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

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.

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.

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).