Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo
Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo
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DOI：
10.1111/j.1349-7006.2009.01463.x
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发表时间：
2010-04-01
期刊：
影响因子：
5.7
通讯作者：
Hino, Okio
中科院分区：
文献类型：
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作者：
Inami, Koichi;Abe, Masaaki;Hino, Okio
间皮瘤是一种侵袭性癌症，通常由慢性石棉暴露引起，尽管目前使用的治疗方法，其预后非常差。由于石棉暴露和肿瘤发展之间的潜伏期较长，未来几十年全球发病率将大幅增加。因此，新的有效的治疗方法是必要的，以改善预后。ERC/间皮素基因（MSLN）在包括间皮瘤在内的多种人类癌症中表达，并且编码被蛋白酶切割以产生C-ERC/间皮素和N-ERC/间皮素的前体蛋白。在这项研究中，我们研究了C-ERC/间皮素特异性小鼠单克隆抗体，22 A31，对来自人类间皮瘤细胞系，ACC-MESO-4，在异种移植实验模型，使用雌性BALB/c无胸腺裸鼠的肿瘤的抗肿瘤活性。用22 A31处理在体外不抑制ACC-MESO-4的细胞增殖;然而，用22 A31治疗性处理在体内显著抑制肿瘤生长。在体外，22 A31通过自然杀伤（NK）细胞而非巨噬细胞诱导抗体依赖性细胞介导的细胞毒性。一致地，22 A31的F（ab '）（2）片段在体内不抑制肿瘤生长，在体外也不诱导抗体依赖性细胞介导的细胞毒性（ADCC）。此外，NK细胞耗竭减弱了22 A31的抗肿瘤作用。因此，22 A31诱导NK细胞介导的ADCC并在体内发挥抗肿瘤活性。22 A31可能具有作为治疗C-ERC/间皮素表达癌症（包括间皮瘤）的治疗工具的潜力。（Cancer Sci 2010; 101：969-974）
Mesothelioma is an aggressive cancer often caused by chronic asbestos exposure, and its prognosis is very poor despite the therapies currently used. Due to the long latency period between asbestos exposure and tumor development, the worldwide incidence will increase substantially in the next decades. Thus, novel effective therapies are warranted to improve the prognosis. The ERC/mesothelin gene (MSLN) is expressed in wide variety of human cancers, including mesotheliomas, and encodes a precursor protein cleaved by proteases to generate C-ERC/mesothelin and N-ERC/mesothelin. In this study, we investigated the antitumor activity of C-ERC/mesothelin-specific mouse monoclonal antibody, 22A31, against tumors derived from a human mesothelioma cell line, ACC-MESO-4, in a xenograft experimental model using female BALB/c athymic nude mice. Treatment with 22A31 did not inhibit cell proliferation of ACC-MESO-4 in vitro; however, therapeutic treatment with 22A31 drastically inhibited tumor growth in vivo. 22A31 induced antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells, but not macrophages, in vitro. Consistently, the F(ab')(2) fragment of 22A31 did not inhibit tumor growth in vivo, nor did it induce antibody-dependent cell mediated cytotoxicity (ADCC) in vitro. Moreover, NK cell depletion diminished the antitumor effect of 22A31. Thus, 22A31 induced NK cell-mediated ADCC and exerted antitumor activity in vivo. 22A31 could have potential as a therapeutic tool to treat C-ERC/mesothelin-expressing cancers including mesothelioma. (Cancer Sci 2010; 101: 969-974)