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Submitted on December 28, 2006
Accepted on January 22, 2007
Autoimmune Disease Unit, Cedars-Sinai Research Institute and UCLA School of Medicine, Los Angeles, CA
* To whom correspondence should be addressed. E-mail: rapoportb{at}cshs.org.
Thyrotropin (TSH) binding to the TSH receptor (TSHR) induces thyrocyte growth and proliferation primarily by activating the adenylyl cyclase signaling pathway. Relative to the other glycoprotein hormone receptors, the TSHR has considerable ligand-independent (constitutive) activity. We describe a TSHR monoclonal antibody (CS-17) with the previously unrecognized property of being an inverse agonist for TSHR constitutive activity. This property is retained even when constitutive activity is extremely high consequent to diverse TSHR extracellular region mutations. A similar effect on an activating mutation at the base of the sixth transmembrane helix (not accessible to direct CS-17 contact) indicates that the latter is acting allosterically. Administered to mice in vivo, CS-17 reduces serum T4 levels. The CS-17 epitope is conformational and a significant portion lies in the C-terminal region of the TSHR leucine-rich domain (residues 260-289). By interacting with the large TSHR extracellular domain CS-17 is, to our knowledge, the first antibody reported to be an inverse agonist for a member of the G protein receptor super family. After humanization of its murine constant region, CS-17 has the potential to be an adjunctive therapeutic agent in athyreotic patients with residual well-differentiated thyroid carcinoma, as well as pending definitive treatment in some selected hyperthyroidism states.
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