225Ac-Labeled Antibody for Fibroblast Activation Protein-Targeted Alpha Therapy

Targeted alpha therapy (TAT) is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues. 225Ac, an alpha radionuclide with a half-life of 10 days and emitting 4 alpha particles and 2 beta particles in its decay chain, has shown promise for TAT. Fibroblast activation protein (FAP) has emerged as a valuable target for the development of radiopharmaceuticals in the context of TAT, given its expression in various cancers. However, a challenge arises when using FAP-targeting agents such as FAP inhibitors (FAPIs) in combination with 225Ac due to their rapid clearance from the tumor. To address this challenge, the FAP-targeting antibody PKU525 was developed as a TAT drug. The conjugation ratios of the chelator and the labeling procedure were systematically investigated, resulting in an efficient and stable radiolabeling method. Biodistribution studies were conducted using [225Ac]­Ac-DOTA-PKU525 with average drug-to-antibody ratios (DARs) of 1.85, 3.87, and 7.72. A single dose of 11.1 kBq of [225Ac]­Ac-DOTA-PKU525 with DAR 3.87 demonstrated significant inhibition of 4T1-hFAP tumor growth. No significant weight changes were observed throughout the treatment period, and histological examination of the major organs revealed no adverse side effects. In conclusion, [225Ac]­Ac-DOTA-PKU525 exhibited both safety and efficacy in 4T1-hFAP tumor-bearing mice, indicating its potential for clinical translation in FAP-targeted alpha therapy. Further development and evaluation of this TAT approach hold promise for improving cancer treatment outcomes.