Preclinical Safety Evaluation and First-in-Human Translational Study of [¹⁷⁷Lu]Lu-TEFAPI-06: An Albumin-Binding...

Current quinoline-based fibroblast activation protein (FAP) inhibitors typically exhibit rapid pharmacokinetics, which limits their effective energy deposition and therapeutic efficacy in radionuclide therapy. To address this limitation, a novel albumin-binding radiopharmaceutical, [¹⁷⁷Lu]Lu-TEFAPI-06, was developed to extend circulatory half-life and enhance tumor retention. This study reports a systematic "bench-to-bedside" translational investigation of [¹⁷⁷Lu]Lu-TEFAPI-06, encompassing comprehensive preclinical toxicology evaluation and an exploratory first-in-human (FIH) trial. In the preclinical phase, safety assessment in Sprague-Dawley rats demonstrated a favorable toxicity profile; no overt adverse effects or histopathological organ damage were observed. Biodistribution studies in tumor-bearing mice confirmed prolonged tumor retention compared to conventional ligands. In the subsequent FIH trial enrolling five patients with metastatic solid tumors, [¹⁷⁷Lu]Lu-TEFAPI-06 demonstrated acceptable tolerability. The primary adverse events were mild, reversible hematotoxicity, with no signs of hepatotoxicity or nephrotoxicity detected. Dosimetric analysis identified the kidneys as the dose-limiting organ. Clinically, the radiotracer exhibited significant heterogeneity in biodistribution, displaying the most favorable kinetic profile and absorbed dose in the patient with leiomyosarcoma. Furthermore, preliminary observations of therapeutic response in this patient indicated reductions in both standardized uptake values (SUVmax) and serum tumor markers. These findings preliminarily indicate the manageable safety and translational potential of [¹⁷⁷Lu]Lu-TEFAPI-06 within this small exploratory cohort, supporting further evaluation of albumin-binding FAP-targeted therapies.