Implications of New Monoclonal Antibodies and the Crystal Structure of the Tsh Receptor for the Treatment and Management of Thyroid Diseases

Abstract

Autoantibodies to the thyroid-stimulating hormone receptor (TSHR) cause the hyperthyroidism of Graves‘ disease and contribute to Graves‘ eye signs. Human monoclonal TSHR autoantibodies prepared from patients‘ lymphocytes have important clinical applications in terms of their ability to stimulate TSHR-containing tissues. Also, TSHR monoclonal antibodies that act as antagonists may well be useful in treating Graves‘ eye disease. Recently, the high-resolution (2.55 Å) crystal structure of the TSHR in complex with a monoclonal thyroid-stimulating autoantibody has been determined, and this provides key insights into how the autoantibodies interact with the receptor. Furthermore, the structure can be used in the rational design of small molecules that will disrupt receptor binding by thyroid-stimulating autoantibodies, thus providing new strategies to control TSHR activation in addition to monoclonal antibodies.

Keywords:

• autoimmunity
• Graves‘ disease
• monoclonal antibodies
• thyroid
• thyroid-stimulating hormone
• TSH
• TSH receptor

Financial & competing interests disclosure

All authors are employees and/or directors and/or shareholders in the RSR Ltd group of companies, which develops and manufactures in vitro and in vivo diagnostics. B Rees Smith is also a director of Kronus Inc., which distributes RSR Ltd products. The authors are also named inventors on granted patents and patent applications related to monoclonal antibodies to the TSH receptor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.