A mechanistic quantitative systems pharmacology framework enriched by multiscale data enables model-informed translational development of mesenchymal stem cell therapy in lupus nephritis.
7 affiliations
- 1School of Pharmacy, Nanjing Medical University, Nanjing 210000, China.
- 2School of Medicine, Yangzhou Polytechnic University, Yangzhou 225000, China.
- 3Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210000, China.
- 4Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China.
- 5Jiangsu Renocell Biotech Co., Ltd., Nanjing 210000, China.
- 6QSPMed Technologies, Nanjing 210000, China.
- 7Department of Pharmacy, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210000, China.
Abstract
Lupus nephritis (LN) is a complex autoimmune disease and mesenchymal stem cells (MSCs), given their unique immune-modulatory potential, have emerged as a promising route for treating LN. Understanding the multiscale dynamic LN-MSC interactions and selecting the optimal clinical design for MSCs is critical to enhance their therapeutic potential and achieve meaningful benefit-risk differentiation in patients. To guide MSC clinical development, we constructed the first mechanistic quantitative systems pharmacology model of LN pathophysiology that integrated multimodal preclinical-clinical data, with detailed illustration of standard-of-care immunosuppressant pharmacology and physiologically-based biodistribution and therapeutic mechanisms of MSCs. We created model-based virtual LN patients that well captured clinical interpatient heterogeneity and were validated by numerous sets of clinical efficacy readouts, including first-hand results from our investigator-initiated trial testing MSCs in LN patients. We used this computational framework and identified that a spaced two-infusion MSC dosing strategy would yield optimal clinical response in LN patients, which directly informed the phase 2 design of a novel MSC therapy. Modeling analyses further identified that CXCL10 in combination with proteinuria are potential predictive biomarkers that could boost clinical renal response to MSCs. These results demonstrated the exceptional importance of our QSP framework in driving MSC clinical development for LN patients.
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BibTeX
@article{zhang2026mechanistic,
title = {{A mechanistic quantitative systems pharmacology framework enriched by multiscale data enables model-informed translational development of mesenchymal stem cell therapy in lupus nephritis.}},
author = {Sujie Zhang and Qixiang Zhang and Dandan Wang and Zichun Li and Xia Xiao and Qi Rao and Siyuan Yang and Yuchen Qu and Yiyang Xu and Ning Wei and Jing Wang and Yuan Gao and Lingyun Sun and Guangji Wang and Fang Zhou and Chen Zhao},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.018},
url = {https://europepmc.org/article/MED/42948386},
note = {CC BY},
}
RIS
TY - JOUR
TI - A mechanistic quantitative systems pharmacology framework enriched by multiscale data enables model-informed translational development of mesenchymal stem cell therapy in lupus nephritis.
AU - Sujie Zhang
AU - Qixiang Zhang
AU - Dandan Wang
AU - Zichun Li
AU - Xia Xiao
AU - Qi Rao
AU - Siyuan Yang
AU - Yuchen Qu
AU - Yiyang Xu
AU - Ning Wei
AU - Jing Wang
AU - Yuan Gao
AU - Lingyun Sun
AU - Guangji Wang
AU - Fang Zhou
AU - Chen Zhao
PY - 2026
DA - 2026/08/25
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.018
UR - https://europepmc.org/article/MED/42948386
AB - Lupus nephritis (LN) is a complex autoimmune disease and mesenchymal stem cells (MSCs), given their unique immune-modulatory potential, have emerged as a promising route for treating LN. Understanding the multiscale dynamic LN-MSC interactions and selecting the optimal clinical design for MSCs is critical to enhance their therapeutic potential and achieve meaningful benefit-risk differentiation in patients. To guide MSC clinical development, we constructed the first mechanistic quantitative systems pharmacology model of LN pathophysiology that integrated multimodal preclinical-clinical data, with detailed illustration of standard-of-care immunosuppressant pharmacology and physiologically-based biodistribution and therapeutic mechanisms of MSCs. We created model-based virtual LN patients that well captured clinical interpatient heterogeneity and were validated by numerous sets of clinical efficacy readouts, including first-hand results from our investigator-initiated trial testing MSCs in LN patients. We used this computational framework and identified that a spaced two-infusion MSC dosing strategy would yield optimal clinical response in LN patients, which directly informed the phase 2 design of a novel MSC therapy. Modeling analyses further identified that CXCL10 in combination with proteinuria are potential predictive biomarkers that could boost clinical renal response to MSCs. These results demonstrated the exceptional importance of our QSP framework in driving MSC clinical development for LN patients.
SN - 2211-3835
SN - 2211-3843
ER -