The generation of a novel HER2-targeting nano PE25 immunotoxin with superior anti-tumor activity and high productivity

Abstract

Immunotoxins have the potential to be developed into anti-tumor drugs due to their targeting and strong tumor-killing activity. However, at present, issues such as dose limitations due to off-target toxicity and immunogenicity hinder the clinical use of immunotoxins. A novel HER2-targeted immunotoxin F02 was devised in this study. F02 links an anti-HER2 single-domain camelid antibody to a domain III mutant of PE toxin via a cleavable linker. The PE domain III mutant has seven point-mutations, which potentially remove B-cell and T-cell binding epitopes, thus reducing immunogenicity risks. F02 maintains anti-tumor activity in vivo and in vitro. In animals, F02 effectively inhibited the growth of NCI-N87 tumors at 1.0 mg/kg, and showed a dose-effect relationship, as the effect of completely removing tumors could be achieved at doses above 2.5 mg/kg. F02 also has low toxicity. In cynomolgus monkey models, good tolerability was observed even at 5 mg/kg, a much higher dose than the effective dose. In addition, the molecule has good druggability and can achieve soluble expression in E. coli with a high expression level. Thus, this new molecule has the potential to become a new option for treatment of HER2-positive tumors.