EGF receptor and p185(erbB‐2)‐specific single‐chain antibody toxins differ in their cell‐killing activity on tumor cells expressing both receptor proteins Journal Article


Authors: Wels, W.; Beerli, R.; Hellmann, P.; Schmidt, M.; Marte, B. M.; Kornilova, E. S.; Hekele, A.; Mendelsohn, J.; Groner, B.; Hynes, N. E.
Article Title: EGF receptor and p185(erbB‐2)‐specific single‐chain antibody toxins differ in their cell‐killing activity on tumor cells expressing both receptor proteins
Abstract: Many human tumors over‐express erbB‐2 and EGF receptors. The membrane localization of these receptor tyrosine kinases make them appropriate targets for directed tumor therapy. We have used recombinant DNA technology to produce single‐chain antibody exotoxin A (scFv‐ETA) fusion proteins which specifically bind the erbB‐2 and EGF receptors. The scFv portion is composed of the heavy‐ and light‐chain variable domains of monoclonal antibodies which recognize the extracellular portion of each receptor. We have previously described the anti‐tumor activity of the bacterially produced scFv(FRP5)‐ETA directed to the erbB‐2 receptor. In this paper we describe the characteristics of scFv(225)‐ETA, a protein which binds the EGF receptor. The bacterially produced recombinant protein binds to the receptor with high affinity and inhibits the in vitro growth of the EGF receptor over‐expressing tumor cell lines A431 and MDA‐MB468. Combination treatment with scFv‐(FRPS)‐ETA and scFv(225)‐ETA led to an additive inhibitory effect on the in vitro growth of A431 cells. SKBR3 cells expressing low levels of EGF receptor but high levels of p 185erbB‐2 were not affected by scFv(225)‐ETA treatment but were sensitive to scFv(FRP5)‐ETA. Stimulation of SKBR3 cells and HCII RI#11 mouse mammary epithelial cells expressing the human erbB‐2 with EGF led to an increase in scFv(FRP5)‐ETA activity, showing that the EGF‐induced activation of erbB‐2 can potentiate the action of the erbB‐2‐directed toxin. Treatment of athymic nude mice with scFv(FRP5)‐ETA and the combination of both scFv‐ETA proteins led to the transient arrest of growth of established A431 tumors. scFv(22S)‐ETA treatment alone was the most effective, leading to tumor shrinkage during the course of treatment, whereas treatment with the parental monoclonal antibody 225 led to retarded tumor growth. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company
Keywords: epidermal growth factor; controlled study; oncoprotein; human cell; genetics; squamous cell carcinoma; carcinoma, squamous cell; comparative study; molecular genetics; sensitivity and specificity; mouse; animal; metabolism; mice; cell survival; cell division; gene expression; epidermal growth factor receptor; neoplasm proteins; receptor, epidermal growth factor; antineoplastic activity; drug effect; breast neoplasms; monoclonal antibody; immunology; antibodies, monoclonal; amino acid sequence; molecular sequence data; hybrid protein; recombinant fusion proteins; nude mouse; mice, nude; nucleotide sequence; breast tumor; recombinant protein; tumor protein; tumor cell line; base sequence; antibody specificity; receptor, erbb-2; ultrastructure; vulvar neoplasms; immunotoxin; immunotoxins; growth factor receptor; exotoxin; exotoxins; vulva tumor; human; female; priority journal; article; support, non-u.s. gov't; exotoxin a, pseudomonas aeruginosa; receptor, erbb 2
Journal Title: International Journal of Cancer
Volume: 60
Issue: 1
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 1995-01-03
Start Page: 137
End Page: 144
Language: English
DOI: 10.1002/ijc.2910600120
PUBMED: 7814146
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 28 August 2018 -- Source: Scopus
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