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

The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the role of human Fc-FcγR interactions in the activity of 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 FcγR mice. We identified an Fc-optimized human IgG scaffold that increased binding to activating FcγRIIa and FcγRIIIa, enhancing anti-tumor efficacy. This Fc-optimized activity was mediated by multiple mechanisms that are unique to GITR mAb, including FcγR-mediated Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxic activity of CD4+ T cells and enhanced CD8+ T cell activity.