Role of isotype and FcγR interactions in therapeutic mAb function. Multiple mechanisms can mediate mAb therapeutic efficacy, influenced differentially by mAb isotype and FcγR interactions. (A) Direct targeting (depleting) mAbs mediate clearance of cells expressing their Ag target by recruitment of activatory FcγR (FcγRIIA or FcγRIIIA)-expressing cytotoxic immune effectors. Interaction of the mAb Fc with inhibitory FcγRIIB can prevent this process. Thus, hIgG1 and Fc- or glyco-engineered forms of mAb with a high activatory:inhibitory FcγR binding ratio are optimal. (B) Agonistic mAbs are designed to stimulate signaling through their receptor targets, typically TNFR, through receptor clustering. This can be achieved either by crosslinking of the mAb Fc by FcγRIIB on adjacent cells enhanced by the SE/LF mutation in hIgG1 (top) or through the unique configuration of human IgG2(B) (bottom; see also Figure 2). (C) Blocking mAbs are designed to block receptor-ligand interactions mediating immune suppression (eg, CTLA4, PD-1) or required for tumor cell growth/survival (eg, HER2, epidermal growth factor receptor [EGFR]). Recent preclinical data suggest that optimal activity, at least for PD1 mAbs, is achieved in the absence of FcγR engagement.³⁷  Isotypes with minimal FcγR binding, such as hIgG4 or “FcγR null” mAbs engineered to prevent FcγR engagement, may therefore be optimal. For each mechanism, example targets are listed on the left, with those in blue demonstrated to engage multiple mechanisms in preclinical models. The roles of FcγR (black, positive role; red, negative role) and optimal isotypes are listed on the right and are detailed in the text.