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

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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 [ 177 Lu]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 [ 161 Tb]Tb-AKIR001 before therapeutic efficacy was evaluated in both squamous cell carcinoma and pancreatic ductal adenocarcinoma xenograft models.Mice were administered [ 161 Tb]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 [ 161 Tb]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: [ 161 Tb]Tb-AKIR001 demonstrated favorable biodistribution and dosimetry profiles, together with encouraging therapeutic effects without signs of severe toxicity.Compared to [ 177 Lu]Lu-AKIR001, [ 161 Tb]Tb-AKIR001 may offer added advantages in certain therapeutic contexts, and our results highlight [ 161 Tb]Tb-AKIR001 as a promising candidate for further development in targeted radionuclide therapy.

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