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.

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