Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism

Abstract

GITR is a TNF receptor that promotes immune responses and drives anti-tumor activity. The receptor is activated by its ligand, GITRL, which is believed to cluster receptors into a high-order array. Anti-tumor IgG agonists also activate the receptor but their mechanisms are not understood. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer and each subunit binds one Fab in an orientation suggesting the antibody clusters receptors. Binding experiments with purified proteins show DTA-1 IgG and GITRL both drive extensive clustering of GITR.