HER2-specific immunotoxins constructed based on single-domain antibodies and the improved toxin PE24X7

Publication date: Available online 10 December 2019Source: International Journal of PharmaceuticsAuthor(s): Li Cao, Qiyu Li, Zhen Tong, Yutong Xing, Keyuan Xu, Jessica Yijia Wang, Wenjing Li, Jianhua Zhao, Liqing Zhao, Zhangyong HongAbstractHuman epidermal growth factor receptor 2 (HER2) is an attractive target for cancer therapy, although a large fraction of tumors that express HER2 may still resist first-line therapies. Immunotoxins with antibodies that are armed with extremely potent cytotoxic toxin molecules may provide an important solution to this problem. In this work, we constructed three new anti-HER2 immunotoxins by using single-domain antibody (sdAb) molecules as the targeting moiety and the improved toxin PE24X7 as the effector with the aim of simplifying the preparation and reducing the off-target toxicity of the immunotoxins. Due to the beneficial outcomes of sdAb molecules, the synthesized immunotoxins were efficiently expressed in soluble form, avoiding the refolding process required by the common immunotoxin design and having high solubility and stability. Cell toxicity experiments showed that they have high cytotoxicity against various HER2-positive tumor cells and good selectivity (more than 1,000-fold) towards HER2-positive rather than HER2-negative cells. Importantly, in vivo treatment experiments showed that one of the new immunotoxins could efficiently halt tumor growth at doses lower than 0.75 mg/kg, and it had a maximum tolerated dose (MTD) higher tha...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research