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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1571844
This article is part of the Research Topic Integrated PK/PD and Drug Metabolism Approaches in Drug Development and Evaluation View all articles
A mechanistic quantitative systems pharmacology model platform for translational efficacy evaluation and checkpoint combination design of bispecific immuno-modulatory antibodies
Provisionally accepted
Yiyang Xu 1
Siyuan Yang 1
Qi Rao 1 Yuan Gao 2 Guanyue Zhou 3 Dongmei Zhao 3 Xinsheng Shi 3 Yi Chai 4*
Chen Zhao 1*- 1 Nanjing Medical University, Nanjing, China
- 2 QSPMed Technologies, Nanjing, Liaoning Province, China
- 3 Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing, China
- 4 First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
Over the past two decades, tumor immunotherapies have witnessed remarkable advancements, especially with the emergence of immune checkpoint-targeting bispecific antibodies. However, a quantitative understanding of the dynamic cross-talking mechanisms underlying different immune checkpoints as well as the optimal dosing and target design of checkpoint-targeting bispecific antibodies still remain challenging to researchers. To address this challenge, we have here developed a multi-scale quantitative systems pharmacology (QSP) model platform that integrates a diverse array of immune checkpoints and their interactive functions. The model has been calibrated and validated against an extensive collection of multiscale experimental datasets covering 20+ different monoclonal and bispecific antibody treatments at over 60 administered dose levels. Based on high-throughput simulations, the QSP model platform comprehensively screened and characterized the potential efficacy of different bispecific antibody target combination designs, and model-based preclinical population-level simulations revealed target-specific dose-response relationships as well as alternative dosing strategies that can maintain anti-tumor treatment efficacy while reducing dosing frequencies. Model simulations also pointed out that combining checkpoint-targeting bispecific antibodies with monoclonal antibodies can lead to significantly enhanced anti-tumor efficacy. Our mechanistic QSP model can serve as an integrated precision medicine simulation platform to guide the translational research and clinical development of checkpoint-targeting immuno-modulatory bispecific antibodies.
Keywords: Quantitative Systems Pharmacology, Immune checkpoint, bispecific antibody, therapeutic combination, Model-informed drug development
Received: 06 Feb 2025; Accepted: 31 Mar 2025.
Copyright: © 2025 Xu, Yang, Rao, Gao, Zhou, Zhao, Shi, Chai and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yi Chai, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
Chen Zhao, Nanjing Medical University, Nanjing, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.