Role of DCIR in neutrophil and monocyte regulation: insights from humanized agonist and cell-depleting antibodies in autoimmune diseases 2818

Abstract Description Defective DC inhibitory receptor (DCIR) function is associated with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus, and Sjögren’s syndrome. In our previous publication, we demonstrated that DCIR is selectively expressed on myeloid cells, particularly neutrophils and monocytes, as opposed to B and T cells. We developed a potent anti-DCIR agonist (9D9) and a DCIR+ cell-depleting antibody (5E11). In this study, we further explore the role of DCIR in monocytes and neutrophils by utilizing these fully humanized antibodies. Additionally, 9D9, but not 3F7 reduced ROS production and the oxidative burst of neutrophils, measured as oxygen consumption rate (OCR). Given that DCIR is highly expressed on activated neutrophils, 5E11 and, to a lesser extent, 3F7 exhibited Fc-mediated antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) effects on neutrophils. In human DCIR–knock-in mouse models, both 9D9 and 5E11 ameliorated experimental acute peritonitis by reducing the accumulation of neutrophils and monocytes through cytokine reduction (by 9D9) or direct DCIR+ cell depletion (by 5E11). Administration of 9D9, but not 3F7, attenuated experimental colitis by reducing the infiltration of inflammatory neutrophils and neutrophil elastase. These findings provide compelling evidence that DCIR is a potential target on monocytes and neutrophils for developing transformative therapies in autoimmune diseases. Funding Sources Supported by AbbVie Inc. Topic Categories Therapeutic Approaches to Autoimmunity (THER)