FcγRIIB as a key determinant of agonistic antibody efficacy

Fc gamma Receptor (FcγR) IIB (CD32B) is an immunoreceptor tyrosine inhibitory motif (ITIM)-bearing Fc receptor that is involved in abrogating the signalling and function delivered from other receptors; archetypally those arising from other, activatory, FcγR and from the B cell receptor (BCR) for antigen. In the context of immunotherapy, it has convincingly been shown to limit a variety of clinically important therapeutic monoclonal antibodies (mAb) such as rituximab and trastuzumab in preclinical models. However, recent exploration of so-called immunomodulatory mAb, for example agonist mAb directed against various members of the TNFR super-family, has cast new light on the ability of FcγRIIB to regulate immune responses and immunotherapy. These data, accumulated by several independent groups, have shown the seemingly paradoxical ability of FcγRIIB to augment or even be absolutely required for the activity of this class of mAb. In this review we highlight the key role of FcγRIIB in regulating agonistic mAb, detail the likely mechanism of action and propose new ways in which this information may be exploited therapeutically.