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全身生理学基础的药代动力学建模框架用于CD3双特异抗体的组织向激活

Monica E Susilo¹, Stephan Schaller², Luis David Jiménez-Franco²

¹Genentech, Inc., South San Francisco, CA 94080, USA.

|April 26, 2025

概括

一个新的模型模拟了T细胞参与双特异性 (TCB) 抗体分布,优化了癌症治疗. 它显示较高的CD3亲和力可以减少瘤暴露,指导更好的剂量固体瘤.

科学领域:

免疫学免疫学免疫学
药理动力学药理动力学
计算生物学计算生物学

背景情况:

参与T细胞的双特异性 (TCB) 抗体显示了癌症治疗的前景,通过重定向T细胞来消除恶性细胞.
诸如细胞因子释放综合征和非瘤毒性等挑战阻碍了TCB在固体瘤中的有效性,需要优化生物分布.

研究的目的:

开发一种基于生理学的药理动力学 (PBPK) 模型,以模拟TCB生物分布和T细胞在固体瘤中的参与.
研究TCB格式和CD3亲和力对T细胞分布和瘤暴露的影响.

主要方法:

创建了一个全身PBPK模型,集成T细胞传播,保留,受体结合,周转和细胞参与.
来自转基因瘤携带小鼠的临床前生物分布数据使用具有不同CD3亲和度的TCB格式进行了分析.

主要成果:

该PBPK模型准确地描述了T细胞和TCB分布,预测了临床前生物分布模式.
较高的CD3亲和力导致更快的血液清理和T细胞丰富的器官增加积累,可能减少瘤暴露.
模拟显示了瘤内的剂量依赖性突触形成,在较高的TCB剂量下,血液的药理动力学是一个不太可靠的预测指标.

结论:

建立了一个全面的PBPK模型来模拟TCB和T细胞生物分布.
模型洞察力增强了对影响药理动力学,突触形成和TCB活动的因素的理解.
这种方法有助于优化TCB的剂量,并为固体瘤设计更有效的治疗策略.

关键词:

PBPKK PBPK 的意思是什么意思参与T细胞的双特异性T细胞.在TCB TCB中使用.剂量优化剂量优化暴露响应反应免疫突触的突触发生.

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