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Life sciences · Journal article
Molecular Pharmaceutics · September 28, 2026
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Abstract The cell adhesion protein Nectin-4 has been proven as an effective target for therapeutic approaches in bladder cancer. In addition, the interest as a target protein for targeted radionuclide theranostic approaches is growing. While several promising radioligands for imaging purposes have been described in recent years, therapeutic radioligands are largely missing so far, which is mainly reasoned by a comparatively low uptake into the tumor tissue accompanied by a fast washout kinetic of the radioligand. In this study, we investigated how the introduction of an albumin-binding unit into our previously developed ligand NECT-224, which is structurally derived from the bicyclic toxin conjugate BT8009, can improve the integral tumor uptake. The resulting heterobivalent ligand NECT-308 was successfully synthesized via solid-phase peptide synthesis. Nectin-4-selective binding was confirmed by surface plasmon resonance interaction analysis. The radiopharmacological characterization of [64Cu]Cu-NECT-308 in vitro revealed an albumin-binding affinity of 25 μM and an apparent binding affinity to cellular Nectin-4 of 14 nM as assessed by an ultrafiltration assay using human serum albumin and saturation binding analysis using intact HT-1376 cells (urothelial carcinoma cell line), respectively. PET imaging studies in HT-1376 tumor-bearing mice highlighted an almost fourfold higher integral tumor uptake of [64Cu]Cu-NECT-308 over 24 h compared to [64Cu]Cu-NECT-224. As expected, this was accompanied by an increased activity retention in the blood circulation and also by an increased kidney uptake. Control experiments with either a radioligand that exhibits a comparable binding affinity to albumin but bears no Nectin-4-targeting unit or by blocking the binding of [64Cu]Cu-NECT-308 to tumor-associated Nectin-4 revealed that the increase in tumor uptake is mainly attributed to Nectin-4-independent mechanisms. The implications of this finding, in particular regarding the clinical translation of such heterobivalent radioligands, are discussed in detail. The radiopharmacological characterization of [64Cu]Cu-NECT-308 was complemented by dosimetric calculations for [64/67Cu]Cu-NECT-224 and [64/67Cu]Cu-NECT-308 in mice and humans, which indicated that the kidneys are the dose-limiting organs. Overall, our results reveal that further structural optimizations of the Nectin-4-directed bicyclic peptide scaffold are necessary to achieve a higher and longer Nectin-4-dependent tumor uptake as well as a lower kidney uptake to enable a potential radioligand therapy. The introduction of an albumin-binding unit as done herein can only partly address these requirements.