Although monoclonal antibodies against cytotoxic lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) alone or in combination showed high efficacies in cancer therapies, other immune-checkpoint inhibitors are expected to obtain curative effects. Because CTLA-4 and PD-1 act as T cell silencer in adaptive immune system, we considered that T-cell immunoglobulin and mucin domain 3 (TIM-3), which negatively regulates both innate and adaptive immune systems, is a new target for the next generation of immune checkpoint inhibitors.
TIM-3 is known to interact with four ligands, galectin-9, phosphatidylserie (PtdSer), CEACAM-1and HMGB1 (high mobility group box-1). It is also known that galectin-9 is implicated in T cell regulation, but HMGB1 and PtdSer are involved in innate immunity. Recent report has described that HMGB1 is the key ligand which mediates nucleic acid sensing and activation of normal dendritic cells (DCs) and that TIM-3 inhibit the role of HMGB1 in tumor-infiltrating DCs. We have already identified TIM-3-binding HLHP and are now carefully investigating the effects on binding of TIM-3 and its ligands to develop the new generation of immune checkpoint inhbitors.