Jia-Li Gu,Wen-Yan Pi,Wei-Feng Xie,Jia-Wen Gu,Ya-Jun Wang,Li Xiao,Yong-Jin Li,Jing-Fen Li
The present work is aimed to improve the antibody adsorption performance of phenyl-based mixed-mode adsorbents by adjusting the functional group of ligand. Two new mixed-mode adsorbents coupled with 4-(aminomethyl)phenol (AMP) and 4-(aminomethyl)benzonic acid (AMA) were designed based on the structure of benzylamine (BA), where a hydroxyl or carboxyl group was introduced. Bovine serum Immunoglobulin G (IgG) and bovine serum albumin (BSA) were used as the model proteins. The adsorption isotherms of IgG and BSA were investigated at different pH values ranging from 4.0–8.9 to evaluate the adsorption performance, and protein-ligand molecular interactions were explored through addition of sodium chloride and glycerol. The results showed that both of adsorbents coupled with AMP or AMA had lower saturated binding capacities ( Q m ) towards BSA and higher adsorption capacity ratio of IgG to BSA when compared to BA-based adsorbents. The contributions of electrostatic interactions and hydrophobic interactions to proteins binding were different among these phenyl-based mixed mode adsorbents. Finally, AMP-based adsorbent possessing high adsorption capacity ratio of IgG to BSA and salt tolerance was selected to separate IgG from mimetic serum with purity higher than 96 %. The results indicated adjusting the functional groups of ligand to regulate the electrostatic and hydrophobic interactions of protein-ligand was useful to improve the antibody separation performance of mixed-mode adsorbents.
Hanbo Song,Mengxin Xu,Jie Cai,Junyi Chen,Yu Liu,Qi Su,Zhu Li,Zhibo Liu
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.
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