title: Fusion of an albumin-binding domain extends the half-life of immunotoxins.
abstract: Immunotoxins have documented potential as a cancer treatment due to their extreme potency; a single toxin molecule delivered to the cytosol may be sufficient to kill a cell. However, their short half-life in the circulatory system may be one of the key problems associated with the clinical use of immunotoxins and may continue to limit their therapeutic activity. Herein, we genetically fused an albumin-binding domain (ABD) to the human epidermal growth factor receptor 2 (HER2)-specific immunotoxin ZHER2-PE38 to extend the circulation time and thus improve the therapeutic outcome of this immunotoxin. Furthermore, the fusion of an ABD to the immunotoxin was found to promote non-covalent interactions between the immunotoxin and serum albumin, which rescue the immunotoxin from lysosomal degradation through a serum albumin-mediated interaction with the neonatal Fc receptor (FcRn). This manuscript reports the construction, purification, and characterization of the ABD-fused HER2-specific immunotoxin, ABD-ZHER2-PE38, both in vitro and in vivo. Compared with non-fused ZHER2-PE38, this new construct exhibits a clearly increased half-life in plasma (330.8 versus 13.5min, approximately 24.4-fold extension) and remarkably improved antitumor effects in an NCI-N87 subcutaneous xenograft model. Therefore, the new construct represents a potentially attractive therapeutic modality, and the proposed strategy may also have useful applications for current immunotoxin designs.
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: 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: 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: 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: Jieyu
authors.initials: J
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: Kanghong Yaoyuan Biotech Co., Ltd., Tianjin 300192, PR China. Electronic address: hwq0324@hotmail.com.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Huang
authors.affiliation: People⿿s Hospital of Tianjin, Tianjin 300180, PR China. Electronic address: wfengwei2004@163.com.
authors.forename: Fengwei
authors.initials: F
authors.lastname: Wang
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: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012709:Serum Albumin; C508053:ERBB2 protein, human
keywords: Affibody; Albumin binding domain; Half-life extension; Immunotoxin; Pseudomonas exotoxin