Anti-PD-1 antibodies recognizing the membrane-proximal region are agonists that can stimulate immunosuppressive activity of PD-1

Abstract The success of immunoenhancing anti-PD-1 blocking antibodies in cancer treatment indicates the biological significance of PD-1-dependent immunoregulation in the human immune system. Active stimulation of PD-1 is potentially an effective approach in treating various inflammatory disorders; however, agonistic anti-PD-1 antibodies stimulating the immunosuppressive activity are not clearly defined. Here, by assessing the biological activities of anti-human PD-1 mAbs, we have identified functional anti-PD-1 agonists in the antibody group recognizing the membrane-proximal extracellular region (MPER). MPER recognition was characteristic to anti-PD-1 agonist mAbs and distinct from blocking mAbs binding to the membrane-distal region of PD-1. The agonistic activity was mediated by Fc receptor-dependent co-ligation of PD-1 molecules. In vivo anti-inflammatory efficacy of the PD-1 agonist in murine disease models suggests its clinical potential to various inflammatory disorders including autoimmune diseases. Meiji Seika Pharma, Co., Ltd. Foundation for Biomedical Research and Innovation at Kobe