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
| Autor: | Huili Lu, Mingyuan Wu, Hua Jiang, Ninghuan Li, Tianyuan Sun, Tong Lin, Yueqing Xie, Cedric Cagliero, Shuai Hao, Meiqi Zhao, Mengxiao Zhang, Hui Yang, Hao Ye, Jianwei Zhu, Manyu Luo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Programmed Cell Death 1 Receptor Mammalian expression RM1-950 Pharmacology Immunoglobulin G 03 medical and health sciences Mice 0302 clinical medicine Immune system Antineoplastic Agents Immunological Cancer immunotherapy Drug Development Interleukin-15 Receptor alpha Subunit In vivo PD-1 medicine Animals Humans Receptor Interleukin-15 Mice Inbred BALB C biology Chemistry IL-15 complex General Medicine Immunotherapy Xenograft Model Antitumor Assays Recombinant Proteins Immunoglobulin Fc Fragments 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis biology.protein Female Therapeutics. Pharmacology Antibody HT29 Cells CD8 Half-Life |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 112, Iss, Pp-(2019) |
| ISSN: | 0753-3322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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