Blocking common γ chain cytokine signaling ameliorates T cell–mediated pathogenesis in disease models.

The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell–mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell–mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of 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. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell–mediated diseases. Curbing counterproductive cytokines: The common γ chain (γc; IL-2RG) is a component of cytokine receptors specific to the γc cytokine family that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Studies of the γc cytokines have been constrained by the lack of a neutralizing antibody that can recognize IL-2RG. Le Floc'h et al. describe the generation and characterization of REGN7257, a monoclonal antibody specific to IL-2RG. In vitro studies confirmed that REGN7257 binds with high affinity to IL-2RG and specifically blocks γc cytokine signaling. Treatment of nonhuman primates with REGN7257 suppressed NK cells and T cells without affecting granulocytes, erythrocytes, or platelets. Interestingly, REGN7257 curbed pathogenic responses in mouse models of allogeneic and xenogeneic graft-versus-host-disease, immune aplastic anemia, and multiple sclerosis, thus confirming the critical role of the γc cytokines in these immune mediated disorders.—CNF [ABSTRACT FROM AUTHOR]

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