Molecular Imaging of PD-L1 Expression and Dynamics with the Adnectin-Based PET Tracer ¹⁸F-BMS-986192

Abstract

18 F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to noninvasively determine whole-body PD-L1 expression by PET. We evaluated the usability of 18 F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes in PD-L1 expression in tumors. Methods: In vitro binding assays with 18 F-BMS-986192 were performed on human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was performed on immunodeficient mice xenografted with these cell lines. The mice were treated with interferon γ (IFNγ) intraperitoneally for 3 d or with the mitogen-activated protein kinase kinase inhibitor selumetinib by oral gavage for 24 h. Afterward, 18 F-BMS-986192 was administered intravenously, followed by a 60-min dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram of tissue. Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results: 18 F-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 a 12-fold increase in tracer binding. In vivo, IFNγ affected neither PD-L1 tumor expression measured immunohistochemically nor 18 F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 in 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 18 F-BMS-986192 tumor uptake was observed. Conclusion: 18 F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1 as soon as 60 min after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.

Response Prediction and Evaluation Using PET in Patients with Solid Tumors Treated with Immunotherapy

“…Due to slow tissue penetration, the scans with 89 Zr were obtained on day 3 and 6, or day 4 and 7 after tracer injection [ 19 , 48 ]. Small anti-PD-L1 protein tracers are under research [ 80 ]. These tracers penetrate and bind, due to their size, much quicker in the target tissue.…”

Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic

“…Clinical 18 F-FDG PET ( 85 ) and 18 F-BMS-986192 ( 72 , 86 ) imaging of PD-L1 are both assessed at 60 minutes post-injection. Conversely, imaging with antibodies (e.g., 89 Zr-labeled nivolumab) is best achieved 5 to 7 days post-tracer injection ( 72 ).…”

Quantifying PD-L1 Expression to Monitor Immune Checkpoint Therapy: Opportunities and Challenges

“…MEK inhibitor treatment leads to downregulation of PD-L1 expression in tumors that could potentially be quantified using PET. Studies with [ 18 F]BMS-986192 have demonstrated a significant reduction in imaging agent uptake reflecting the 50% down regulation in PD-L1 levels following treatment with MEK inhibitor selumetinib for 24 h [158]. Additionally, EGFR inhibitor induced changes in PD-L1 downregulation were quantified using 89 Zr-Df-KN035, a nanobody derived radiotracer [159].…”