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Updated: Jul 11, 2025
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
212Pb-Pretargeted Theranostics for Pancreatic Cancer
David Bauer1, Lukas M Carter2, Mohamed I Atmane3
1Department of Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
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 212Pb. Combined with the imaging-compatible radionuclide 203Pb, this theranostic match is a promising modality rapidly translating into the clinic. Methods: Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-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, [212Pb]Pb-DO3A-PEG7-Tz, whereby administered activity levels were guided by dosimetric analysis. Results: 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). Conclusion: This foundational study demonstrated the feasibility and safety of pretargeted TAT with 212Pb in PDAC while considering dose limitations and potential adverse effects.
Insights
Targeted alpha therapy (TAT) using lead-212 shows promise for pancreatic ductal adenocarcinoma (PDAC). This study demonstrated pretargeted TAT feasibility and safety in a mouse model, doubling survival in the highest dose group.
Area of Science:
- Oncology
- Nuclear Medicine
- Radiopharmaceutical Therapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options and poor prognoses.
- Targeted alpha therapy (TAT) offers a promising approach for metastatic and treatment-resistant cancers.
- The in vivo alpha-generator 212Pb, paired with imaging-compatible 203Pb, presents a theranostic strategy for clinical translation.
Purpose of the Study:
- To evaluate the feasibility and safety of pretargeted TAT using 212Pb in a PDAC xenograft mouse model.
- To assess the therapeutic efficacy and dose-limiting toxicities of this novel approach.
Main Methods:
- A pretargeting strategy utilizing a 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO)-modified antibody was employed.
- Mice received single administrations of [212Pb]Pb-DO3A-PEG7-Tz at varying activity levels (1.1, 2.2, or 3.7 MBq), guided by dosimetric analysis.
- Therapeutic outcomes and potential adverse effects, particularly renal toxicity, were monitored.
Main Results:
- Minimal-to-mild renal tubular necrosis was observed in treated mice.
- Median survival was significantly increased, doubling in the highest dose cohort (10.7 weeks) compared to controls (5.1 weeks).
Conclusions:
- Pretargeted TAT with 212Pb is a feasible and safe therapeutic strategy for PDAC.
- This study provides foundational evidence for clinical translation, highlighting the importance of dose limitation and toxicity monitoring.
