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

TL;DR

This study compares the effectiveness of two radiopharmaceuticals, Lu-177 and Tb-161, in treating pancreatic cancer in mice, finding similar results but a slight benefit when alternating treatments.

Contribution

The study provides a direct comparison of Lu-177 and Tb-161 in FAP-targeted radionuclide therapy for pancreatic cancer in a preclinical model.

Findings

Lu-177 and Tb-161 showed similar uptake in cell and tumor models.

Tandem therapy with Lu-177 followed by Tb-161 modestly prolonged survival in mice.

Dosimetry suggested higher tumor dose with Tb-161 despite lower binding.

Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13550-026-01372-5.

Figures