A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease
| Autor: | Peterson, L, Bell, C, Howlett, S, Pekalski, M, Brady, K, Hinton, H, Sauter, D, Todd, J, Umana, P, Ast, O, Waldhauer, I, Freimoser-Grundschober, A, Moessner, E, Klein, C, Hosse, R, Wicker, L |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
Models Molecular Recombinant Fusion Proteins IL-2 mutein Mice Transgenic Autoimmunity chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Lymphocyte Activation T-Lymphocytes Regulatory Protein Structure Secondary Article Autoimmune Diseases Epigenesis Genetic Mice STAT5 Transcription Factor Animals Humans Protein Isoforms CTLA-4 Antigen Lymphotoxin-alpha Cell Proliferation Cytokine therapy Binding Sites Treg expansion Forkhead Transcription Factors hemic and immune systems DNA Methylation Interleukin-2 Receptor beta Subunit Disease Models Animal Macaca fascicularis Immunoglobulin G Interleukin-2 Immunotherapy Protein Binding Signal Transduction |
| Zdroj: | Journal of Autoimmunity |
| ISSN: | 1095-9157 0896-8411 |
| Popis: | 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 • A human IL-2 molecule mutated to decrease binding to the intermediate affinity IL-2 receptor preferentially activates Tregs. • Two IL-2 muteins fused to human IgG1 allow for sustained, preferential expansion of Tregs in cynomolgus and humanized mice. • As compared to the wild type IL-2 fusion protein, humanized mice expand fewer NK cells in response to the mutein. • The dynamic range of Treg increase based on dose suggests the ability to individualize dosing for particular diseases. |
| Databáze: | OpenAIRE |
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