中国仓鼠卵巢细胞
白细胞介素15
化学
受体
分子生物学
细胞因子
融合蛋白
CD8型
生物
重组DNA
生物化学
白细胞介素
免疫系统
免疫学
基因
作者
Kaiping Han,Xiaoyun Zhu,Bai Liu,Emily K. Jeng,Lin Kong,Jason L. Yovandich,Vinay Vyas,Warren D. Marcus,Pierre-André Chavaillaz,Christian A. Romero,Peter R. Rhode,Hing C. Wong
出处
期刊:Cytokine
[Elsevier]
日期:2011-12-01
卷期号:56 (3): 804-810
被引量:164
标识
DOI:10.1016/j.cyto.2011.09.028
摘要
IL-15, a promising cytokine for treating cancer and viral diseases, is presented in trans by the IL-15 receptor (IL-15R) alpha-chain to the IL-15Rβγc complex displayed on the surface of T cells and natural killer (NK) cells. We previously reported that an asparagine to aspartic acid substitution at amino acid 72 (N72D) of IL-15 provides a 4-5-fold increase in biological activity compared to the native molecule. In this report, we describe Chinese hamster ovary (CHO) cell expression of a soluble complex (IL-15 N72D:IL-15RαSu/Fc) consisting of the IL-15 N72D superagonist and a dimeric IL-15Rα sushi domain-IgG1 Fc fusion protein. A simple but readily scalable affinity and ion exchange chromatography method was developed to highly purify the complex having both IL-15 binding sites fully occupied. The immunostimulatory effects of this complex were confirmed using cell proliferation assays. Treatment of mice with a single intravenous dose of IL-15N72D:IL-15RαSu/Fc resulted in a significant increase in CD8+ T cells and NK cells that was not observed following IL-15 treatment. Pharmacokinetic analysis indicated that the complex has a 25-h half-life in mice which is considerably longer than <40-min half-life of IL-15. Thus, the enhanced activity of the IL-15N72D:IL-15RαSu/Fc complex is likely the result of the increased binding activity of IL-15N72D to IL-15Rβγc, optimized cytokine trans-presentation by the IL-15RαSu domain, the dimeric nature of the cytokine domain and its increased in vivo half-life compared to IL-15. These findings indicate that this IL-15 superagonist complex could serve as a superior immunostimulatory therapeutic agent.
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