Ligand non-competitive GITR antibody prevents formation of the obligatory signal-triggering GITRL: GITR stoichiometry

The prevalence of autoimmune diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is increasing. Glucocorticoid-induced TNFR-related protein (GITR), a TNF receptor superfamily (TNFRSF) member, is activated by GITR-ligand (GITRL). GITR signaling is pathogenic in models of RA and IBD, leading to lymphocyte proliferation and secretion of pro-inflammatory cytokines. Despite promising preclinical data, GITR neutralization in autoimmune diseases remains under-explored, due to challenges in avoiding antibody-mediated GITR activation. Therefore, we developed a human GITR-specific antibody that inhibits GITRL-mediated GITR-signaling, while preserving the GITRL epitope on GITR. The antibody strongly inhibited GITR signaling in the in vitro assays via a novel mechanism of disrupting downstream higher-order structures rather than direct blocking of GITR binding. Even though the antibody did not demonstrate efficacy in an NSG human skin graft transplant model, this general mechanism might be a viable therapeutic intervention for other TNFRSF members relying more significantly on soluble ligands.