2. Academic Validation
  3. Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics

Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics

  • Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):e2107982118. doi: 10.1073/pnas.2107982118.
Dhiraj Kumar 1,  Akhilesh Mishra 1 2,  Ala Lisok 1,  Rakeeb Kureshi 2,  Sagar Shelake 1,  Donika Plyku 1,  Rupashree Sen 3 4,  Michele Doucet 3 4,  Ravindra A De Silva 1,  Ronnie C Mease 1,  Patrick M Forde 3 4,  Elizabeth M Jaffee 3 4,  Prashant Desai 5,  Sudipto Ganguly 3 4,  Edward Gabrielson 3 4 6,  Dhananjay Vaidya 7,  Jamie B Spangler 2 3 4,  Sridhar Nimmagadda 8 3 4 9 10
Affiliations

Affiliations

  • 1 The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 2 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218.
  • 3 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 4 The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 5 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 6 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 7 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 8 The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287; [email protected].
  • 9 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 10 Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
PMID: 34508005 DOI: 10.1073/pnas.2107982118
Abstract

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.

Keywords

PET; drug disposition; immune checkpoint therapy; pharmacodynamics; pharmacokinetics.

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