Abstract
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.
Highlights
Interleukin-2 (IL-2), a molecule critical for immune homeostasis, both promotes and regulates immune responses to foreign antigens as well as to naturally occurring self-antigens [1,2]
We developed an IL-2 mutein having a 30–80-fold reduced ability to activate IL-2 receptors present on CD4+ and CD8+ effector T cells and NK cells, which predominately signal through the intermediate affinity form of the receptor (IL-2Rβγ), with only a minimal reduction in its ability (6-fold) to activate high affinity IL2Rαβγ receptors present at the highest levels on Tregs
A loss of tolerance and a disruption in immune homeostasis are at the core of autoimmunity and many inflammatory diseases and have been strongly associated with impaired Treg responses, inadequate numbers of Tregs, as well as effector T cells resistant to suppression [49]
Summary
Interleukin-2 (IL-2), a molecule critical for immune homeostasis, both promotes and regulates immune responses to foreign antigens as well as to naturally occurring self-antigens [1,2]. Genetic studies in autoimmune disease identified polymorphisms in IL-2 pathway genes encoding IL-2RA (CD25), IL-2, CTLA-4 and PTPN2 as key drivers in autoimmune disease susceptibility [5,6,7,8,9,10]. Consistent with these genetic studies, functional studies demonstrated diminished effects of Tregs in vitro and in vivo.
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