212 Pb-Pretargeted Theranostics for Pancreatic Cancer

Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator Pb. Combined with the imaging-compatible radionuclide Pb, this theranostic match is a promising modality rapidly translating into the clinic. Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a -cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [ Pb]Pb-DO3A-PEG -Tz, whereby administered activity levels were guided by dosimetric analysis. The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). This foundational study demonstrated the feasibility and safety of pretargeted TAT with Pb in PDAC while considering dose limitations and potential adverse effects.