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使用开放流微 perfusion 猪模型预测单克隆抗体的人体皮下生物可用性

Gerd Schwagerle¹, Rodolfo Hernandes Bonan², Mikolaj Milewski³

¹HEALTH Institute for Biomedical Research and Technologies, JOANNEUM RESEARCH Forschungsgesellschaft bmH, Graz, Austria; University for Continuing Education Krems, Krems, Austria.

Journal of controlled release : official journal of the Controlled Release Society

|November 23, 2025

概括

现在更准确地预测人类皮下单克隆抗体的生物可用性. 使用开放流微 perfusion 和 PBPK 建模的新方法通过分析局部抗体-组织相互作用来改善预测.

科学领域:

药理动力学和药物输送方法
生物技术和生物制品生物技术和生物制品
翻译医学是一种翻译医学.

背景情况:

单克隆抗体 (mAbs) 的皮下 (SC) 给药提供了诸如患者自我给药和降低成本等优势.
准确预测人类SC mAbs的生物利用性仍然是一个重大挑战.
了解局部mAb-组织相互作用对于改善生物可用性预测至关重要.

研究的目的:

开发和验证一种新的方法,结合开放流微 perfusion (OFM) 和基于生理的药理动力学 (PBPK) 建模,以预测人类SC mAb的生物可用性.
在猪模型中研究局部mAb-组织相互作用,包括结合和沉.
评估OFM-PBPK综合方法对三大商业数据的预测准确度.

主要方法:

使用开放流微 perfusion (OFM) 探针缓慢注入 mAbs 猪皮下组织,最大限度地减少仓库的形成.
每小时通过OFM探针收集间歇性液体 (ISF),并通过组织活检分析mAb度.
估计mAb扩散和结合速率常数使用一个分区模型,将OFM衍生参数集成到人类PBPK模型中.

主要成果:

综合的OFM-PBPK模型预测了人类SC mAb的生物可用性,准确度在临床数据的5%以内.
与标准模型相比,人类度-时间概况的预测准确度明显提高.
观察到在组织中的局部mAb保留和人类SC生物可用性之间存在逆相关性.

结论:

结合了OFM技术和OFM知情的PBPK建模,为预测人类SC mAb生物可用性提供了一个强大的策略.
这种方法提高了对局部mAb-组织相互作用的理解,这对于药物开发至关重要.
为优化SC药物输送策略和降低开发成本提供了一个有价值的工具.

关键词:

在模型建模.间歇性流体采样间歇性流体采样当地组织相互作用.基于生理学的药理动力学 (PBPK)临床前的OFM研究组织活检组织活检.

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