Protein Conjugation For Antigen-Specific Treatment Of Thyroid Autoimmune Diseases

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Abstract Autoimmune disorders effect 1 in 6 Americans and cost the American Healthcare system over $100 billion annually. One of the most common autoimmune disorders is Graves’ disease, which effects 3% of women and 0.5% of men. The primary cause of Graves’ disease is the formation of antibodies against the Thyroid Stimulating Hormone Receptor (TSHR). The TSHR is a G-protein coupled receptor with a soluble extracellular A-subunit. It is understood that this A-subunit is the trigger for autoimmune recognition of the TSHR and resultant production of antibodies. These Thyroid Stimulating Antibodies (TSAb) cause over activation of the thyroid by mimicking the effect of thyroid hormones on the TSHR. Overstimulation of the thyroid leads to hyperthyroidism, or an overproduction of the thyroid hormone thyroxine which results in anxiety, weight loss, and ultimately osteoporosis and thyroid cancer. A common co-morbidity of Graves’ disease is Graves’ opthalmopathy (GO) which is caused by immunological attack on optical fibroblasts and can lead to optical fibrosis and eventually loss of vision. As with most autoimmune disorders, there is not treatment available to address the root cause of Graves’ disease –the immune recognition of the TSHR. Instead, modern approaches to treatment of Graves’ disease rely on symptom management, primarily through a combination of radioactive iodine (RAI) and thyroid inhibitors such as methimazole. In RAI therapy, iodine 131 is given to the patient with the goal of ablating thyroid function, thus diminishing hyperthyroid symptoms. Unfortunately, RAI often results in complete thyroid ablation, triggering chronic hypothyroidism and necessitation lifelong dependence on thyroxine supplements. RAI is also associated with a 20% increase in severe GO, a highly problematic outcome for a putative therapy. Thyroid inhibitors such as methimazole in contrast can be given for years at a time as a daily treatment, but often lead to relapse. Analysis of Graves’ patients across treatment strategies has shown significant decrease in quality of life, suggesting that improved therapeutic strategies are required. What is needed is a therapeutic strategy that addresses the fundamental cause of autoimmune disorders, in this case the recognition and targeting of the TSHR. Recent work has shown that antigen specific immune tolerance is possible when antigens can be coupled to certain tolerogenic receptors, nanoparticles, and proteins. However, as with most protein antigens, the TSHR is challenging to produce as a genetic fusion. We have developed a novel protein coupling technique capable of fusing intact proteins together using only native amino acids. We propose to apply this technique to the creation of antigen specific therapeutics by fusing the TSHR to tolerogenic cariers and delivering these to mouse models of Graves’ to assess the impact on serum thyroxine and TSAb levels.