<sup>225</sup>Ac-Labeled Antibody for Fibroblast Activation Protein-Targeted Alpha Therapy
Hanbo Song, Mengxin Xu, Jie Cai, Junyi Chen, Yu Liu, Qi Su, Zhu Li, Zhibo Liu
Abstract
High Resolution Image Download MS PowerPoint Slide 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. 225 Ac, 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 225 Ac 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 [ 225 Ac]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 [ 225 Ac]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, [ 225 Ac]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.