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

The mesothelin (MSLN)-targeted Th-227 conjugate is a novel a-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with Zr-89 to evaluate whether PET imaging with Zr-89-MSLN matches Th-227-MSLN tumor uptake, biodistribution, and antitumor activity. Methods: Serial PET imaging with protein doses of 4, 20, or 40 mg of Zr-89-MSLN and Zr-89-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-89-MSLN and Th-227-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time points in HT29-MSLN and inmedium-MSLNexpressing (OVCAR-3) tumor-bearing mice. Zr-89-MSLN PET imaging was performed before Th-227-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Results: Zr-89-MSLN PET imaging showed an SUVmean 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 Th-227-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. Pretreatment SUVmean was 2.2 6 0.2 in HT29-MSLN tumors, which decreased in volume on Th-227-MSLN treatment. BxPc3 tumors showed an SUVmean of 1.2 +/- 0.3 and remained similar in size after (ThMSLN)-Th-227 treatment. Conclusion: Zr-89-MSLN PET imaging reflected MSLN expression and matched Th-227-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of (ZrMSLN)-Zr-89 PET imaging together with Th-227-MSLN therapy, both using the same antibody-chelator conjugate.

Automated summary

The study compares Zr-89-MSLN PET imaging with Th-227-MSLN treatment and finds that Zr-89-MSLN PET imaging reflects MSLN expression and matches Th-227-MSLN tumor uptake and biodistribution.