Shinohara Hisashi, Morita Shinsho, Kawai Masaru, Miyamoto Akiko, Sonoda Toyooki, Pastan Ira, Tanigawa Nobuhiko
Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
J Surg Res. 2002 Feb;102(2):169-77. doi: 10.1006/jsre.2001.6305.
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.
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.
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.
We conclude that an erb-38 anti-HER2 immunotoxin has specific antitumor activities against human gastric cancer cells overexpressing HER2.
人表皮生长因子受体2（HER2）基因扩增及HER2蛋白过表达与不良预后相关。我们测定了一种抗HER2免疫毒素erb-38 [e23(dsFv)PE38]对人胃癌细胞的疗效。
免疫毒素是通过将单克隆抗体e23的二硫键稳定化Fv片段（dsFv）与缺乏细胞结合结构域的M(r) 38铜绿假单胞菌外毒素（PE38）的截短突变体融合而成。
免疫毒素介导的细胞毒性与人胃癌细胞中HER2基因和蛋白的表达水平直接相关。有趣的是，MKN-45P细胞是MKN-45的变体株，在体内可产生腹膜播散和腹水，其HER2表达水平较高，对erb-38比MKN-45细胞更敏感。对照抗CD22免疫毒素RFB-4对所有测试的人胃癌细胞均无细胞毒性，这也表明erb-38介导的细胞裂解对HER2表达具有特异性。以0.5或5微克/体的剂量连续3次静脉注射erb-38可剂量依赖性地根除MKN-45P产生的实验性肝转移和腹膜播散。
我们得出结论，erb-38抗HER2免疫毒素对过表达HER2的人胃癌细胞具有特异性抗肿瘤活性。
