Data from First-in-Human Study of the Radioligand <sup>68</sup>Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma

Abstract

<div>AbstractPurpose:<p>Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody–drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response.</p>Experimental Design:<p>In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer <b><sup>68</sup>Ga-N188</b>. Initially, we performed preclinical evaluations of <b><sup>68</sup>Ga-N188</b> in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT.</p>Results:<p>In the preclinical study, <b><sup>68</sup>Ga-N188</b> showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for <b><sup>68</sup>Ga-N188</b>, and the nectin-4 relative expression level in different organs was quantitatively imaged.</p>Conclusions:<p>A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of <b><sup>68</sup>Ga-N188</b> PET as a companion diagnostic tool for optimizing treatments that target nectin-4.</p></div>