TSH receptor autoantibodies - a personal experience

Nineteen fifty six was a pivotal year in our understanding of thyroid disease with the discovery of long acting thyroid stimulator (LATS) in the serum of patients with Graves' disease and autoantibodies to thyroglobulin in Hashimoto's disease. Soon after its discovery, LATS was shown to be a thyroid stimulating autoantibody and then in 1974 to be an autoantibody to the TSH receptor. Further major advances were made in 1989 (cloning the TSH receptor) and production of the thyroid stimulating human monoclonal autoantibody M22™ in 2002. The availability of M22™ enabled determination of the crystal structure of the TSH receptor in complex with M22™. Subsequently, three more human monoclonal autoantibodies to the TSH receptor were produced. One with stimulating activity (K1-18™) and two with blocking (antagonist) activity (5C9™ and K1-70™). Cryo-EM analysis of these four monoclonal autoantibodies in complex with the TSH receptor has provided a detailed understanding of how TSH receptor autoantibodies with different properties function. The monoclonal autoantibody K1-70™ with powerful TSH receptor blocking activity is in clinical trials and shows the expected beneficial effect on Graves' hyperthyroidism and Graves' ophthalmopathy. It is an exciting new TSH receptor specific drug.