Inamoto Teruo, Yamada Taketo, Ohnuma Kei, Kina Shinichiro, Takahashi Nozomu, Yamochi Tadanori, Inamoto Sakiko, Katsuoka Yoji, Hosono Osamu, Tanaka Hirotoshi, Dang Nam H, Morimoto Chikao
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Japan.
Clin Cancer Res. 2007 Jul 15;13(14):4191-200. doi: 10.1158/1078-0432.CCR-07-0110.
CD26 is a 110-kDa cell surface antigen with a role in tumor development. In this report, we show that CD26 is highly expressed on the cell surface of malignant mesothelioma and that a newly developed humanized anti-CD26 monoclonal antibody (mAb) has an inhibitory effect on malignant mesothelioma cells in both in vitro and in vivo experiments.
Using immunohistochemistry, 12 patients' surgical specimens consisting of seven malignant mesothelioma, three reactive mesothelial cells, and two adenomatoid tumors were evaluated for expression of CD26. The effects of CD26 on malignant mesothelioma cells were assessed in the presence of transfection of CD26-expressing plasmid, humanized anti-CD26 mAb, or small interfering RNA against CD26. The in vivo growth inhibitory effect of humanized anti-CD26 mAb was assessed in human malignant mesothelioma cell mouse xenograft models.
In surgical specimens, CD26 is highly expressed in malignant mesothelioma but not in benign mesothelial tissues. Depletion of CD26 by small interfering RNA results in the loss of adhesive property, suggesting that CD26 is a binding protein to the extracellular matrix. Moreover, our in vitro data indicate that humanized anti-CD26 mAb induces cell lysis of malignant mesothelioma cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct anti-tumor effect via p27(kip1) accumulation. In vivo experiments with mouse xenograft models involving human malignant mesothelioma cells show that humanized anti-CD26 mAb treatment drastically inhibits tumor growth in tumor-bearing mice, resulting in enhanced survival.
Our data strongly suggest that humanized anti-CD26 mAb treatment may have potential clinical use as a novel cancer therapeutic agent in CD26-positive malignant mesothelioma.
CD26是一种110 kDa的细胞表面抗原，在肿瘤发展中起作用。在本报告中，我们表明CD26在恶性间皮瘤细胞表面高度表达，并且一种新开发的人源化抗CD26单克隆抗体（mAb）在体外和体内实验中对恶性间皮瘤细胞均具有抑制作用。
使用免疫组织化学方法，对12例患者的手术标本进行评估，其中包括7例恶性间皮瘤、3例反应性间皮细胞和2例腺瘤样肿瘤，以检测CD26的表达情况。在转染表达CD26的质粒、人源化抗CD26 mAb或针对CD26的小干扰RNA的情况下，评估CD26对恶性间皮瘤细胞的影响。在人恶性间皮瘤细胞小鼠异种移植模型中评估人源化抗CD26 mAb的体内生长抑制作用。
在手术标本中，CD26在恶性间皮瘤中高度表达，但在良性间皮组织中不表达。小干扰RNA介导的CD26缺失导致黏附特性丧失，这表明CD26是一种细胞外基质结合蛋白。此外，我们的体外数据表明，人源化抗CD26 mAb除了通过p27（kip1）积累产生直接抗肿瘤作用外，还通过抗体依赖性细胞介导的细胞毒性诱导恶性间皮瘤细胞裂解。用人恶性间皮瘤细胞的小鼠异种移植模型进行的体内实验表明，人源化抗CD26 mAb治疗可显著抑制荷瘤小鼠的肿瘤生长，从而提高生存率。
我们的数据强烈表明，人源化抗CD26 mAb治疗可能作为一种新型癌症治疗药物在CD26阳性恶性间皮瘤中具有潜在的临床应用价值。
