Dual-Target Nectin-4/FAP Heterobivalent Probe ⁶⁸Ga/¹⁷⁷Lu-FZ-NF-1 for Triple-Negative Breast Cancer: Preclinical Theranostic Evaluation and First-in-Human Translation.

Abstract

Triple-negative breast cancer (TNBC) features pronounced molecular heterogeneity and poor prognosis, restricting the efficacy of single-targeted strategies. Leveraging the complementary theranostic targets fibroblast activation protein (FAP) and Nectin-4, we designed the novel hetero-bivalent agent FZ-NF-1 for dual targeting. Preclinically, both ⁶⁸Ga-labeled and ¹⁷⁷Lu-labeled FZ-NF-1 exhibited high radiochemical purity, good stability, and high affinity for both Nectin-4 and FAP. ⁶⁸Ga-FZ-NF-1 revealed better tumor uptake and prolonged retention time compared to monomeric FAP- or Nectin-4 targeted tracers. Moreover, ¹⁷⁷Lu-FZ-NF-1 exhibited sustained tumor accumulation for upto 120 h post-injection, leading to significant, dose-dependent tumor regression in TNBC mouse models, with no obvious systemic toxicity observed. In a preliminary first-in-human translational study involving 13 patients with TNBC, ⁶⁸Ga-FZ-NF-1 demonstrated comparable tumor uptake to that of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), while successfully identifying additional lesions missed by ¹⁸F-FDG. Complementary tissue microarray analysis of 60 TNBC cases confirmed the heterogeneous expression of Nectin-4 and FAP in TNBC. By concurrently targeting the tumor cells and stroma, ⁶⁸Ga/¹⁷⁷Lu-FZ-NF-1 effectively mitigates the limitations associated with single-target imaging and therapy. These results indicate that the heterodimeric theranostic pair offers enhanced imaging performance and significant therapeutic efficacy, providing a promising strategy for the personalized management of refractory TNBC.