Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity

Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that involves increased effector T cell activity and regulatory T cell (Treg) elimination. The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the role of FcgR pathways in the activity of human GITR mAbs has not been comprehensively addressed. To this end, we employed Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized FcgR mice. We identified an Fc-optimized human IgG scaffold that increases binding to activating FcgRIIa and FcgRIIIa, enhancing anti-tumor efficacy. This Fc-optimized activity is mediated by multiple mechanisms, including FcgR-mediated Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells. Our findings suggest a strategy to optimize human GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.