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Purpose <p>This study aimed to develop and evaluate [<sup>64</sup>Cu]Cu-NOTA-EV-F(ab’)<sub>2</sub> as a rapid and specific immunoPET imaging probe targeting Nectin-4 in gastric cancer (GC) and non-small cell lung cancer (NSCLC).</p> Materials and methods <p>F(ab’)<sub>2</sub> fragments were generated from enfortumab vedotin (EV) using IdeS protease and conjugated with <i>p</i>-SCN-Bn-NOTA for radiolabeling with <sup>64</sup>CuCl<sub>2</sub>. The radiochemical yield was 85.40 ± 2.43% (<i>n</i> = 5). In vitro binding affinity and specificity were assessed <i>via</i> flow cytometry and cell uptake assays using Nectin-4-positive (NCI-N87, H1975) and Nectin-4-low (HGC-27, H520) cell lines. In vivo PET imaging and biodistribution studies were conducted in murine models of GC and NSCLC to evaluate tumor targeting efficiency and tracer pharmacokinetics.</p> Results <p>[<sup>64</sup>Cu]Cu-NOTA-EV-F(ab’)<sub>2</sub> demonstrated rapid tumor accumulation, with peak uptake observed at 4&#xa0;h post-injection (10.23 ± 0.70%ID/g in NCI-N87 tumors, 3.03 ± 0.35%ID/g in HGC-27, 11.56 ± 1.12%ID/g in H1975, 2.77 ± 0.47%ID/g in H520). Compared to full-length EV, the tracer exhibited faster blood clearance and reduced off-target uptake. Blocking with excess EV-F(ab’)<sub>2</sub> significantly reduced subsequent tumor uptake (6.27 ± 0.49%ID/g in NCI-N87, <i>P</i> = 0.0029; 5.23 ± 0.31%ID/g in H1975, <i>P</i> = 0.00074), confirming Nectin-4 specificity. Ex vivo biodistribution analysis supported high tumor retention consistent with in vivo imaging findings.</p> Conclusions <p>[<sup>64</sup>Cu]Cu-NOTA-EV-F(ab’)<sub>2</sub> offers rapid, specific, and high-contrast immunoPET imaging of Nectin-4-expressing tumors in GC and NSCLC models, highlighting its potential as a non-invasive diagnostic tool for Nectin-4-targeted cancer imaging.</p>

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Rapid and specific immunoPET imaging of Nectin-4 in gastric cancer and non-small cell lung cancer using [64Cu]Cu-NOTA-EV-F(ab’)2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月21日

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  • Wenpeng Huang,
  • Xinyao Sun,
  • Xiaoyan Li,
  • Jessica C. Hsu,
  • Yongkang Qiu,
  • Molly C. DeLuca,
  • Jonathan W. Engle,
  • Liming Li,
  • Jun Lu,
  • Tianyao Wang,
  • Lei Kang,
  • Weibo Cai

摘要

Purpose

This study aimed to develop and evaluate [64Cu]Cu-NOTA-EV-F(ab’)2 as a rapid and specific immunoPET imaging probe targeting Nectin-4 in gastric cancer (GC) and non-small cell lung cancer (NSCLC).

Materials and methods

F(ab’)2 fragments were generated from enfortumab vedotin (EV) using IdeS protease and conjugated with p-SCN-Bn-NOTA for radiolabeling with 64CuCl2. The radiochemical yield was 85.40 ± 2.43% (n = 5). In vitro binding affinity and specificity were assessed via flow cytometry and cell uptake assays using Nectin-4-positive (NCI-N87, H1975) and Nectin-4-low (HGC-27, H520) cell lines. In vivo PET imaging and biodistribution studies were conducted in murine models of GC and NSCLC to evaluate tumor targeting efficiency and tracer pharmacokinetics.

Results

[64Cu]Cu-NOTA-EV-F(ab’)2 demonstrated rapid tumor accumulation, with peak uptake observed at 4 h post-injection (10.23 ± 0.70%ID/g in NCI-N87 tumors, 3.03 ± 0.35%ID/g in HGC-27, 11.56 ± 1.12%ID/g in H1975, 2.77 ± 0.47%ID/g in H520). Compared to full-length EV, the tracer exhibited faster blood clearance and reduced off-target uptake. Blocking with excess EV-F(ab’)2 significantly reduced subsequent tumor uptake (6.27 ± 0.49%ID/g in NCI-N87, P = 0.0029; 5.23 ± 0.31%ID/g in H1975, P = 0.00074), confirming Nectin-4 specificity. Ex vivo biodistribution analysis supported high tumor retention consistent with in vivo imaging findings.

Conclusions

[64Cu]Cu-NOTA-EV-F(ab’)2 offers rapid, specific, and high-contrast immunoPET imaging of Nectin-4-expressing tumors in GC and NSCLC models, highlighting its potential as a non-invasive diagnostic tool for Nectin-4-targeted cancer imaging.