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Susceptibility to multiple autoimmune diseases is associated with common gene polymorphisms influencing IL-2 signaling and Treg function, making Treg-specific expansion by IL-2 a compelling therapeutic approach to treatment. As an in vivo IL-2 half-life enhancer we used a non-targeted, effector-function-silent human IgG1 as a fusion protein. An IL-2 mutein (N88D) with reduced binding to the intermediate affinity IL-2Rβγ receptor was engineered with a stoichiometry of two IL-2N88D molecules per IgG, i.e. IgG-(IL-2N88D)2. The reduced affinity of IgG-(IL-2N88D)2 for the IL-2Rβγ receptor resulted in a Treg-selective molecule in human whole blood pSTAT5 assays. Treatment of cynomolgus monkeys with single low doses of IgG-(IL-2N88D)2 induced sustained preferential activation of Tregs accompanied by a corresponding 10-14-fold increase in CD4+ and CD8+ CD25+FOXP3+ Tregs; conditions that had no effect on CD4+ or CD8+ memory effector T cells. The expanded cynomolgus Tregs had demethylated FOXP3 and CTLA4 epigenetic signatures characteristic of functionally suppressive cells. Humanized mice had similar selective in vivo responses; IgG-(IL-2N88D)2 increased Tregs while wild-type IgG-IL-2 increased NK cells in addition to Tregs. The expanded human Tregs had demethylated FOXP3 and CTLA4 signatures and were immunosuppressive. These results describe a next-generation immunotherapy using a long-lived and Treg-selective IL-2 that activates and expands functional Tregsin vivo. Patients should benefit from restored immune homeostasis in a personalized fashion to the extent that their autoimmune disease condition dictates opening up the possibility for remissions and cures.

Original publication




Journal article


J Autoimmun

Publication Date





1 - 14


Autoimmunity, Cytokine therapy, IL-2 mutein, Immunotherapy, T(reg) expansion, Animals, Autoimmune Diseases, Binding Sites, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Cell Proliferation, DNA Methylation, Disease Models, Animal, Epigenesis, Genetic, Forkhead Transcription Factors, Humans, Immunoglobulin G, Immunotherapy, Interleukin-2, Interleukin-2 Receptor beta Subunit, Lymphocyte Activation, Lymphotoxin-alpha, Macaca fascicularis, Male, Mice, Mice, Transgenic, Models, Molecular, Protein Binding, Protein Isoforms, Protein Structure, Secondary, Recombinant Fusion Proteins, STAT5 Transcription Factor, Signal Transduction, T-Lymphocytes, Regulatory