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, Michele 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

Research output: Contribution to journalArticlepeer-review


Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18-labeled PET imaging agent, [18F]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.

Original languageEnglish (US)
Article numbere2107982118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 14 2021


  • Drug disposition
  • Immune checkpoint therapy
  • PET
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics'. Together they form a unique fingerprint.

Cite this