Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model

• Published in: Biomedicine & pharmacotherapy Vol. 112; p. 108677
• Main Authors: Zhao, Meiqi, Luo, Manyu, Xie, Yueqing, Jiang, Hua, Cagliero, Cedric, Li, Ninghuan, Ye, Hao, Wu, Mingyuan, Hao, Shuai, Sun, Tianyuan, Yang, Hui, Zhang, Mengxiao, Lin, Tong, Lu, Huili, Zhu, Jianwei
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2019; Elsevier
• Subjects: IL-15 complex; Immunotherapy; Mammalian expression; PD-1; IL-15 complex; PD-1; Mammalian expression; Immunotherapy
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.108677

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.