Fig. 2.

Engineered interleukin-15 (IL-15) variants. IL-15 is mainly produced as a membrane-bound heterodimer associated with IL-15Rα. The interaction of the IL-15–IL15-Rα complex with IL-2/IL-15Rβ and the common γc receptor triggers the phosphorylation of Janus kinase-1 (JAK1) and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3 (STAT3) and STAT5. Clinical trials have tested the safety and efficacy of recombinant aglycosylated IL-15 and engineered variants to mimic the trans-presentation process and to enhance the half-life in circulation. These variants included the superagonist RLI protein (comprising the binding domain of IL-15Rα fused to IL-15), ALT-803 (comprising mutated IL-15 fused to the binding domain of IL-15Rα and an IgG1 Fc domain) and Sushi-IL15-Apo (a fusion protein encompassing the binding domain of IL-15Rα, IL-15 and apolipoprotein A-I)