Expression of HER2 in human gastric cancer cells directly correlates with antitumor activity of a recombinant disulfide-stabilized anti-HER2 immunotoxin.
BACKGROUND
Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein have been associated with an unfavorable prognosis. We determined the efficacy of an anti-HER2 immunotoxin, erb-38 [e23(dsFv)PE38], against human gastric cancer cells.


METHODS
Immunotoxin was made by fusing the disulfide-stabilized Fv fragments (dsFv) of a monoclonal antibody e23 to a truncated mutant of M(r) 38 Pseudomonas exotoxin (PE38) that lacks its cell-binding domain.


RESULTS
The immunotoxin-mediated cytotoxicity directly correlated with the expression levels of the HER2 gene and protein in human gastric cancer cells. Interestingly, MKN-45P cells, a variant line of MKN-45 producing peritoneal dissemination and ascites in vivo, expressed a higher level of HER2 and were more sensitive to erb-38 than MKN-45 cells. RFB-4, a control anti-CD22 immunotoxin, was cytotoxic against none of the tested human gastric cancer cells, also suggesting that the lysis mediated by erb-38 was specific for HER2 expression. Three consecutive iv injections of erb-38 at doses of 0.5 or 5 microg/body eradicated experimental liver metastases and peritoneal disseminations produced by MKN-45P in a dose-dependent manner.


CONCLUSIONS
We conclude that an erb-38 anti-HER2 immunotoxin has specific antitumor activities against human gastric cancer cells overexpressing HER2.
Shinohara
Hisashi
H
Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. sur065@poh.osaka-med.ac.jp
Morita
Shinsho
S
Kawai
Masaru
M
Miyamoto
Akiko
A
Sonoda
Toyooki
T
Pastan
Ira
I
Tanigawa
Nobuhiko
N
D000818:Animals; D001201:Ascites / Q000188:drug therapy; D004220:Disulfides; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D004220:Disulfides; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases