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 voor dit werk

    Onderzoeksoutput: ArticleAcademicpeer review

    38 Citaten (Scopus)
    122 Downloads (Pure)

    Samenvatting

    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.

    Originele taal-2English
    Artikelnummer000938
    Aantal pagina's12
    TijdschriftJournal for immunotherapy of cancer
    Volume8
    Nummer van het tijdschrift2
    DOI's
    StatusPublished - 5-okt.-2020

    Vingerafdruk

    Duik in de onderzoeksthema's van 'Zr-89-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs'. Samen vormen ze een unieke vingerafdruk.

    Citeer dit