TY - JOUR
T1 - 89Zr-Immuno-PET with Immune Checkpoint Inhibitors
T2 - Measuring Target Engagement in Healthy Organs
AU - Miedema, Iris H. C.
AU - Wijngaarden, Jessica E.
AU - Pouw, Johanna E. E.
AU - Zwezerijnen, Gerben J. C.
AU - Sebus, Hylke J.
AU - Smit, Egbert
AU - de Langen, Adrianus J.
AU - Bahce, Idris
AU - Thiele, Andrea
AU - Vugts, Daniëlle J.
AU - Boellaard, Ronald
AU - Huisman, Marc C.
AU - Menke-van der Houven van Oordt, C. Willemien
N1 - Funding Information: This work received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 831,514 (Immune-Image). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The clinical trials received funding from the Cancer Center Amsterdam, the Dutch Cancer Society Alpe d’HuZes Grant (Towards patient tailored cancer treatment supported by molecular imaging), IMPACT: IMaging PAtients for Cancer drug selection, and Bristol Myers Squibb Pharmaceuticals, Boehringer Ingelheim, and AstraZeneca. Publisher Copyright: © 2023 by the authors.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - INTRODUCTION: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([ 89Zr]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 [ 89Zr]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: 89Zr-immuno-PET data from five [ 89Zr]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 i). To identify target engagement, K i values were compared to ns-baseline K i values previously reported, and the effect of increasing mass doses on K i was investigated. RESULTS: All mAbs, except ipilimumab, showed K i values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K i 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 i 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 i 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 i values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.
AB - INTRODUCTION: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([ 89Zr]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 [ 89Zr]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: 89Zr-immuno-PET data from five [ 89Zr]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 i). To identify target engagement, K i values were compared to ns-baseline K i values previously reported, and the effect of increasing mass doses on K i was investigated. RESULTS: All mAbs, except ipilimumab, showed K i values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K i 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 i 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 i 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 i values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.
KW - Zr-immuno-PET
KW - immune checkpoint inhibitors
KW - target engagement
UR - http://www.scopus.com/inward/record.url?scp=85179313723&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers15235546
DO - https://doi.org/10.3390/cancers15235546
M3 - Article
C2 - 38067257
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 23
M1 - 5546
ER -