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
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
复制标题
开发重组人 IL-15·sIL-15Rα/Fc 超级激动剂，在小鼠模型中单独或与 PD-1 阻断剂联合使用，可改善半衰期及其抗肿瘤活性
DOI：
10.1016/j.biopha.2019.108677
复制
发表时间：
2019
影响因子：
7.5
通讯作者：
Jianwei Zhu
中科院分区：
文献类型：
--
作者：
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 Zhu
重组人白细胞介素-15 （IL-15）具有良好的免疫刺激作用，是一种有效的肿瘤免疫治疗候选药物。以往的研究表明，IL-15在循环系统中半衰期较短，而与其受体的复合物可以延长其半衰期并有利于其在体内的活性。因此，IL-15复合物更有利于临床开发。在此，我们开发了IL-15·sIL-15Rα/Fc，这是一个由IL-15及其受体α亚基的细胞外区域组成的复合物，它与免疫球蛋白G (IgG1) Fc融合，进一步延长了其在血浆中的半衰期。通过在HEK293细胞中的瞬时基因表达，我们分别用编码IL-15和sIL-15Rα/Fc的质粒共转染表达了超激动剂，纯化后的产物为36 mg/L。药代动力学研究表明，联合用药可使IL-15在小鼠体内的半衰期显著延长至13.1 h，比单用IL-15的半衰期（0.7 h左右）延长约18倍。体外CTLL-2细胞增殖实验表明，超激动剂具有刺激小鼠脾脏记忆性CD8+T细胞（分化簇）扩增的作用。使用HT-29异种移植NOD-SCID小鼠模型，我们观察到接受超级激动剂的所有组的肿瘤生长抑制，表明其抗肿瘤功效是通过刺激输注的人免疫细胞。此外，与单分子治疗相比，IL-15·sIL-15Rα/Fc和程序性死亡-1 （PD-1）抗体联合治疗癌症显示出更强的抑制作用。因此，我们开发了IL-15·sIL-15Rα/Fc作为一种长半衰期的潜在癌症免疫治疗候选药物，可以单独应用或与PD-1/PD-L1阻断剂协同应用。
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 activitiesin 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 assayin 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 efficacyviastimulating 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.