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

  • EJNMMI Res. 2026 Jan 9;16(1):29. doi: 10.1186/s13550-026-01372-5.
Circe D van der Heide  1 ,  Carolline M Ntihabose  1  2 ,  Mark Konijnenberg  1 ,  Hanyue Ma  1 ,  Debra Stuurman  1 ,  Corrina de Ridder  3 ,  Yann Seimbille  1 ,  Michail C Doukas  4 ,  Erik de Blois  1 ,  Simone U Dalm  5
Affiliations
  • 1. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
  • 2. Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands.
  • 3. Department of Experimental Urology, Erasmus MC, Rotterdam, The Netherlands.
  • 4. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
  • 5. Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. [email protected].
PMID: 41511675 DOI: 10.1186/s13550-026-01372-5
Abstract

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.

Keywords
Cancer-associated fibroblast (CAF); Fibroblast activation protein (FAP); Pancreatic ductal adenocarcinoma (PDAC); Targeted radionuclide therapy (TRT); Terbium-161.
Products