Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics
Dhiraj Kumar, Akhilesh Mishra, Ala Lisok, Rakeeb Kureshi, Sagar Shelake, Donika Plyku, Rupashree Sen, Michèle Doucet, Ravindra A. De Silva, Ronnie C. Mease, Patrick M. Forde, Elizabeth M. Jaffee, Prashant Desai, Sudipto Ganguly, Edward Gabrielson, Dhananjay Vaidya, Jamie B. Spangler, Sridhar Nimmagadda
Abstract
F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti-PD-1 and anti-PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti-PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti-PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients.