Kurzfassung

An in-vitro study to evaluate Byondis’ five thyroid stimulating hormone receptor (TSHR) antagonist(s) in Proof of Principle (PoP) models that support preclinical research and characterization of TSHR antagonists for GO/GD treatment in cell-based bioassays. Graves’ disease (GD) is characterized by the production of autoantibodies to thyroid-associated antigens such as the thyrotropin receptor (TSHR). The pathophysiology of the hyperthyroidism of GD is related to thyroid-stimulating antibodies...An in-vitro study to evaluate Byondis’ five thyroid stimulating hormone receptor (TSHR) antagonist(s) in Proof of Principle (PoP) models that support preclinical research and characterization of TSHR antagonists for GO/GD treatment in cell-based bioassays. Graves’ disease (GD) is characterized by the production of autoantibodies to thyroid-associated antigens such as the thyrotropin receptor (TSHR). The pathophysiology of the hyperthyroidism of GD is related to thyroid-stimulating antibodies (TSAb) that activate the TSHR on thyroid follicular cells, leading to unregulated thyroid hormone production. These functional autoantibodies mimic the receptor’s natural ligand by stimulating cyclic adenosine monophosphate (cAMP)-dependent signal transduction, but other anti-TSHR antibodies antagonize the TSHR by either blocking TSH binding (TBAb) or interacting with TSHR epitopes that inhibit cAMP production. These Ab can be measured either via competitive-binding immunoassays or with cell-based bioassays. Functional TSHR Ab bioassays distinguish between TSHR-stimulating and blocking Ab through their effect on cyclic adenosine monophosphate production in a cell line stably transfected with a chimeric human receptor. Bioassays for TSHR-stimulating and blocking Ab are routinely performed in our research lab.
 Aims of the project are to test the potency (IC50) of Byondis’ TSHR antagonists in M22-stimulated human TSHR cell-based bioassays standardly performed at the JGU Molecular Thyroid Research Laboratory. Selection of the EC80 of the M22 induced signaling to test the anticipated inhibition of the antagonists in dose-response curves (DRC). Evaluate Byondis’ lead compound for its potential to inhibit TSHR-mediated signaling induced by GO/GD patient samples and evaluate Byondis’ lead compound for its potential to inhibit TSHR-mediated signaling in Human Orbital fibroblasts isolated from GO patients (GOF) to demonstrate dose-dependent inhibition of TSHR signaling by the TSHR antagonist.
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