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

The common ? chain (?c; IL2RG) is a subunit of the interleukin (IL) receptors for the ?c cytokines IL2, IL4, IL7, IL9, IL15, and IL21. Because of the lack of appropriate neutralizing antibodies recognizing IL2RG, it has been difficult to thoroughly interrogate the role of ?c cytokines in inflammatory and autoimmune disease settings. To determine whether ?c cytokines might be targeted for T-cell-mediated disease prevention and treatment, we generated a new ?c cytokine receptor antibody, REGN7257. Biochemical, structural and in vitro analysis showed that REGN7257 binds with high affinity to IL2RG and potently blocks signaling of all ?c cytokines. In nonhuman primates, REGN7257 efficiently suppressed T-cells without impacting granulocytes, platelets or red blood cells. Using REGN7257, we showed that ?c cytokines drive T-cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis, by impacting multiple aspects of the pathogenic response. Importantly, we discovered that our xenogeneic GVHD mouse model recapitulates 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. And we showed that ?c cytokines contribute to disease pathology by driving all of these features. Overall, by demonstrating that broad inhibition of ?c cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of ?c cytokines as key drivers of pathogenic T-cell responses, offering a potentially novel strategy for the management of T-cell-mediated diseases. Overall design: Freshly isolated human PBMCs were activated with beads coated with anti-CD3 and anti-CD28. PBMCs with and without activation are incubated with REGN7257 (anti-IL2RG) or isotype for 3 days. PBMCs from 5 unique donors were isolated. Each condition was tested in duplicate. Experimental autoimmune encephalomyelitis (EAE) is the mouse model of human MS and is useful to investigate immune cell infiltration into the central nervous system. EAE was induced in all test animals. Three treatment groups: PBS treatment (n=8), IgG4 isotype control treatment (n=9), and REGN7257 treatment (n=10).