Cancer Cell Article Conformation of the Human Immunoglobulin G2 Hinge Imparts Superagonistic Properties to Immunostimulatory Anticancer Antibodies

sults with ‘‘checkpoint blocker’ ’ mAbs designed to antagonize related protein (GITR), in clinical development (Moran et al., directed against CD20 or epidermal growth factor receptorprovided by a detailed understanding of their mechanisms o regions provide mAbs targeting three immunostimulatory coreceptors in clinical development—CD40, 4-1BB, and CD28— with agonistic activity independent of Fcg receptor interaction that is usually required for receptor clustering and down-stream intracellular signaling. This exceptional activity is conferred by the unique configuration of disulfide bonds in the h2 hinge and paves the way for engineering improved clinical reagents with defined activity regardless of FcgR expression in the local microenvironment.the inhibitory T cell coreceptors cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 have reinforced the view that T cell immunity can provide long-lasting protection against aggressive and difficult-to-treat cancers, such as metastatic melanoma and non-small-cell lung cancer (Hodi et al., 2010; Topalian et al., 2012; Wolchok et al., 2013). Promising clinical data are also emerging with immunostimulatory mAbs that bind agonistically to the costimulatory receptor CD40 on anti