89Zr-3,2-HOPO-Mesothelin Antibody PET Imaging Reflects Tumor Uptake of Mesothelin-Targeted 227Th-Conjugate Therapy in Mice

Abstract

The mesothelin (MSLN)-targeted ²²⁷Th conjugate is a novel α-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with ⁸⁹Zr to evaluate whether PET imaging with ⁸⁹Zr-MSLN matches ²²⁷Th-MSLN tumor uptake, biodistribution, and antitumor activity. Methods: Serial PET imaging with protein doses of 4, 20, or 40 μg of ⁸⁹Zr-MSLN and ⁸⁹Zr-control was performed up to 168 h after tracer injection in human tumor-bearing nude mice with high (HT29-MSLN) and low (BxPc3) MSLN expression. ⁸⁹Zr-MSLN and ²²⁷Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time points in HT29-MSLN and in medium-MSLN-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 an SUV_mean of 2.2 ± 0.5 in HT29-MSLN tumors. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram 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. Pretreatment SUV_mean was 2.2 ± 0.2 in HT29-MSLN tumors, which decreased in volume on ²²⁷Th-MSLN treatment. BxPc3 tumors showed an SUV_mean of 1.2 ± 0.3 and remained similar in size after ²²⁷Th-MSLN treatment. Conclusion: ⁸⁹Zr-MSLN PET imaging reflected MSLN expression and matched ²²⁷Th-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of ⁸⁹Zr-MSLN PET imaging together with ²²⁷Th-MSLN therapy, both using the same antibody-chelator conjugate.

Keywords: 89Zr; PET imaging; antibody conjugate; mesothelin; targeted 227Th therapy.