A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo
A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo
复制标题
人源化抗骨桥蛋白抗体在体内抑制乳腺癌生长和转移
DOI：
10.1007/s00262-009-0754-z
复制
发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
--
作者：
Dai, Jianxin;Li, Bohua;Guo, Yajun
骨桥蛋白(OPN)被认为是乳腺癌进展和转移的重要介质，并已被研究作为乳腺癌治疗的潜在靶点。然而，抗OPN抗体对乳腺癌的体内抗肿瘤作用尚未见报道。本研究采用基于计算机辅助分子模拟的互补决定区嫁接方法，人源化小鼠抗人OPN抗体(1A12)。1A12的人源化版本，表示为hu1A12，被证明具有与其亲本抗体相当的亲和力。在高转移的人乳腺癌细胞系MDA-MB-435S中，研究了hu1A12抑制细胞迁移、黏附、侵袭和克隆形成的能力。结果表明，hu1A12在体外能有效抑制MDA-MB-435S细胞的黏附、迁移、侵袭和集落形成。在人乳腺癌小鼠肺转移模型中，Hu1A12也显示出显著的抑制原发肿瘤生长和自发转移的作用。经鉴定，hu1A12识别的特异性表位为212NAPSD216，与OPN的钙结合结构域相邻。我们的数据有力地支持了OPN是乳腺癌抗体治疗的潜在靶点。人源化抗OPN抗体hu1A12有望成为治疗乳腺癌的有效药物。
Osteopontin (OPN) has been implicated as an important mediator of breast cancer progression and metastasis and has been investigated for use as a potential therapeutic target in the treatment of breast cancer. However, the in vivo antitumor effect of anti-OPN antibodies on breast cancer has not been reported. In this study, a mouse anti-human OPN antibody (1A12) was humanized by complementarity-determining region grafting method based on computer-assisted molecular modeling. A humanized version of 1A12, denoted as hu1A12, was shown to possess affinity comparable to that of its parental antibody. The ability of hu1A12 to inhibit cell migration, adhesion, invasion and colony formation was assessed in a highly metastatic human breast cancer cell line MDA-MB-435S. The results indicated that hu1A12 was effective in inhibiting the cell adhesion, migration, invasion and colony formation of MDA-MB-435S cells in vitro. hu1A12 also showed significant efficacy in suppressing primary tumor growth and spontaneous metastasis in a mouse lung metastasis model of human breast cancer. The specific epitope recognized by hu1A12 was identified to be212NAPSD216, adjacent to the calcium binding domain of OPN. Our data strongly support that OPN is a potential target for the antibody-based therapies of breast cancer. The humanized anti-OPN antibody hu1A12 may be a promising therapeutic agent for the treatment of human breast cancer.