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. It is an autoimmune disorder caused by thyroid stimulating antibodies (TSAbs), which bind to the thyrotropin (or thyroid-stimulating hormone (TSH)) receptor on the surface of a thyroid cell. This leads to stimulation of the thyroid gland and subsequent synthesis and secretion of excess thyroid hormone. One crucial diagnostic tool is the use of assays for the quantification of TSAb, which can provide important guidance for the diagnosis and management of patients with both thyroidal GD and extrathyroidal manifestation. In addition, detection of TSAb is critical in predicting relapse or remission after initial anti-thyroid drug treatment or disease progression. Although many assays have been developed to detect autoantibodies against TSHR (TRAbs), it has been shown that among all commercially available assays, only cell-based bioassays can differentiate between stimulatory and inhibitory activity (TBAb) of circulating TRAb. However, cell-based bioassays are time-consuming, laborious, and relatively expensive. Therefore, there is a need for the development of simple, cost effective, and sensitive immunoassays that can differentiate between TSAb and TBAb in patient blood samples. Mediomics has developed a novel assay platform (PINCER assays) that allows simple homogenous mix-and-read detection of a variety of targets. These rapid-result assays can reach high specificity while remaining easy to use and at a low cost. In addition, our long-term collaborator, Dr. Tomasz Heyduk?s laboratory, developed a novel screening platform by combining both ribosome display and Next Generation Sequencing (NGS) technologies to quickly identify linear and conformational epitopes of antibodies from patient samples. Here, we propose to take advantage of Mediomics? innovative assay technology and the novel screening platform to develop highly specific immunoassays to detect stimulating and blocking autoantibodies (TSAbs and TBAbs) against the thyrotropin receptor. We have two specific aims in our Phase I project.
Aim 1. Explore the entire protein sequence space of TSHR to identify peptide ligands specifically recognizing isolated human TSAbs or TBAbs.
Aim 2. Prepare, optimize, and evaluate the performance of peptide-based immunoassays. If this project is successful, we would have validated the commercial potential of our assay, and will thus lay a foundation for transition to Phase II, where we will embark on the development of a commercialization-ready product and its clinical validation with well-defined clinical samples.
This project is aimed at developing novel immunoassays for thyroid stimulating and TSH blocking autoantibodies. The improved performance of Mediomics? assays and ELISA-based assays, especially increased specificity and reduced cost, will assure a large impact on efforts in the diagnosis of Graves? diseases and other autoimmune diseases.
