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

Checkpoint inhibitors that target PD-1 or PD-L1 have had a profound effect in a variety of cancers, both as a single therapy and in combinations. Meta-analyses suggest that monoclonal antibodies (mAbs) targeting PD-1 may yield better survival outcomes compared to anti-PD-L1 mAbs, however these conclusions are limited by a lack of direct clinical comparisons between the two classes. There is a shared hypothesis for the mechanism of action of these drugs: inhibition of the PD-1:PD-L1 signaling pathway through binding to either target. Using a Quantitative Systems Pharmacology (QSP) model-based analysis, we test whether differential inhibition of PD-1:PD-L1 complex formation (a surrogate for inhibition of the signaling pathway) is sufficient to explain the efficacy difference between anti-PD-1 and anti-PD-L1 mAbs observed in clinical meta-analyses. The model predicts that high levels of PD-1:PD-L1 complex inhibition are achieved by all the considered mAbs at their clinical dosing regimens, but it does not indicate that anti-PD-1 mAbs yield higher inhibition over anti-PD-L1s, in contrast to the meta-analyses. Significant model parameter variability and a bootstrap sampling analysis mirroring the comparison from Duan et al. (2020) do not change this conclusion. This suggests that anti-PD-1 and anti-PD-L1 mAbs are not differentiable based on PD-1:PD-L1 complex inhibition alone, and that the hypothesized shared mechanism of action of the two classes of drugs is incomplete.