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 Graves病（GD）是甲状腺功能亢进症的最常见原因，占更多的60％至80％全球甲状腺功能亢进症的2.5亿例。量化TSHR刺激自身抗体（TSABS）可以为疾病的诊断和管理提供重要的指导，包括预测继电器或初始抗甲状腺药物治疗或疾病进展后的缓解。但是，TSHR阻塞自身抗体（TBABS）也可以在GD患者中发现，使疾病诊断复杂并产生A 临床表现范围。为了准确诊断，测量TSHR自身抗体的测定应为可以区分TSABS和TBAB。目前，TSAB和TBAB是通过基于细胞的生物测定或通过绑定测定。基于细胞的生物测定可以检测功能性TSAB的总和 TBABS，但耗时，实验室且相对昂贵。商业绑定测定很大更简单，更快。但是，最近的研究清楚地表明，没有市售的结合测定可以区分TSAB和TBAB。考虑到当前的特异性非常缺乏绑定测定，以及基于细胞的生物测定的成本和时间相关的缺点，有一个可证明的需求和商业机会，用于简单，具有成本效益和敏感测定法在患者血液样本中区分TSAB和TBAB。开发和商业化此类测定是该项目的目标。在第一阶段，我们成功地使用了新型的表位筛选方法来识别可以区分TSAB和TBAB的独特胡椒配体。第二阶段的目的是使用这些独特的胡椒配体以开发，优化和验证GD的新型诊断测定法，然后进行测试他们的临床实用程序。为此，我们将使用从GD患者样本中隔离的自身抗体来识别额外的肽配体（目标1）以确保测定法的高特异性和灵敏度。在AIM 2中，我们将使用在AIM 1中鉴定出的最佳肽配体以及第一阶段确定的配体，以开发特定的测定法分析性能提高。最终验证新近的性能和临床实用性开发的测定法，我们将将结果与约1,100名识别患者的两个FDA清除测定法进行比较样品（目标3）。第二阶段项目的成功将使Mediomys能够建立我们独特的组装以及基于细胞的生物测定的更具成本效益的替代品，具有歧视能力在患者样品中的TSAB和TBAB之间。它还将允许Mediomys发展快速且具有成本效益用于监测一系列其他疾病的免疫测定法，包括传染病。在第三阶段，我们将寻求额外的资金并与我们的公司合作伙伴合作，进入FDA 510（k）许可的临床试验并将这些测定作为体外诊断免疫测定法，以监测人类的TSAB和TBABS GD患者治疗过程中的血清或血浆样品。