改造的IL-18变种具有延长半衰期和改善癌症免疫治疗的稳定性
Travis W Bainbridge1, Lifen Wang2, Marina Moskalenko3
1Protein Sciences, Genentech Inc, South San Francisco, California, USA.
Journal for immunotherapy of cancer
|July 15, 2025
概括
与Fc域融合的工程介素-18 (IL-18) 显示了增强的稳定性和半衰期,改善了用于癌症免疫治疗的抗瘤免疫力. 这种修改后的细胞因子有效地激活免疫细胞,并且在组合疗法中表现有前途.
科学领域:
- 免疫学 免疫学 免疫学
- 生物技术是生物技术.
- 在瘤学瘤学.
背景情况:
- 介素-18 (IL-18) 是一种促进炎症的细胞因子,对抗瘤免疫力至关重要.
- IL-18的治疗用途受到IL-18结合蛋白 (IL-18BP) 中和,体内半衰期短,物理化学性质差等因素的阻碍.
研究的目的:
- 为了改进IL-18的稳定性,药理动力学和可制造性,以提高癌症免疫疗法.
- 评估在体外和体内稳定二硫化物IL-18 Fc融合蛋白 (dsIL-18-Fc) 的特性.
主要方法:
- 通过安装人工二硫化物键和去除原生半氨酸来改造IL-18.
- 将稳定IL-18与IgG Fc域融合在一起,形成dSIL-18-Fc.
- 评估了稳定性,功效,药理动力学,药理动力学和抗瘤疗效在体外和体内.
主要成果:
- 与野生型IL-18相比,dSIL-18-Fc表现出更好的稳定性和哺乳动物细胞生产产量.
- 设计的细胞因子保持了生物效能和受体相互作用,由于Fc融合而延长了半衰期.
- dsIL-18-Fc在激活T和自然杀手 (NK) 细胞方面表现出有效性,单独和与抗PD-L1治疗一起诱导抗瘤反应.
结论:
- 工程 IL-18 (dsIL-18-Fc) 提供了增强的稳定性,延长半衰期和改进的可制造性.
- 修改后的细胞因子在癌症免疫治疗中表现出有利的类似药物的特性和治疗潜力.
- dsIL-18-Fc是增强抗瘤免疫力的有希望的候选者,特别是在组合治疗中.
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