Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis
Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis
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DOI：
10.1158/1535-7163.mct-17-1198
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发表时间：
2018-11-01
影响因子：
5.7
通讯作者：
Okada, Yasunori
中科院分区：
文献类型：
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作者：
Mochizuki, Satsuki;Shimoda, Masayuki;Okada, Yasunori
ADAM28（一种解整合素和金属蛋白酶 28）在非小细胞肺癌 (NSCLC) 中的癌细胞中过度表达，通过重新激活胰岛素样生长因子-1 (IGF-1) 并分别通过消化 IGF 结合蛋白-3 和 VWF 来逃避冯维勒布兰德因子 (VWF) 诱导的细胞凋亡，从而在癌细胞增殖和转移中发挥重要作用。为了给NSCLC患者提供新的靶向治疗，我们开发了针对ADAM28的人中和抗体211-12和211-14，其IC50值分别为62.4和37.5 nmol/L。抗体211-14识别富含半胱氨酸结构域和分泌特异性结构域之间的连接区域，并且对于含有表位的肽显示出94.7 pmol/L的K-D值。该抗体检测到猴子和人类分泌型 ADAM28，但它不与小鼠膜锚定的 ADAM28m 发生反应。抗体 211-14 有效抑制 IGF-1 刺激的表达 ADAM28 的肺腺癌细胞系（包括 PC-9 细胞）的细胞增殖，并促进这些细胞系中 VWF 诱导的细胞死亡。在肺转移模型中，与对照 IgG 处理的小鼠相比，抗体 211-14 显着减少了 PC-9 细胞的肿瘤生长和转移，延长了抗体处理小鼠的生存期。抗体和多西他赛的联合治疗比 bev-acizwnab 和多西他赛的联合治疗更有效，并且与单一疗法相比，生存时间进一步延长。即使给正常小鼠施用超过有效剂量10倍的抗ADAM28抗体，也没有观察到不良反应。我们的数据表明，抗体 211-14 是 ADAM28 特异性的中和抗体，并且最确定的是，该抗体可能是 NSCLC 患者的有用治疗药物。 (C) 2018 年 AACR。
ADAM28 (a disintegrin and metalloproteinase 28) is overexpressed by carcinoma cells in non-small cell lung carcinomas (NSCLC) and plays an important role in cancer cell proliferation and metastasis by reactivation of insulin-like growth factor-1 (IGF-1) and escaping from von Willebrand factor (VWF)-induced apoptosis through digestion of IGF-binding protein-3 and VWF, respectively. To aim for new target therapy of NSCLC patients, we developed human neutralizing antibodies 211-12 and 211-14 against ADAM28, which showed IC50 values of 62.4 and 37.5 nmol/L, respectively. Antibody 211-14 recognized the junctional region between cysteine-rich domain and secreted-specific domain and showed a K-D value of 94.7 pmol/L for the epitope-containing peptide. This antibody detected monkey and human secreted-form ADAM28s, although it was not reactive with mouse membrane-anchored ADAM28m. Antibody 211-14 effectively inhibited IGF-1-stimulated cell proliferation of lung adenocarcinoma cell lines with ADAM28 expression, including PC-9 cells, and promoted VWF-induced cell death in these cell lines. In lung metastasis models, antibody 211-14 significantly reduced tumor growth and metastases of PC-9 cells and prolonged survivals in the antibody-treated mice compared with the control IgG-treated ones, Combination therapy of the antibody and docetaxel was more effective than that of bev-acizwnab and docetaxel and showed further elongation of survival time compared with monotherapy. No adverse effects were observed even after administration of 10-fold more than effective dose of anti-ADAM28 antibody to normal mice. Our data demonstrate that antibody 211-14 is a neutralizing antibody specific to ADAM28s and surest that this antibody may be a useful treatment remedy for NSCLC patients. (C) 2018 AACR.