Dual‐Target Nectin‐4/FAP Heterobivalent Probe 68 Ga/ 177 Lu‐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 68 Ga‐labeled and 177 Lu‐labeled FZ‐NF‐1 exhibited high radiochemical purity, good stability, and high affinity for both Nectin‐4 and FAP. 68 Ga‐FZ‐NF‐1 revealed better tumor uptake and prolonged retention time compared to monomeric FAP‐ or Nectin‐4 targeted tracers. Moreover, 177 Lu‐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, 68 Ga‐FZ‐NF‐1 demonstrated comparable tumor uptake to that of 18 F‐fluorodeoxyglucose ( 18 F‐FDG), while successfully identifying additional lesions missed by 18 F‐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, 68 Ga/ 177 Lu‐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.