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

Publication date: April 2019Source: Biomedicine & Pharmacotherapy, Volume 112Author(s): Meiqi Zhao, Manyu Luo, Yueqing Xie, Hua Jiang, Cedric Cagliero, Ninghuan Li, Hao Ye, Mingyuan Wu, Shuai Hao, Tianyuan Sun, Hui Yang, Mengxiao Zhang, Tong Lin, Huili Lu, Jianwei ZhuAbstractRecombinant 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 diff...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research