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

Abstract

BackgroundTo 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 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.MethodsHumanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.ResultsPET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-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.Conclusion89Zr-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 89Zr-pembrolizumab whole-body distribution in patients.

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma

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The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

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Mesothelin/CD3 Half-Life–Extended Bispecific T-Cell Engager Molecule Shows Specific Tumor Uptake and Distributes to Mesothelin and CD3-Expressing Tissues

“…The in-vivo biodistribution of 50 µg 89 Zr-MSLN HLE BiTE was visualized in 8 tumorbearing BALB/c mice by microPET scans at 1, 3, 5, 7 and 9 days after injection. This dose was based on previous experience with immune cell targeting tracers (29).…”