Key result
Novel 64Cu-labeled PD-L1 radiotracers show high in vitro binding but poor in vivo tumor uptake.
Why the study?
Many cancer patients do not respond to PD-1/PD-L1 immune checkpoint inhibitor therapy, creating a need for diagnostic molecular imaging tools to assess PD-L1 expression and predict treatment outcomes.
Despite providing high water solubility, the incorporation of phosphonic acids into PD-L1 radiotracers can compromise their pharmacokinetic behavior by causing unexpected accumulation in bone and liver.
Low tumor uptake precludes clinical translation of these tracers; leaves open chemical optimization of phosphonic acid linkers for PD-L1 imaging.
Immune checkpoint inhibitor therapy targeting the PD-1/PD-L1 axis in cancer patients, is a promising oncological treatment. However, the number of non-responders remains high, causing a burden for the patient and the healthcare system. Consequently, a diagnostic tool to predict treatment outcomes would help with patient stratification. Molecular imaging provides said diagnostic tool by offering a whole-body quantitative assessment of PD-L1 expression, hence supporting therapy decisions. Four PD-L1 radioligand candidates containing a linker-chelator system for radiometalation, along with three hydrophilizing units—one sulfonic and two phosphonic acids—were synthesized. After labeling with 64Cu, log D7.4 values of less than −3.03 were determined and proteolytic stability confirmed over 94% intact compound after 48 h. Binding affinity was determined using two different assays, revealing high affinities up to 13 nM. µPET/CT imaging was performed in tumor-bearing mice to investigate PD-L1-specific tumor uptake and the pharmacokinetic profile of radioligands. These results yielded an unexpected in vivo distribution, such as low tumor uptake in PD-L1 positive tumors, high liver uptake, and accumulation in bone/bone marrow and potentially synovial spaces. These effects are likely caused by Ca2+-affinity and/or binding to macrophages. Despite phosphonic acids providing high water solubility, their incorporation must be carefully considered to avoid compromising the pharmacokinetic behavior of radioligands.
No takes yet. Share an insight, caveat, or question.
Krutzek et al. (2023) studied PD-L1 expression in cancer. 64Cu-labeled PD-L1 radiotracers ([64Cu]Cu-1-4) vs. Mock tumor / blocking with unlabeled compound was evaluated on In vivo pharmacokinetic profile and tumor uptake. Four novel 64Cu-labeled PD-L1 radiotracers demonstrated high in vitro binding affinities up to 13 nM, but exhibited unexpected in vivo pharmacokinetics characterized by low tumor uptake and high accumulation in liver, bone, and joints.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: