Zr-89-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

Elly L. van der Veen, Danique Giesen, Linda Pot-de Jong, Annelies Jorritsma-Smit, Elisabeth G. E. De Vries, Marjolijn N. Lub-de Hooge*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background To better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (Zr-89) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice. Methods Humanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post(89)Zr-pembrolizumab (10 mu g, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 mu g) unlabeled pembrolizumab or(89)Zr-IgG(4)control (10 mu g, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1. Results PET imaging and biodistribution studies showed high(89)Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of(89)Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative. Conclusion Zr-89-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of(89)Zr-pembrolizumab whole-body distribution in patients.

Original languageEnglish
Article number000938
Number of pages12
JournalJournal for immunotherapy of cancer
Volume8
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • immunotherapy
  • T-lymphocytes
  • tumor biomarkers
  • PD-1 CHECKPOINT EXPRESSION
  • MURINE MODEL
  • IMMUNO-PET
  • ANTIBODY
  • RADIOTRACER
  • TRACERS
  • TUMORS

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