PET/CT Imaging of Zr-89-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

Wenping Li*, Yuchuan Wang, Daniel Rubins, Idriss Bennacef, Marie Holahan, Hyking Haley, Mona Purcell, Liza Gantert, SuChun Hseih, Michael Judo, Wolfgang Seghezzi, Shuli Zhang, Elly L. van der Veen, Marjolijn N. Lub-de Hooge, Elisabeth G. E. de Vries, Jeffrey L. Evelhoch, Michael Klimas, Eric D. Hostetler

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

PURPOSE: Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (89Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1-positive immune cells.

PROCEDURES: Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal-Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with 89Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUVmean) were quantified by region of interest (ROI) analysis.

RESULTS: 89Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (> 99 %) and acceptable molar activity (> 7 MBq/nmol). In animals dosed with tracer only, 89Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation.

CONCLUSIONS: 89Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. 89Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02760225.

Original languageEnglish
Pages (from-to)250–259
Number of pages10
JournalMolecular Imaging and Biology
Volume23
Early online date26-Oct-2020
DOIs
Publication statusPublished - Apr-2021

Keywords

  • PD-1-positive immune cells
  • Positron emission tomography (PET) imaging
  • Zr-89-N-sucDf-pembrolizumab
  • Cynomolgus monkeys
  • Mesenteric lymph nodes
  • Spleen and tonsils
  • Standardized uptake values (SUVmean)
  • BIODISTRIBUTION
  • ZR-89-TRASTUZUMAB
  • PEMBROLIZUMAB
  • ANTI-PD-1
  • ANTIBODY

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