89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

Linda N Broer, Daan G Knapen, Frans Valentijn Suurs, Ingrid Moen, Danique Giesen, Stijn J H Waaijer, Baard Indrevoll, Christine Ellingsen, Alexander Kristian, Alan S Cuthbertson, Derk-Jan A de Groot, Patricia E Cole, Elisabeth G E de Vries, Urs B Hagemann, Marjolijn N Lub-de Hooge*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity.

Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice.

Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity.

Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

Original languageEnglish
Pages (from-to)1715-1721
Number of pages7
JournalThe Journal of Nuclear Medicine
Volume63
Issue number11
Early online date14-Apr-2022
DOIs
Publication statusPublished - 1-Nov-2022

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