短暂失活的抗体-药物偶联物的QSP模型突出了抗体半衰期短的好处。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Eshita Khera, Lekshmi Dharmarajan, Dominik Hainzl, Volker Engelhardt, Helena Vostiarova, John Davis, Nicolas Ebel, Kuno Wuersch, Vincent Romanet, Sherif Sharaby, Jeffrey D Kearns
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引用次数: 0

摘要

抗体药物偶联物(ADC)是一类很有前途的肿瘤治疗药物,由抗体通过连接物偶联到有效载荷上组成。DYP688是一种新型ADC,由信号蛋白抑制剂有效载荷(FR900359)组成,在血浆中经历独特的抗体失活,导致复杂的药理学。为了评估FR失活对DYP688药理学和临床可开发性的影响,我们对临床前PK和肿瘤生长抑制(TGI)数据进行了翻译建模,同时进行了机械Krogh圆柱肿瘤建模。使用PK-TGI模型,我们确定了一个复合暴露于肿瘤以上浓度(AUCTSC)指标作为pk -疗效的驱动因素。为了支持AUCTSC作为疗效驱动因素背后的机制,我们对DYP688的肿瘤内药代动力学和药效学进行了定量系统药理学(QSP)建模。通过探索性仿真,我们表明,尽管DYP688具有瞬时失活,但它偏离了典型的ADC设计教条,具有最佳的FR900359活性。最后,我们成功地完成了DYP688 PK的临床前到临床转化,包括有效载荷失活动力学,证明了预测的PK与观察到的中期临床PK非常一致。总的来说,这项工作强调了早期定量药代动力学是ADC设计-可开发性差距中缺失的一环。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life.

Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling. Using a PK-TGI model, we identified a composite exposure-above-tumorostatic concentration (AUCTSC) metric as the PK-driver of efficacy. To underpin the mechanisms behind AUCTSC as the driver of efficacy, we performed quantitative systems pharmacology (QSP) modeling of DYP688 intratumoral pharmacokinetics and pharmacodynamics. Through exploratory simulations, we show that by deviating from canonical ADC design dogma, DYP688 has optimal FR900359 activity despite its transient inactivation. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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