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

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.