Immune agonism through FcγR scaffolding
Agonistic mAbs induce responses in target cells by stimulating signaling of their molecular target. Typically, this is to either enhance antitumor immunity by engaging costimulatory molecules on antigen‐presenting cells or T cells (i.e. CD40, 4‐1BB, OX40) or promote apoptosis by engaging death receptors on cancer cells (i.e. DR4, DR5, Fas).116
The role of FcγR in the action of these types of mAbs appears to be primarily as a scaffold. FcγRIIb is often the predominate receptor involved and the extent of its involvement is complex. In the case of CD40, the degree of FcγRIIb scaffolding potency is linked to the epitope location of the targeting mAb with greater potency seen for membrane proximal epitopes.43, 117 It is also noteworthy that depending on the epitope location, the scaffolding of anti‐CD40 mAbs may convert antagonist mAbs to agonistic.
Engineering of the IgG1 Fc region for enhanced and/or specific binding to FcγRIIb can greatly improve agonistic function.72, 118, 119, 120 Such mutations induced significantly greater agonistic activity in an anti‐DR5 model through increased induction of apoptotic death and decreased tumor growth compared with unmodified IgG1.121 The “SELF” modifications that dramatically and selectively increase affinity for FcγRIIb have also been used to enhance immune agonism in an anti‐OX40 model.122
The incorporation of the "V12" Fc mutations into IgG1 specifically enhance FcγRIIb interaction 200‐fold, conferring the enhanced agonistic activity of an anti‐CD137 antibody and an anti‐OX40 mAb.115, 122