title: HER2-targeted immunotoxins with low nonspecific toxicity and immunogenicity.
abstract: Immunotoxins have efficient anti-tumor activity due to their extreme potency. However, dose-limiting off-target toxicity and immunogenicity are the critical barriers for these immunotoxins to be used in a clinical setting. In this study, we designed a Pseudomonas exotoxin A (PE)-based human epidermal growth factor receptor-2 (HER2)-specific immunotoxin HER2-PE25-X7 by deleting most of domain II and introducing seven point mutations into domain III of the PE38 toxin. The anti-cancer activity, off-target toxicity and immunogenicity of this immunotoxin were carefully evaluated in vitro and in vivo. This new construct maintained the therapeutic potency of the original PE38-based immunotoxin HER2-PE38, with a greatly reduced off-target toxicity and immunogenicity. To compare with HER2-PE38, which resulted in the death of most of the mice after a single dose of 1.0 mg/kg, the new construct was completely tolerated at a dose of 10 mg/kg by the mice and almost completely depleted the tumor after treatment with five doses of 5 mg/kg of the immunotoxin. This work demonstrates a potentially attractive therapeutic modality for HER2-specific cancer treatment.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Quzhou People's Hospital, Quzhou, Zhejiang, 324000, PR China. Electronic address: 48932575@qq.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, PR China. Electronic address: hongzy@nankai.edu.cn.
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
mesh_terms: D036002:ADP Ribose Transferases / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011549:Pseudomonas / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508053:ERBB2 protein, human
keywords: HER2-target; Immunogenicity; Immunotoxins; Nonspecific toxicity