JTA–009, a fully human antibody against human AILIM/ICOS, ameliorates graft–vs–host reaction in SCID mice grafted with human PBMCs

Objective Activation–inducible lymphocyte immunomediatory molecule (AILIM; also referred to as inducible costimulator [ICOS]) is the third molecule identified in the CD28 family participating in T–cell activation. AILIM/ICOS has been implicated in both effector and pathogenic T–cell functions, as evidenced by the beneficial effects of AILIM/ICOS blockade in several murine disease models. In the present study, the role of human AILIM/ICOS in T–cell function was investigated using a fully human monoclonal antibody specific to human AILIM/ICOS (JTA–009). Materials and Methods The effect of JTA–009 on allogenic T–cell proliferation was examined using human mixed lymphocyte reaction (MLR). To investigate the efficacy of AILIM/ICOS blockade in vivo, a graft–vs–host disease (GVHD) model, in which severe combined immunodeficient (SCID) mice were grafted with human peripheral blood mononuclear cells (PBMCs), was used. Results In MLR, suppressive effect of JTA–009 on allogenic T–cell proliferation was detected with comparable potency to CD28 blockade by cytotoxic T–lymphocyte antigen 4 (CTLA4)–Ig at an intermediate culture phase. JTA–009 acts as a blocking antibody in vivo and inhibited binding of human AILIM/ICOS to mouse AILIM/ICOS ligand (B7 h). Treatment with JTA–009 significantly prolonged survival of mice, with reductions of human interferon–γ levels in blood and number of human cells in spleens. Conclusion These results demonstrate that human AILIM/ICOS plays a role in the GVHD pathogenesis mediated by human T cells, and its blockade is attractive for abrogating undesired T–cell responses as is well–documented in mice.