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一个定量系统药理模型,以告知工程IL-15的PKPD动态关系的临床翻译

Louis R Joslyn¹, Mohammad Jafarnejad¹, Rajbharan Yadav¹

¹Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

|October 1, 2025

概括

定量系统药理学建模预测了工程Interleukin-15 (IL-15) 免疫疗法的淋巴细胞扩张. 这种方法有助于理解药理动力学/药理动力学 (PK/PD),并支持IL-15癌症治疗的临床剂量.

科学领域:

免疫学免疫学免疫学
药理学药理学是指药理学的学科.
计算生物学计算生物学

背景情况:

介质素-15 (IL-15) 对于淋巴细胞免疫非常重要,但其半衰期很短,限制了其癌症治疗潜力.
工程IL-15激动剂在药理动力学 (PK),药理动力学 (PD) 和由于复杂的免疫反应而导致的安全性方面面临挑战.
了解免疫细胞扩张的机制对于优化基于IL-15的疗法至关重要.

研究的目的:

开发一种定量系统药理 (QSP) 模型,用于对工程IL-15疗法的反应中淋巴细胞扩张动态.
分析三个不同的IL-15/IL-15Rα结构的PK/PD关系:Efbalropendekin alfa,PD1/IL15 TaCk和RSV/IL15 TaCk.
利用QSP模型预测临床PK/PD结果,并支持IL-15免疫疗法的剂量决定.

主要方法:

开发一个QSP模型来模拟在工程IL-15变体的管理后的淋巴细胞动态.
在模型中包含了三种不同的IL-15/IL-15Rα治疗药物,其特性各不相同.
模拟PK和淋巴细胞扩张在不同剂量水平的每个治疗.
虚拟患者队列的生成,以预测临床PK/PD反应.

主要成果:

QSP模型成功地捕获了所有测试的IL-15分子的系统性PK和淋巴细胞扩张.
模型模拟预测了Efbalropendekin alfa与PD1/IL15 TaCk相比,在摩拉匹配剂量下,对终端药物暴露的更高.
结果表明,虽然血液细胞扩张反映了组织动态,但在血液和组织中,不同的细胞群体是目标.
该模型确定了PD-1表达T细胞作为Efbalropendekin alfa和PD1/IL15 TaCk组织中的关键标.

结论:

QSP建模为整合非临床数据和预测基于细胞因子的免疫疗法的临床结果提供了强大的框架.
开发的模型提供了对工程IL-15疗法的PK/PD关系的见解.
这种方法支持翻译研究,并有助于优化新型癌症免疫疗法的剂量策略.

关键词:

临床翻译临床翻译工程融合蛋白质的工程融合蛋白质.淋巴增殖性细胞因子 (Lymphoproliferative cytokines) 是一种细胞因子.药理动力学 (PD) 增强的TMDD.量化系统药理学 (QSP) 模型模型目标介导性药物排放 (TMDD) 是指指导性药物排放.

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