 TSAb 和 TBAb 的独特肽配体第二阶段的目标是使用这些。独特的肽配体，用于开发、优化和验证新的 GD 诊断方法，然后进行测试为了实现这一目标，我们将使用从 GD 患者样本中分离出的自身抗体来识别。额外的肽配体（目标 1）以确保检测的高特异性和灵敏度。在目标 2 中，我们将使用。目标 1 中确定的最佳肽配体以及第一阶段中确定的肽配体，以开发特定的检测方法具有改进的分析性能，用于新产品的性能和临床实用性的最终验证。开发的检测方法，我们将比较约 1,100 名身份不明的患者的两种经 FDA 批准的检测方法的结果样品（目标 3）。第二阶段项目的成功将使 Mediomics 能够更简单地建立我们独特的检测方法。以及基于细胞的生物测定法的更具成本效益的替代方案，具有区分能力它还将使 Mediomics 能够快速且经济高效地开发 TSAb 和 TBAb。在第三阶段，我们将寻求用于监测一系列其他疾病（包括传染病）的免疫测定。额外资金以及与我们的企业合作伙伴的合作，以进入 FDA 510(k) 许可的临床试验并将这些测定商业化为体外诊断免疫测定，以监测人体中的 TSAb 和 TBAb GD 患者管理期间的血清或血浆样本。