Antibody‐mediated depletion of lymphocyte‐activation gene‐3 (LAG‐3+)‐activated T lymphocytes prevents delayed‐type hypersensitivity in non‐human primates

Summary Lymphocyte‐activation gene‐3 (LAG‐3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG‐3+ T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti‐LAG‐3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG‐3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non‐human primate model of delayed‐type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)‐activated CD4+ and CD8+ human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0·1 mg/kg was sufficient to deplete LAG‐3+‐activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)‐driven skin inflammation in a tuberculin‐induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long‐lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG‐3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.