Blocking common ? chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models

The common gamma chain (gamma c; IL-2RG) is a subunit of the interleukin (IL) receptors for the gamma c 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 gamma c cytokines in inflammatory and autoimmune disease settings. Here, we generated a gamma c cytokine receptor antibody, REGN7257, to determine whether gamma c 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 gamma c cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that gamma c 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 gamma c cytokines contribute to GVHD and aplas-tic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of gamma c cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of gamma c cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.

Automated summary

The study generated an antibody called REGN7257, which can bind to IL-2RG with high affinity and effectively block signaling of all gamma c cytokines, thus inhibiting T cell-mediated diseases. By using REGN7257, the researchers found that gamma c cytokines play a key role in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis, suggesting that inhibition of gamma c cytokine signaling is a potential strategy for the management of T cell-mediated diseases.