8EPA

Structure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies

Summary for 8EPA

• Entry DOI: 10.2210/pdb8epa/pdb
• EMDB information: 28523
• Descriptor: Cytokine receptor common subunit gamma, REGN7257 Fab heavy chain, REGN7257 Fab light chain, ... (6 entities in total)
• Functional Keywords: interleukin signaling, lymphocyte maturation, blocking antibody, immunoglobulin, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 125760.90

Authors

Franklin, M.C.,Romero Hernandez, A. (deposition date: 2022-10-05, release date: 2023-01-25, Last modification date: 2024-11-13)

Primary citation

Le Floc'h, A.,Nagashima, K.,Birchard, D.,Scott, G.,Ben, L.H.,Ajithdoss, D.,Gayvert, K.,Romero Hernandez, A.,Herbin, O.,Tay, A.,Farrales, P.,Korgaonkar, C.K.,Pan, H.,Shah, S.,Kamat, V.,Chatterjee, I.,Popke, J.,Oyejide, A.,Lim, W.K.,Kim, J.H.,Huang, T.,Franklin, M.,Olson, W.,Norton, T.,Perlee, L.,Yancopoulos, G.D.,Murphy, A.J.,Sleeman, M.A.,Orengo, J.M.
Blocking common gamma chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models.
Sci Transl Med, 15:eabo0205-eabo0205, 2023

PubMed Abstract: 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.

PubMed: 36630481
DOI: 10.1126/scitranslmed.abo0205

Experimental method

ELECTRON MICROSCOPY (3.4 Å)