P800: BLOCKADE OF COMMON GAMMA CHAIN CYTOKINE SIGNALING WITH REGN7257, AN INTERLEUKIN 2 RECEPTOR GAMMA (IL2RG) MONOCLONAL ANTIBODY, PROTECTED MICE FROM GRAFT-VERSUS-HOST DISEASE AND IMMUNE APLASTIC ANEMIA

Abstract

Background: Pathogenic T-cell responses in T cell-mediated diseases can be driven by cytokines of the common gamma chain (γc) cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). γc cytokines signal through their corresponding receptors, expressed primarily on immune cells (including T cells), that share a common coreceptor, interleukin 2 receptor subunit gamma (IL2RG) that is required for signaling. Aims: To understand the roles of γc cytokines in driving graft-versus-host disease (GVHD) and bone marrow failure disorders such as immune aplastic anemia (AA), we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γc cytokine-induced signaling, and we tested its ability to suppress pathogenic T-cell responses in mouse models of T cell-mediated disease. Methods: We evaluated the efficacy of REGN7257 in a xenogeneic mouse model of GVHD, where immunodeficient NOD-scid-IL2RGnull mice were engrafted with human peripheral blood mononuclear cells (huPBMC). Mice were treated with REGN7257 either prophylactically or therapeutically, and monitored for weight loss and survival, peripheral human T-cell engraftment as well as serum pro-inflammatory cytokine levels over time. In a separate experiment, mice were sacrificed at day 49 post-huPBMC injection (after 4 weeks of antibody treatment) for tissue analysis (liver, lung, skin and bone marrow) of immune cell infiltration (T cells and macrophages), inflammation and/or fibrosis. Results: In a xenogeneic model of GVHD, both prophylactic and therapeutic γc cytokine signaling blockade with REGN7257 effectively protected mice from weight loss and resulted in improved survival, by reducing T-cell expansion in blood and production of pro-inflammatory cytokines in serum. Consistent with the classic pathology of GVHD, lungs, liver and skin of control mice were highly infiltrated by T cells, while γc cytokine signaling blockade strongly reduced T-cell infiltration, with reduced tissue levels of pro-inflammatory cytokines. Importantly, therapeutic γc cytokine signaling blockade in established GVHD (i.e. when mice already showed weight loss) provided similar benefit. Blockade of γc cytokine signaling also led to a reduction in the severity of chronic GVHD, with decreased macrophage infiltration in liver and associated hepatic fibrosis. In this xenogeneic model of GVHD, hemoglobin levels and platelet numbers in blood were both reduced, indicating anemia and thrombocytopenia, respectively, which are two complications associated with aplastic anemia. In addition to peripheral pancytopenia, recipient mice that were engrafted with huPBMC also showed severe marrow aplasia. Importantly, this phenotype of aplastic anemia was prevented by blockade of γc cytokine signaling. Summary/Conclusion: Blockade of γc cytokine signaling with REGN7257 protected against T cell-mediated pathology in a xenogeneic GVHD mouse model that uniquely presents hallmarks of both acute and chronic GVHD, with T-cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and immune AA.