Cancers (Basel)
Department of Medical Oncology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Published: November 2023
Introduction: Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses.
Method: Zr-immuno-PET data from five [Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2-3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (K). To identify target engagement, K values were compared to ns-baseline K values previously reported, and the effect of increasing mass doses on K was investigated.
Results: All mAbs, except ipilimumab, showed K values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed K values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. K values were near zero in brain tissue for all mass doses of all mAbs.
Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the K values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.
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http://dx.doi.org/10.3390/cancers15235546 | DOI Listing |
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Institute of Scientific Instruments of the Czech Academy of Sciences, Kralovopolska 147, 61200 Brno, Czech Republic.
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Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, Brazil.
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