Anti-Glypican 3 Antibody as a Potential Antitumor Agent for Human Liver Cancer
Anti-Glypican 3 Antibody as a Potential Antitumor Agent for Human Liver Cancer
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DOI：
10.1158/0008-5472.can-08-1973
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Yamada-Okabe, Hisafumi
中科院分区：
文献类型：
--
作者：
Ishiguro, Takahiro;Sugimoto, Masamichi;Yamada-Okabe, Hisafumi
人GPC3基因在肝癌患者的肿瘤组织中优先表达。在本研究中，我们获得了一种抗GPC3羧基末端的单抗，它能诱导抗体依赖的细胞毒作用(ADCC)。命名为GC33的单抗对S.C.有明显的肿瘤生长抑制作用。移植表达GPC3的Hep G2和HH-7异种移植瘤，但不抑制GPC3阴性的SK-Hep-1细胞的生长。GC33即使在原位模型上也是有效的；它显著降低了Hep G2细胞肝内移植小鼠的血液甲胎蛋白水平。人源化GC33(HGC33)对Hep G2移植瘤的抑制作用与GC33相同，但缺乏糖基的hGC33既不能抑制ADCC，也不能抑制肿瘤生长。去除人外周血单个核细胞中CD56(+)细胞可显著消除hGC33引起的ADCC。结果表明，hGC33的抗肿瘤活性主要来源于ADCC，在人体内，自然杀伤细胞介导的ADCC是其抗肿瘤作用的可能机制之一。HGC33将为GPC3阳性肿瘤的肝癌患者提供一种新的治疗选择。[癌症资源2008；68(23)：9832-8]
Human glypican 3 (GPC3) is preferentially expressed in the tumor tissues of liver cancer patients. In this study, we obtained a monoclonal antibody (mAb) against the COOH-terminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated GC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. GC33 was efficacious even in an orthotopic model; it markedly reduced the blood a-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. Humanized GC33 (hGC33) was as efficacious as GC33 against the Hep G2 xenograft, but hGC33 lacking carbohydrate moieties caused neither ADCC nor tumor growth inhibition. Depletion of CD56(+) cells from human peripheral blood mononuclear cells markedly abrogated the ADCC caused by hGC33. The results show that the antitumor activity of hGC33 is mainly attributable to ADCC, and in human, natural killer cell-mediated ADCC is one possible mechanism of the antitumor effects by GC33. hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors. [Cancer Res 2008;68(23):9832-8]