Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists. • Activated/exhausted tumor-infiltrating CD8 + T cells co-express PD1 and GITR • Anti-GITR antibody IBI37G5 shows FcγRs-independent agonism and antitumor effect • IBI37G5 synergizes with anti-PD1 antibody to control established murine tumors • IBI37G5 exhibits best antitumor efficacy at doses near-saturating target receptors Determining the optimal in vivo efficacious doses is essential for the success of anti-GITR antibody development. Liu et al. propose a dose-finding strategy by monitoring the target saturation levels of GITR receptors to predict antitumor efficacy. This finding also has implications for therapeutic antibodies targeting other co-stimulatory receptors.