Navigating the landscape of PD-1/PD-L1 imaging tracers: from challenges to opportunities



Immunotherapy targeted to immune checkpoint inhibitors, such as the program cell death receptor (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, it is now well-known that PD-1/PD-L1 immunotherapy response is inconsistent among patients. The current challenge is to customize treatment regimens per patient, which could be possible if the PD-1/PD-L1 expression and dynamic landscape are known. With positron emission tomography (PET) imaging, it is possible to image these immune targets non-invasively and system-wide during therapy. A successful PET imaging tracer should meet specific criteria concerning target affinity, specificity, clearance rate and target-specific uptake, to name a few. The structural profile of such a tracer will define its properties and can be used to optimize tracers in development and design new ones. Currently, a range of PD-1/PD-L1-targeting PET tracers are available from different molecular categories that have shown impressive preclinical and clinical results, each with its own advantages and disadvantages. This review will provide an overview of current PET tracers targeting the PD-1/PD-L1 axis. Antibody, peptide, and antibody fragment tracers will be discussed with respect to their molecular characteristics and binding properties and ways to optimize them.

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Positron emission tomography imaging using a suitable radiotracer to assess the dynamic expression landscape of PD-1 and PD-L1 could provide a better prediction of treatment response compared to the current FDA-approved evaluation by invasive biopsy and IHC. While great progress has been made toward finding an optimal PD-1/PD-L1 radiotracer, the optimal tracer that can be used routinely has not been identified yet. Optimizing a binder is a crucial step during the development phase and a clear understanding of the structural and molecular basis of the radiotracer-target interaction is imperative for optimizing physico-chemical properties to achieve high specificity of the PET signal in patients.



Melinda Badenhorst, Bert Windhorst, Wissam Beaino

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