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Background <p>Terbium-161 (Tb-161) emits internal conversion and Auger electrons, in addition to beta-minus radiation, which might be of added benefit for targeted radionuclide therapy (TRT) compared to Lutetium-177 (Lu-177). We extensively compared Lu-177 and Tb-161 for fibroblast activation protein (FAP)- TRT in a preclinical setting. To study this, FAP-2286 was labeled with Lu-177 and Tb-161 and characterized in vitro on FAP-expressing cells and ex vivo using patient tumor samples. Moreover, in vivo studies (i.e. biodistribution and efficacy) were performed using a clinically representative pancreatic ductal adenocarcinoma (PDAC) mouse model. Biodistribution was performed 1, 4, 24, and 48&#xa0;h post injection of 5 MBq/500 pmol [<sup>177</sup>Lu]Lu-FAP-2286 or [<sup>161</sup>Tb]Tb-FAP-2286. Subsequently, animals were treated with 4 × 40 MBq/500 pmol [<sup>177</sup>Lu]Lu-FAP-2286 or [<sup>161</sup>Tb]Tb-FAP-2286 and with alternating doses of 2 × 40 MBq/500 pmol of each radiopharmaceutical.</p> Results <p>No difference in [<sup>177</sup>Lu]Lu-FAP-2286 and [<sup>161</sup>Tb]Tb-FAP-2286 uptake was observed in the cell models. In vivo studies did not show a survival benefit of 4 × 40 MBq/500 pmol [<sup>177</sup>Lu]Lu-FAP-2286 or [<sup>161</sup>Tb]Tb-FAP-2286, while Kaplan-Meier analyses demonstrated a modest prolonged survival after tandem therapy in mice that first received [<sup>177</sup>Lu]Lu-FAP-2286 followed by [<sup>161</sup>Tb]Tb-FAP-2286. Dosimetry calculations based on autoradiography studies on patient tumor samples showed that even with lower binding, a higher absorbed dose to the tumor can be accomplished with [<sup>161</sup>Tb]Tb-FAP-2286.</p> Conclusions <p>In our in vitro and in vivo studies, [<sup>177</sup>Lu]Lu-FAP-2286 and [<sup>161</sup>Tb]Tb-FAP-2286 demonstrated similar behavior. In the applied PDAC mouse model, FAP-TRT showed limited therapeutic efficacy, most likely due to the limited radiopharmaceutical uptake observed in the tumors. This hampered determination of a potential benefit of either radioisotope for FAP-TRT. Of note, a modest response was observed in the tandem therapy group that first received [<sup>177</sup>Lu]Lu-FAP-2286, followed by [<sup>161</sup>Tb]Tb-FAP-2286.</p>

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Head-to-head comparison of [177Lu]Lu-FAP-2286 and [161Tb]Tb-FAP-2286 efficacy in a PDAC mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Circe D. van der Heide,
  • Carolline M. Ntihabose,
  • Mark Konijnenberg,
  • Hanyue Ma,
  • Debra Stuurman,
  • Corrina de Ridder,
  • Yann Seimbille,
  • Michail C. Doukas,
  • Erik de Blois,
  • Simone U. Dalm

摘要

Background

Terbium-161 (Tb-161) emits internal conversion and Auger electrons, in addition to beta-minus radiation, which might be of added benefit for targeted radionuclide therapy (TRT) compared to Lutetium-177 (Lu-177). We extensively compared Lu-177 and Tb-161 for fibroblast activation protein (FAP)- TRT in a preclinical setting. To study this, FAP-2286 was labeled with Lu-177 and Tb-161 and characterized in vitro on FAP-expressing cells and ex vivo using patient tumor samples. Moreover, in vivo studies (i.e. biodistribution and efficacy) were performed using a clinically representative pancreatic ductal adenocarcinoma (PDAC) mouse model. Biodistribution was performed 1, 4, 24, and 48 h post injection of 5 MBq/500 pmol [177Lu]Lu-FAP-2286 or [161Tb]Tb-FAP-2286. Subsequently, animals were treated with 4 × 40 MBq/500 pmol [177Lu]Lu-FAP-2286 or [161Tb]Tb-FAP-2286 and with alternating doses of 2 × 40 MBq/500 pmol of each radiopharmaceutical.

Results

No difference in [177Lu]Lu-FAP-2286 and [161Tb]Tb-FAP-2286 uptake was observed in the cell models. In vivo studies did not show a survival benefit of 4 × 40 MBq/500 pmol [177Lu]Lu-FAP-2286 or [161Tb]Tb-FAP-2286, while Kaplan-Meier analyses demonstrated a modest prolonged survival after tandem therapy in mice that first received [177Lu]Lu-FAP-2286 followed by [161Tb]Tb-FAP-2286. Dosimetry calculations based on autoradiography studies on patient tumor samples showed that even with lower binding, a higher absorbed dose to the tumor can be accomplished with [161Tb]Tb-FAP-2286.

Conclusions

In our in vitro and in vivo studies, [177Lu]Lu-FAP-2286 and [161Tb]Tb-FAP-2286 demonstrated similar behavior. In the applied PDAC mouse model, FAP-TRT showed limited therapeutic efficacy, most likely due to the limited radiopharmaceutical uptake observed in the tumors. This hampered determination of a potential benefit of either radioisotope for FAP-TRT. Of note, a modest response was observed in the tandem therapy group that first received [177Lu]Lu-FAP-2286, followed by [161Tb]Tb-FAP-2286.