Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system， while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore， IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc， a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells， we expressed the superagonist b... More
Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system， while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore， IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc， a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells， we expressed the superagonist by co-transfection of plasmids encoding IL-15 and sIL-15Rα/Fc respectively， yielding 36 mg/L of product after purification. Pharmacokinetic study demonstrated that the combination profoundly prolonged the half-life of IL-15 to 13.1 h in mice， about 18 folds longer than that of IL-15 monomer which is around 0.7 h. The bioactivity of the superagonist was characterized by CTLL-2 cells proliferation assay in vitro， showing its capability of stimulating the expansion of memory CD8 T cells (cluster of differentiation) in mouse spleen. Using a HT-29 xenograft NOD-SCID mouse model， we observed tumor growth inhibition in all groups that received the superagonist， indicating its anti-tumor efficacy via stimulating infused human immune cells. In addition， combo cancer treatment by IL-15·sIL-15Rα/Fc and programmed death-1 (PD-1) antibody have shown stronger inhibitory effects as compared with treatment with either single molecule. Therefore， we developed IL-15·sIL-15Rα/Fc to be a long half-life potential cancer immunotherapy candidate that can be applied alone or in synergy with PD-1/PD-L1 blockade.
