Figure 5.

Antibody preferred mechanism-of-action and FcγR-engagement is dependent on target receptor function and expression. This schematic figure models four exemplary antibody MoA's, pertinent to both immune checkpoint and tumor cell direct-targeting antibody types. (1) Blocking mAb. PD-1, a co-inhibitory antibody checkpoint expressed at high and similar levels on intratumoral Treg and Teff cells, is best targeted using a PD-1/PD-L1 blocking Fc-null antibody variant, since FcγR-mediated Teff cell depletion is undesirable (2) Blocking and depleting mAbs. Anti-CTLA-4 is overexpressed on intratumoral Treg compared with Teff, and activatory FcγR-engagement correlates with survival in melanoma patients treated with ipilimumab. Preferred MoA is two-fold: CTLA-4/B7 blockade and Treg depletion through FcγR-dependent mechanisms (3) Agonist mAb Preferred MoA is FcγR-engaging antibody variant, where FcγRs promote receptor cross-linking and signaling. (4) Depletion only mAb. Anti-IL2R antibody preferred MoA is ligand non-blocking and FcγR-dependent (Treg) cell depletion. IL-2R overexpressing Tregs are selectively depleted, while free IL-2 may promote Teff survival and expansion.