Content area
Abstract
Human cancers produce antigens that can allow a patients immune system to mount an endogenous antitumor response. However, this response is often ineffective because tumor cells can activate key immune checkpoints that cause localized immune suppression. Cancer immunotherapies using immune-checkpoint inhibitors can be used to block this localized suppression mechanism, thus promoting an effective endogenous immune response1. Pembrolizumab, a recently approved treatment for advanced melanoma, targets the mechanism of immune suppression by blocking the interaction of the immune-checkpoint PD-1 receptor and its ligand PD-L1 (ref. 2). Pembrolizumab belongs to the immunoglobulin (Ig) G4 subclass of human antibodies, which have been shown to exhibit unusual properties. IgG4 antibodies can be functionally monovalent in vivo3, because of the possibility of exchanging half-molecules (one heavy and one light chain) among themselves, a process known as Fab-arm exchange4. They also display affinities for Fc receptors different from those of the other immunoglobulin G subclasses (IgG1, IgG2 and IgG3)5. The biological consequences of these differences influence the selection of the appropriate IgG isotype for antibody therapeutics6. Because IgG4 only weakly induces complement and cell activation, owing to low affinity for C1q and Fc receptors, this isotype has become the preferred class for immunotherapy when recruitment of host effector function is undesirable.