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Background <p>Radiolabeled FAP-targeting sdAb 4AH29 was developed previously, showing potent therapeutic efficacy. This head-to-head study compares sdAb 4AH29 and peptide FAP-2286, generally considered as most clinically advanced, for their <i>in vitro</i> and <i>in vivo</i> tumor retention, resulting dosimetry, and therapeutic efficacy in relevant rodent tumor models.</p> Results <p><i>In vitro</i>, [<sup>177</sup>Lu]Lu-DOTA-4AH29 showed sustained cell-associated activity until 48&#xa0;h, whereas it dropped to baseline within the first hours for [<sup>177</sup>Lu]Lu-DOTA-FAP-2286. <i>In vivo</i>, in U87-MG, [<sup>177</sup>Lu]Lu-DOTA-FAP-2286 accumulated better at the tumor at early time points but from 24&#xa0;h was significantly less retained than [<sup>177</sup>Lu]Lu-DOTA-4AH29, leading to a threefold higher absorbed dose to the tumor for [<sup>177</sup>Lu]Lu-DOTA-4AH29. Compared to U87-MG, absolute tumor uptake for both tracers in HT-29 was decreased, in line with lower FAP expression of this model. Of note, significant improved tumor retention was observed for [<sup>177</sup>Lu]Lu-DOTA-4AH29 over time, resulting in a twofold higher tumor absorbed dose. The transfected HEK-hFAP model showed an enhanced tumor uptake with [<sup>177</sup>Lu]Lu-DOTA-FAP-2286 at all assessed time points, displaying a 4.8 more elevated absorbed dose to tumor than [<sup>177</sup>Lu]Lu-DOTA-4AH29. Treatment with [<sup>177</sup>Lu]Lu-DOTA-4AH29 or [<sup>225</sup>Ac]Ac-DOTA-4AH29 significantly delayed U87-MG tumor development compared to [<sup>177</sup>Lu]Lu-DOTA-FAP-2286 43 days post inoculation. Survival was improved after administration of [<sup>225</sup>Ac]Ac-DOTA-4AH29 compared to [<sup>177</sup>Lu]Lu-DOTA-FAP-2286, whereas it was a trend with [<sup>177</sup>Lu]Lu-DOTA-4AH29. In HT-29, no significant differences in tumor control were observed at day 29 before first animal reached humane endpoint. Nevertheless, enhanced survival was achieved with a single shot of [<sup>225</sup>Ac]Ac-DOTA-4AH29 at 120&#xa0;kBq.</p> Conclusions <p>These preclinical results underline the potential benefit of radiolabeled 4AH29 over FAP-2286 due to its enhanced tumor retention and more pronounced anti-tumor effects warranting clinical investigation.</p> Graphical abstract <p></p>

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Head-to-head comparison of FAP-targeting single-domain antibody 4AH29 vs. peptide FAP-2286

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月13日

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  • Nina Dumauthioz,
  • Laurent Navarro,
  • Marion Berdal,
  • Surasa Nagachinta,
  • Jonatan Dewulf,
  • Mira Van Eesbeek,
  • Silke Plas,
  • Joar Pinto,
  • Ana Rita Pombo Antunes,
  • Dimitrios Mantzilas,
  • Matthias D’Huyvetter

摘要

Background

Radiolabeled FAP-targeting sdAb 4AH29 was developed previously, showing potent therapeutic efficacy. This head-to-head study compares sdAb 4AH29 and peptide FAP-2286, generally considered as most clinically advanced, for their in vitro and in vivo tumor retention, resulting dosimetry, and therapeutic efficacy in relevant rodent tumor models.

Results

In vitro, [177Lu]Lu-DOTA-4AH29 showed sustained cell-associated activity until 48 h, whereas it dropped to baseline within the first hours for [177Lu]Lu-DOTA-FAP-2286. In vivo, in U87-MG, [177Lu]Lu-DOTA-FAP-2286 accumulated better at the tumor at early time points but from 24 h was significantly less retained than [177Lu]Lu-DOTA-4AH29, leading to a threefold higher absorbed dose to the tumor for [177Lu]Lu-DOTA-4AH29. Compared to U87-MG, absolute tumor uptake for both tracers in HT-29 was decreased, in line with lower FAP expression of this model. Of note, significant improved tumor retention was observed for [177Lu]Lu-DOTA-4AH29 over time, resulting in a twofold higher tumor absorbed dose. The transfected HEK-hFAP model showed an enhanced tumor uptake with [177Lu]Lu-DOTA-FAP-2286 at all assessed time points, displaying a 4.8 more elevated absorbed dose to tumor than [177Lu]Lu-DOTA-4AH29. Treatment with [177Lu]Lu-DOTA-4AH29 or [225Ac]Ac-DOTA-4AH29 significantly delayed U87-MG tumor development compared to [177Lu]Lu-DOTA-FAP-2286 43 days post inoculation. Survival was improved after administration of [225Ac]Ac-DOTA-4AH29 compared to [177Lu]Lu-DOTA-FAP-2286, whereas it was a trend with [177Lu]Lu-DOTA-4AH29. In HT-29, no significant differences in tumor control were observed at day 29 before first animal reached humane endpoint. Nevertheless, enhanced survival was achieved with a single shot of [225Ac]Ac-DOTA-4AH29 at 120 kBq.

Conclusions

These preclinical results underline the potential benefit of radiolabeled 4AH29 over FAP-2286 due to its enhanced tumor retention and more pronounced anti-tumor effects warranting clinical investigation.

Graphical abstract