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Molecular imaging of PD-L1 expression and dynamics with the adnectin-based PET tracer 18F-BMS-986192

Stutvoet, T. S., van der Veen, E. L., Kol, A., Antunes, I. F., de Vries, E. F. J., Hospers, G. A. P., de Vries, E. G. E., de Jong, S. & Lub-de Hooge, M. N., 2020, In : Journal of Nuclear Medicine.

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  • Molecular imaging of PD-L1 expression and dynamics with the adnectin-based PET tracer 18F-BMS-986192

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DOI

18F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to non-invasively determine whole-body PD-L1 expression by positron emission tomography (PET). We evaluated usability of 18F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes of PD-L1 expression in tumors. Methods: In vitro binding assays with 18F-BMS-986192 were performed in human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was executed in immunodeficient mice xenografted with these cell lines. Mice were treated with interferon gamma (IFNγ) intraperitoneally for 3 days or with the mitogen-activated protein kinase kinase (MEK1/2) inhibitor selumetinib by oral gavage for 24 hours. Thereafter 18F-BMS-986192 was administered intravenously, followed by a 60-minute dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram tissue (%ID/g). Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results:18F-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFNγ treatment increased PD-L1 expression in the tumor cell lines and caused up to 12-fold increase in tracer binding. In vivo, IFNγ did neither affect PD-L1 tumor expression measured immunohistochemically nor 18F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 of tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane PD-L1 levels of tumors and consequently no treatment-induced change in 18F-BMS-986192 tumor uptake was observed. Conclusion:18F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1, as soon as 60 minutes after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.

Original languageEnglish
JournalJournal of Nuclear Medicine
Publication statusE-pub ahead of print - 2020

ID: 124234274