Agonistic antibodies to human glucocorticoid-induced tumor necrosis factor receptor as potential stimulators of T cell immunity for the treatment of cancer and viral infections

摘要

The magnitude of adaptive T cell responses is controlled by costimulatory molecules, including cell-surface associated members of the tumor necrosis factor receptor (TNF-R) family that modulate T cell receptor (TCR)-dependent activation, and by a network of regulatory T (Treg) cells that downregulate effector T cell functions. The glucocorticoid-induced TNF-R (GITR) is a type Ⅰ transmembrane protein that is expressed at high levels on CD4~+ CD25~+ Treg cells and on activated effector T cells. In vitro studies have shown that ligation of GITR with an agonistic monoclonal antibody (mAb) could abrogate the suppressive activity of Treg cells and enhance the survival, proliferation and effector functions of TCR-activated CD4~+ and CD8~+ T cells. Furthermore, studies in mice demonstrated that mAb-triggered GITR stimulation could also markedly augment antitumor and virus-specific T cell responses in vivo. This has suggested that agonistic anti-GITR mAbs may serve to stimulate T cell immunity for therapeutic purposes. Accordingly, the present patent application reports the generation of a novel agonistic murine mAb to human GITR that is able to reverse Treg-mediated suppression and costimulate T cell activation in vitro. Humanized versions of the mAb are also described, but without providing data on their binding and functional properties. Further studies will be needed to fully appraise the potential utility of these human mAbs for the immunotherapy of cancer or viral infections.