Figure 4.

Activating and inhibitory antibody checkpoints determine efficacy and mechanism-of-action of immune agonist antibodies. This schematic figure models (A) Antibody engagement of activating and inhibitory FcγRs determine target cell depletion and agonism, respectively. The two mechanism compete when antibody variants (isotype) capable of binding both FcγR are used, resulting in reduced or no therapeutic activity. (B) Antibody variants with enhanced binding to activating FcγR (high A:I ratio) show improved depletion of Treg cells, which express higher numbers of receptors compared with effector cells, resulting in immune activation through elimination of suppressor cells. (C) Antibody variants with enhanced binding to inhibitory FcγR (low A:I ratio) show improved CD8⁺ T cell agonism, resulting in immune activation by expansion and boosting of effector cells.