Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cancer Sci. 2020 Oct;111(10):3478-3492. doi: 10.1111/cas.14566. Epub 2020 Aug 7.
Ovarian cancer has a high recurrence rate after platinum-based chemotherapy. To improve the treatment of ovarian cancer and identify ovarian cancer-specific antibodies, we immunized mice with the human ovarian carcinoma cell line, SKOV-3, and generated hybridoma clones. Several rounds of screening yielded 30 monoclonal antibodies (mAbs) with no cross-reactivity to normal cells. Among these mAbs, OV-Ab 30-7 was found to target integrin α3 and upregulate p53 and p21, while stimulating the apoptosis of cancer cells. We further found that binding of integrin α3 by OV-Ab 30-7 impaired laminin-induced focal adhesion kinase phosphorylation. The mAb alone or in combination with carboplatin and paclitaxel inhibited tumor progression and prolonged survival of tumor-bearing mice. Moreover, immunohistochemical staining of ovarian patient specimens revealed higher levels of integrin α3 in cancer cells compared with normal cells. By querying online clinical databases, we found that elevated ITGA3 expression in ovarian cancer is associated with poor prognosis. Taken together, our data suggest that the novel mAb, OV-Ab 30-7, may be considered as a potential therapeutic for ovarian cancer.
卵巢癌在铂类化疗后复发率很高。为了改善卵巢癌的治疗效果并鉴定卵巢癌特异性抗体，我们用人卵巢癌细胞系 SKOV-3 免疫小鼠，生成杂交瘤克隆。经过几轮筛选，得到了 30 种与正常细胞无交叉反应的单克隆抗体（mAbs）。在这些 mAbs 中，OV-Ab 30-7 被发现靶向整合素 α3，上调 p53 和 p21，并刺激癌细胞凋亡。我们进一步发现，OV-Ab 30-7 与整合素 α3 的结合会损害层粘连蛋白诱导的黏着斑激酶磷酸化。该 mAb 单独或与卡铂和紫杉醇联合使用可抑制肿瘤进展并延长荷瘤小鼠的生存期。此外，对卵巢患者标本的免疫组织化学染色显示，癌细胞中整合素 α3 的水平高于正常细胞。通过在线临床数据库查询，我们发现卵巢癌中 ITGA3 的表达升高与预后不良相关。综上所述，我们的数据表明，新型 mAb OV-Ab 30-7 可能被视为治疗卵巢癌的一种潜在药物。
