具有细胞受限IL-15活性的免疫细胞因子,用于治疗B细胞恶性瘤
Latifa Zekri1,2,3,4, Ilona Hagelstein1,2, Melanie Märklin1,2
1Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, 72076 Tübingen, Germany.
Science translational medicine
|March 6, 2024
概括
改性免疫细胞因子 (MIC+) 通过将Fc优化的抗体与突变的15 (IL-15) 介质素组合起来,增强抗体依赖的细胞细胞毒性 (ADCC). 这种方法改善了NK细胞对B细胞恶性瘤的活性,并可能减少副作用.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 生物技术是生物技术.
背景情况:
- 目前的癌症疗法,如rituximab,虽然先进,但需要优化抗体依赖细胞细胞毒性 (ADCC),以提高疗效.
- 介质素-15 (IL-15) 增强了自然杀手 (NK) 细胞的功能,但由于半衰期短,瘤积累不良和毒性而面临临临床限制.
- 需要改善免疫疗法,增强NK细胞介导的癌细胞杀死,同时最大限度地减少不良影响.
研究的目的:
- 通过将Fc优化的CD19/CD20抗体与改性IL-15部分融合,开发和评估新型免疫细胞因子 (MIC+).
- 设计IL-15以使IL-15Rβγ的目标依赖刺激,并优化其激发力和产能.
- 评估这些MIC+结构在B细胞恶性瘤中的体外和体内疗效和安全性.
主要方法:
- 使用Fc优化的CD19/CD20抗体和双变异IL-15 (L45E-E46K) 构建MIC+免疫细胞因子.
- 在体外评估NK细胞激活,抗白血病反应性和使用B细胞的毒性.
- 在小鼠模型中使用人类淋巴瘤和急性淋巴细胞白血病 (ALL) 细胞与人类和小鼠NK细胞进行体内评估.
主要成果:
- 与单独的Fc优化抗体相比,MIC+结构表明了依赖位的NK细胞激活和优越的抗白血病活性.
- 这些结构诱导了增强的NK细胞增殖和强大的细胞杀死在体外.
- 在体内研究证实了MIC+免疫细胞因子在相关的B细胞恶性瘤模型中具有优越的,依赖于标的抗白血病作用.
- 修改后的IL-15部分 (E46K突变) 取消了IL-15Rα结合,使得有条件的IL-15Rβγ刺激.
结论:
- MIC+免疫细胞因子代表了对B细胞恶性瘤的有前途的新免疫治疗策略.
- 这些结构有效地结合了Fc优化的抗体和IL-15细胞因子活性的好处.
- 由于有条件的,依赖于位的IL-15信号传递,MIC+结构调解了增强的NK细胞免疫力,并潜在地改善了安全性.
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