Preclinical efficacy and dosimetry of CD44v6-directed terbium-161 radionuclide therapy.

RATIONALE: Lutetium-177 has demonstrated clinical success, particularly in neuroendocrine and prostate cancers, but disease recurrence and progression remain frequent. Terbium-161 offers improved therapeutic potential by delivering higher localized radiation doses. We have previously demonstrated preclinical efficacy of the CD44v6-targeted radiopharmaceutical [177Lu]Lu-AKIR001, which is currently under clinical investigation for multiple malignancies (NCT06639191). The present study explored the terbium-161-labeled analogue preclinically, focusing on pancreatic ductal adenocarcinoma, with early proof-of-concept investigations in squamous cell carcinoma, both being highly aggressive and treatment-resistant malignancies. METHODS: Radioligand uptake was evaluated in vitro in squamous cell carcinoma and pancreatic ductal adenocarcinoma cell lines. Ex vivo biodistribution and dosimetry estimations confirmed a selective tumor uptake of [161Tb]Tb-AKIR001 before therapeutic efficacy was evaluated in both squamous cell carcinoma and pancreatic ductal adenocarcinoma xenograft models. Mice were administered [161Tb]Tb-AKIR001 of activities ranging from 4 to 10 MBq and compared to untreated controls. Potential adverse effects were evaluated by blood sampling, monitoring of body weights, and histopathology. RESULTS: Specific, high-affinity binding of [161Tb]Tb-AKIR001 to CD44v6-positive cells was verified in vitro. Tumor uptake in vivo exceeded 30% injected activity per gram of tissue in the A431 model at 96 h post-injection. Peak tumor uptake in the BxPC3 model exceeded 150% injected activity per gram of tissue, with a mean absorbed dose to tumor of 17 Gy/MBq. Activity-dependent antitumor effects were observed in both xenograft models, accompanied by mild to moderate, transient hematologic effects that were significantly mitigated by activity fractionation. Histopathological evaluation revealed no treatment-related tissue damage in kidney, liver or spleen. CONCLUSION: [161Tb]Tb-AKIR001 demonstrated favorable biodistribution and dosimetry profiles, together with encouraging therapeutic effects without signs of severe toxicity. Compared to [177Lu]Lu-AKIR001, [161Tb]Tb-AKIR001 may offer added advantages in certain therapeutic contexts, and our results highlight [161Tb]Tb-AKIR001 as a promising candidate for further development in targeted radionuclide therapy.