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

The mesothelin (MSLN)-targeted Th conjugate is a novel α-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with Zr to evaluate whether PET imaging with Zr-MSLN matches Th-MSLN tumor uptake, biodistribution, and antitumor activity. Serial PET imaging with protein doses of 4, 20, or 40 μg of Zr-MSLN and Zr-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. Zr-MSLN and Th-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. Zr-MSLN PET imaging was performed before Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Zr-MSLN PET imaging showed an SUV 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. Zr-MSLN tumor uptake was higher than uptake of Zr-control ( = 0.0043). Zr-MSLN and Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. Pretreatment SUV was 2.2 ± 0.2 in HT29-MSLN tumors, which decreased in volume on Th-MSLN treatment. BxPc3 tumors showed an SUV of 1.2 ± 0.3 and remained similar in size after Th-MSLN treatment. Zr-MSLN PET imaging reflected MSLN expression and matched Th-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of Zr-MSLN PET imaging together with Th-MSLN therapy, both using the same antibody-chelator conjugate.