Efficacy and safety evaluation of claudin-4-targeted antitumor therapy using a human and mouse cross-reactive monoclonal antibody.
Efficacy and safety evaluation of claudin-4-targeted antitumor therapy using a human and mouse cross-reactive monoclonal antibody.
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DOI：
10.1002/prp2.266
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发表时间：
2016-10
影响因子：
2.6
通讯作者：
Kondoh, Masuo
中科院分区：
文献类型：
--
作者：
Hashimoto, Yosuke;Kawahigashi, Yumi;Hata, Tomoyuki;Li, Xiangru;Watari, Akihiro;Tada, Minoru;Ishii-Watabe, Akiko;Okada, Yoshiaki;Doi, Takefumi;Fukasawa, Masayoshi;Kuniyasu, Hiroki;Yagi, Kiyohito;Kondoh, Masuo
紧密连接蛋白Claudin-4（CLDN-4）是一种紧密连接蛋白，在各种恶性肿瘤中过表达，包括胃癌、结直肠癌、胰腺癌和乳腺癌。然而，CLDN-4也在正常组织中表达，包括肝脏，胰腺，肾脏和小肠。CLDN-4是否是癌症治疗的有效和安全的靶标尚不清楚，因为缺乏具有CLDN-4特异性和对人和鼠细胞的交叉反应性的结合剂。在这项研究中，我们成功地产生了一种大鼠抗CLDN-4单克隆抗体（5D 12），该抗体对人和小鼠CLDN-4具有特异性并与之交叉反应。5D 12以构象依赖性方式识别人CLDN-4的第二胞外结构域。5D 12（xi-5D 12）的人-大鼠嵌合IgG 1可激活Fcγ IIIa受体，表明在表达CLDN-4的细胞中激活了抗体依赖性细胞毒性。此外，xi-5D 12显著抑制了携带人结肠直肠和胃肿瘤的小鼠的肿瘤生长，而没有明显的不良反应，如体重减轻或肝脏和肾脏损伤。这些结果表明，CLDN-4是癌症治疗的有效靶点，抗CLDN-4抗体是有希望的候选抗癌剂。
Claudin‐4 (CLDN‐4), a tight‐junction protein, is overexpressed in various malignant tumors, including gastric, colorectal, pancreatic, and breast cancers. However, CLDN‐4 is also expressed in normal tissues, including the liver, pancreas, kidney, and small intestine. Whether CLDN‐4 is an effective and safe target for cancer therapy has been unclear owing to the lack of a binder with both CLDN‐4 specificity and cross‐reactivity to human and murine cells. In this study, we successfully generated a rat anti‐CLDN‐4 monoclonal antibody (5D12) that was specific to, and cross‐reactive with, human and mouse CLDN‐4. 5D12 recognized the second extracellular domain of human CLDN‐4 in a conformation‐dependent manner. A human–rat chimeric IgG1 of 5D12 (xi‐5D12) activated the Fcγ IIIa receptor, indicating the activation of antibody‐dependent cellular cytotoxicity in CLDN‐4‐expressing cells. Moreover, xi‐5D12 significantly suppressed tumor growth in mice bearing human colorectal and gastric tumors without apparent adverse effects, such as weight loss or liver and kidney damage. These results suggest that CLDN‐4 is a potent target for cancer therapy and that an anti‐CLDN‐4 antibody is a promising candidate anticancer agent.