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Background <p>Despite the clinical implementation of Nectin-4-targeted antibody-drug conjugates (ADCs) and radioligand therapies (RLTs), their therapeutic window is often restricted by systemic toxicities and the emergence of drug resistance. To circumvent these limitations, we developed [<sup>177</sup>Lu]Lu-DOTA-AC-SP, a novel peptide-based radiopharmaceutical specifically engineered for the targeted treatment of Nectin-4-expressing malignancies.</p> Results <p>The synthesis of [<sup>177</sup>Lu]Lu-DOTA-AC-SP was achieved with high radiochemical purity and excellent stability in vitro. Pharmacokinetic evaluations revealed a favorable profile characterized by high binding affinity and rapid systemic clearance. In vivo biodistribution studies demonstrated significant tumor accumulation and prolonged retention, resulting in superior target-to-background ratios. Furthermore, [<sup>177</sup>Lu]Lu-DOTA-AC-SP exhibited robust anti-tumor efficacy in Nectin-4-positive models, maintaining an excellent safety profile with minimal off-target effects.</p> Conclusions <p>These findings characterize [<sup>177</sup>Lu]Lu-DOTA-AC-SP as a potent and safe therapeutic candidate for Nectin-4-positive tumors. Its favorable pharmacokinetic properties and significant therapeutic index support its potential clinical translation as a next-generation treatment for urothelial carcinoma (UC).</p>

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Preliminary biological evaluation of a [177Lu]Lu-labeled peptide targeting Nectin-4

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Dengke Li,
  • Yu Zhang,
  • Chao Mu,
  • Xuecen Cao,
  • Mumei Chen,
  • Xiao Li,
  • Wenxin Chen,
  • Zheng Li

摘要

Background

Despite the clinical implementation of Nectin-4-targeted antibody-drug conjugates (ADCs) and radioligand therapies (RLTs), their therapeutic window is often restricted by systemic toxicities and the emergence of drug resistance. To circumvent these limitations, we developed [177Lu]Lu-DOTA-AC-SP, a novel peptide-based radiopharmaceutical specifically engineered for the targeted treatment of Nectin-4-expressing malignancies.

Results

The synthesis of [177Lu]Lu-DOTA-AC-SP was achieved with high radiochemical purity and excellent stability in vitro. Pharmacokinetic evaluations revealed a favorable profile characterized by high binding affinity and rapid systemic clearance. In vivo biodistribution studies demonstrated significant tumor accumulation and prolonged retention, resulting in superior target-to-background ratios. Furthermore, [177Lu]Lu-DOTA-AC-SP exhibited robust anti-tumor efficacy in Nectin-4-positive models, maintaining an excellent safety profile with minimal off-target effects.

Conclusions

These findings characterize [177Lu]Lu-DOTA-AC-SP as a potent and safe therapeutic candidate for Nectin-4-positive tumors. Its favorable pharmacokinetic properties and significant therapeutic index support its potential clinical translation as a next-generation treatment for urothelial carcinoma (UC).