[212Pb]Pb-AG1206：一种新型成纤维细胞活化蛋白靶向放射性配体疗法，展现出卓越的疗效和安全性

Fibroblast activation protein (FAP) is highly expressed in a wide range of solid tumors, making it an attractive target for agents designed to accumulate within the tumor microenvironment. Lead-212 (²¹²Pb) is highly effective for targeted alpha therapy causing localized tumor cell killing induced by double strand DNA breaks while sparing surrounding healthy tissue. [ 212 Pb]Pb-AG1206 is a novel macrocyclic peptide radioligand that is designed to bind to FAP selectively, and to have rapid and high tumor uptake and fast renal clearance. When conjugated with the radioisotopes 203 Pb (for imaging) or ²¹²Pb (for therapy), AG1206 enables theranostic applications. Preclinical studies demonstrated excellent in vitro and in vivo properties of [ 212 Pb]Pb-AG1206 supporting its clinical development. Methods: Binding affinity and selectivity were assessed using surface plasmon resonance (SPR). Cell binding and internalization were evaluated in FAP-expressing cell lines. In vivo biodistribution, antitumor efficacy, and dosimetry were performed in subcutaneous mouse cell-derived xenograft (CDX) models that express FAP. Results: [ 212 Pb]Pb-AG1206 exhibited FAP-specific cellular uptake and high binding affinity in the picomolar (pM) range. It showed rapid tumor accumulation and fast clearance, and robust tumor growth inhibition with an excellent safety profile. Dosimetry studies in preclinical models demonstrated low radiation absorption in normal organs, indicating a favorable safety margin that is translatable to humans. These findings underscore FAP-targeted radioligand therapy (RLT) as a promising strategy for treating a broad spectrum of solid tumors characterized by desmoplastic microenvironments. Conclusions: In conclusion the data support clinical development of [ 212 Pb]Pb-AG1206 as a novel therapeutic for patients with FAP-expressing solid tumors.