Anti-PD-(L)1 Antibodies: Insights From QSP-Based Meta-Analysis

Anti-PD-1 and anti-PD-L1 antibodies have transformed cancer immunotherapy, yet clinical meta-analyses suggest differences in efficacy despite their shared mechanism of action. In this study, a quantitative systems pharmacology (QSP)-based meta-analysis was used to test whether differential inhibition of the PD-1:PD-L1 signaling complex can explain these observed outcomes. Simulations across approved checkpoint inhibitors and clinical dosing regimens show that both antibody classes achieve high and comparable levels of PD-1:PD-L1 complex inhibition in tumors. Even after accounting for parameter variability and virtual population sampling, the model does not support PD-1:PD-L1 inhibition alone as a differentiating driver of clinical efficacy. These results suggest that additional biological mechanisms beyond the canonical PD-1:PD-L1 axis are likely contributing to observed clinical differences, highlighting the value of QSP for interrogating assumptions, refining mechanistic understanding, and guiding model-informed decision making in oncology drug development.