ILANIT 2020

Extension of IL-2 half-life, by addition of highly-glycosylated sequences, has the added befits of promoting anti-inflammatory immune response

Aner Ottolenghi Priyanka Bolel Angel Porgador
The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel

IL-2 is the master-regulator cytokine for T-cell dependent response. It is crucial for proliferation and survival of T-cells, and therefore was considered as a possible treatment for cancer. It was quickly discovered, however, that IL-2 has a toxic effect at high doses, and does not encourage an ant-cancerous effect as was hypothesized. Eventually it was discovered that IL-2 also promotes the T-regulatory (TReg) subset of T-cells which reduces inflammation and act as a pro-cancerous agent. IL-2 fell out of grace as a cancer treatment in high doses, but a rapidly growing body of research points to a possible other use as a treatment in low doses for autoimmune diseases, utilizing the very same TReg mechanism. IL-2 is still a toxic treatment, and very unstable protein, with short half-life in blood, which makes it less than ideal as a treatment. In this work we show that adding two flanking highly-glycosylated sequences to IL-2, improves the pharmacokinetic properties of IL-2. Furthermore our variant promotes an anti-inflammatory response which is evident from increase in TReg populations in mice. Additionally, administration of the variant impedes the progress of colitis, in a mouse model, and improves recovery. Our results suggest new avenues for an old treatment mostly abounded, and a new technique for manipulating instable cytokines, to form stable non-toxic treatments.









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