However, the use of IgG2 and IgG4 as “inert” subclasses is problematic. Both bind to the activating receptors FcγRIIa‐H131 and FcγRI, respectively (Table 2), and initiate effector functions such as neutrophil activation and apoptosis induction.75, 99 Interestingly, in experimental systems, cross‐linking of anti‐PD‐1 IgG4‐based mAb by FcγRI switched its activity from blocking to activatory.10 Moreover, IgG4 binds to FcγRIIb, which may scaffold the therapeutic mAb. Although scaffolding may be beneficial in some contexts, for example, in immune agonism,43 it can be disastrous and unexpected in others as it was for the anti‐CD28 TGN1412 mAb.59 Thus, the IgG2 and IgG4 subclasses are not the optimum choice for “FcR‐inactive” mAbs, and so modifying the Fc is a more direct approach.