title: A bivalent recombinant immunotoxin with high potency against tumors with EGFR and EGFRvIII expression.
abstract: EGFR and EGFRvIII are overexpressed in various types of cancer, serving as optimal targets for cancer therapy. Capitalizing on the high specificity of humanized antibody 806 (mAb806) to the EGFR and EGFRvIII overexpressed in cancer, we designed and generated a bivalent recombinant immunotoxin (RIT, DT390-BiscFv806) by fusing the mAb806-derived bivalent single-chain variable fragment with a diphtheria toxin fragment, DT390. In vitro, DT390-BiscFv806 efficiently internalized into the cells and exhibited high cytotoxicity against the U87 glioblastoma cells and the EGFRvIII-transfected U87 (U87-EGFRvIII) cells with a half maximal inhibition concentration (IC50) of 1.47 nM and 2.26 × 10(-4) nM, respectively. Notably, DT390-BiscFv806 was 4 orders of magnitude more potent against the U87-EGFRvIII cells than against the parent U87 cells. The cytotoxicity against a group of 6 head and neck squamous cell carcinoma cell lines were further analyzed, showing an IC50 ranging from 0.24 nM to 156 nM, depending on the expression level of EGFR/EGFRvIII. In animals, the U87-EGFRvIII tumor xenografts grew extremely faster than the parental U87, and systemic administration of DT390-BiscFv806 significantly inhibited the growth of established U87-EGFRvIII and U87 tumor xenografts, showing a growth inhibition rate of 76.3% (59.82-96.2%) and 59.4% (31.5-76.0%), respectively. In pathology, the RIT-treated tumors exhibited a low mitotic activity and a large number of degenerative tumor cells, compared with the control tumors. The results indicate that DT390-BiscFv806 is promising for treatment of various types of cancer, especially for those with high EGFR expression or with EGFR and EGFRvIII co-expression.
authors.affiliation: a Molecular Imaging Laboratory; Department of Radiology; Howard University ; Washington , DC USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: b Angimmune LLC ; Rockville , MD USA.
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: b Angimmune LLC ; Rockville , MD USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: Gao
authors.affiliation: a Molecular Imaging Laboratory; Department of Radiology; Howard University ; Washington , DC USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lin
authors.affiliation: c College of Dentistry; Howard University ; Washington , DC USA.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Gu
authors.affiliation: d Department of Radiology ; Johns Hopkins University ; Baltimore , MD USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: a Molecular Imaging Laboratory; Department of Radiology; Howard University ; Washington , DC USA.|e Department of Physics ; Fu Jen Catholic University ; New Taipei City , Taiwan.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wang
authors.affiliation: a Molecular Imaging Laboratory; Department of Radiology; Howard University ; Washington , DC USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Shan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors
keywords: EGFR; EGFRvIII; cancer; recombinant immunotoxin; targeted therapy