Professor, Department Head (Quantitative Clinical Pharmacology) Nanjing Medical University, China (People's Republic)
We implemented a quantitative systems pharmacology (QSP) modeling approach to guide the clinical translation of a new MSC-based cell therapy in lupus nephritis (LN). We constructed the first mechanistic multi-scale QSP model of LN pathophysiology that quantitatively integrated multi-modal preclinical and clinical data, with detailed illustration of standard-of-care immunosuppressant and B cell-targeting antibody pharmacology, as well as physiologically-based biodistribution and therapeutic mechanisms of MSCs. We then created model-based virtual patients that can capture clinical interpatient heterogeneity, which was validated rigorously by numerous sets of clinical-level treatment readouts, including first-hand results from our early phase clinical trials testing MSCs in LN patients. Through modeling analyses, we predicted that a new two-infusion clinical dosing strategy of MSCs would yield optimal clinical response in LN patients, which was adopted in the phase II trial design. Simulations also provided explanation to the early-responding and toxicity-reducing properties of MSCs in treating LN, and we identified a two-biomarker combination that could boost clinical renal response of MSCs in patients. Overall, our data-enriched QSP modeling framework has provided critical guidance for the clinical translation of a novel MSC-based therapy in LN.
