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Purpose <p>Mesothelin (MSLN), a 40&#xa0;kDa glycoprotein normally confined to mesothelial cells, is overexpressed in several malignancies, including triple-negative breast cancer (TNBC). The anti-mesothelin single-domain antibody (sdAb, or “nanobody<sup>®</sup>”) DOTA-A1K2, previously validated for positron emission tomography (PET) imaging using site-specific <sup>68</sup>Ga radiolabeling, may also serve as a radio-theranostic agent when labeled with <sup>177</sup>Lu. Moreover, <sup>161</sup>Tb has recently been proposed as an alternative to <sup>177</sup>Lu that might provide additional efficacy due to the emission of Auger electrons. The aim of this study was to evaluate <i>in vitro</i> and <i>in vivo</i> the therapeutic effect of [<sup>177</sup>Lu]Lu-DOTA-A1K2 and [<sup>161</sup>Tb]Tb-DOTA-A1K2.</p> Methods <p>Biodistribution was assessed in mice from 1 to 168&#xa0;h post-injection. Therapeutic efficacy was tested using MDA-MB-231 TNBC cells transfected or not with MSLN. Clonogenic assays were performed after 24&#xa0;h incubation with either radiotracer. <i>In vivo</i>, efficacy was evaluated over 9 weeks after a single intravenous injection of 2, 5, 10, or 20 MBq.</p> Results <p>DOTA-A1K2 was successfully radiolabeled with both isotopes with RCP &gt; 95%. <i>In vitro</i>, [<sup>161</sup>Tb]Tb-DOTA-A1K2 was significantly more potent than [<sup>177</sup>Lu]Lu-DOTA-A1K2 in inhibiting colony formation (<i>p</i> &lt; 0.01). <i>In vivo</i> in mice, the radiotracers exhibited similar biodistribution profiles. The administration of 5, 10 or 20 MBq of either [<sup>177</sup>Lu]Lu-DOTA-A1K2 or [<sup>161</sup>Tb]Tb-DOTA-A1K2 inhibited tumor growth compared to controls (<i>p</i> &lt; 0.01 vs. vehicle), while no effect was observed at 2 MBq (p = NS). However, no differences in efficacy were observed between the two isotopes at any dose.</p> Conclusions <p>This work provides the first sdAb-based theranostic approach targeting mesothelin-positive tumors. <i>In vivo</i> in mice, both [<sup>177</sup>Lu]Lu-DOTA-A1K2 and [<sup>161</sup>Tb]Tb-DOTA-A1K2 accumulated in tumors. <i>In vivo</i> efficacy was found to be comparable, despite the superior <i>in vitro</i> efficacy of <sup>161</sup>Tb. Further studies are warranted to clarify this discrepancy, which could potentially result from mesothelin shedding that prevents Auger electrons from reaching tumor cells.</p>

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Comparative theranostic efficacy of 177Lu- and 161Tb-labeled A1K2 SdAb in mesothelin-positive tumors

  • 期刊论文

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  • 发表日期：

    2025年12月27日

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  • Émilien N’Guessan,
  • Florian Raes,
  • Mitra Ahmadi,
  • Sandrine Bacot,
  • Laurent Dumas,
  • Julien Leenhardt,
  • Amaury du Moulinet d’Hardemare,
  • Marlène Debiossat,
  • Clémence André,
  • Jean Boutonnat,
  • Jérôme Durivault,
  • Christopher Montemagno,
  • Jean-Luc Lenormand,
  • Loïc Djaïleb,
  • Ulli Köster,
  • Michiel Van de Voorde,
  • Stijn Ramaekers,
  • Ken Verguts,
  • Catherine Ghezzi,
  • Pascale Perret,
  • Charlotte Lombardi,
  • Alexis Broisat

摘要

Purpose

Mesothelin (MSLN), a 40 kDa glycoprotein normally confined to mesothelial cells, is overexpressed in several malignancies, including triple-negative breast cancer (TNBC). The anti-mesothelin single-domain antibody (sdAb, or “nanobody®”) DOTA-A1K2, previously validated for positron emission tomography (PET) imaging using site-specific 68Ga radiolabeling, may also serve as a radio-theranostic agent when labeled with 177Lu. Moreover, 161Tb has recently been proposed as an alternative to 177Lu that might provide additional efficacy due to the emission of Auger electrons. The aim of this study was to evaluate in vitro and in vivo the therapeutic effect of [177Lu]Lu-DOTA-A1K2 and [161Tb]Tb-DOTA-A1K2.

Methods

Biodistribution was assessed in mice from 1 to 168 h post-injection. Therapeutic efficacy was tested using MDA-MB-231 TNBC cells transfected or not with MSLN. Clonogenic assays were performed after 24 h incubation with either radiotracer. In vivo, efficacy was evaluated over 9 weeks after a single intravenous injection of 2, 5, 10, or 20 MBq.

Results

DOTA-A1K2 was successfully radiolabeled with both isotopes with RCP > 95%. In vitro, [161Tb]Tb-DOTA-A1K2 was significantly more potent than [177Lu]Lu-DOTA-A1K2 in inhibiting colony formation (p < 0.01). In vivo in mice, the radiotracers exhibited similar biodistribution profiles. The administration of 5, 10 or 20 MBq of either [177Lu]Lu-DOTA-A1K2 or [161Tb]Tb-DOTA-A1K2 inhibited tumor growth compared to controls (p < 0.01 vs. vehicle), while no effect was observed at 2 MBq (p = NS). However, no differences in efficacy were observed between the two isotopes at any dose.

Conclusions

This work provides the first sdAb-based theranostic approach targeting mesothelin-positive tumors. In vivo in mice, both [177Lu]Lu-DOTA-A1K2 and [161Tb]Tb-DOTA-A1K2 accumulated in tumors. In vivo efficacy was found to be comparable, despite the superior in vitro efficacy of 161Tb. Further studies are warranted to clarify this discrepancy, which could potentially result from mesothelin shedding that prevents Auger electrons from reaching tumor cells.