Doxorubicin-conjugated anti-midkine monoclonal antibody as a potential anti-tumor drug
Doxorubicin-conjugated anti-midkine monoclonal antibody as a potential anti-tumor drug
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DOI：
10.1093/jjco/hyl004
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发表时间：
2006-04-01
影响因子：
2.4
通讯作者：
Muramatsu, Takashi
中科院分区：
文献类型：
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作者：
Inoh, Kazuhiko;Muramatsu, Hisako;Muramatsu, Takashi
背景：Midkine是一种在肿瘤细胞中优先表达的肝素结合生长因子。本研究旨在利用抗midkine抗体治疗肿瘤。方法：通过免疫midkine基因缺失小鼠，制备midkine单克隆抗体。利用化学合成的midkine的n端半和c端半来研究抗体的结合位点。该抗体的多柔比星（DOX）偶联物通过化学偶联产生。利用分泌midkini的肿瘤细胞，即人肝癌细胞（HepG2），检测了抗体和偶联物对细胞生长的影响。结果：该单克隆抗体结合到midkine的n端。该抗体对HepG2细胞的生长没有抑制作用，可能是由于midkine的活性区域在c端半。我们制备了与DOX偶联的抗体，希望偶联物能与midkine一起内化。事实上，与dox偶联的对照IgG相比，抗体- dox偶联物明显抑制HepG2细胞的生长。结论：本研究结果为抗midkine抗体结合DOX用于肿瘤治疗提供了可能。
Background: Midkine is a heparin-binding growth factor preferentially expressed in tumor cells. The present study was performed to utilize anti-midkine antibody for tumor therapy.Methods: A monoclonal antibody to midkine was raised by immunizing mice deficient in the midkine gene. The binding site of the antibody was studied by using N-terminal half and C-terminal half of midkine, both of which were chemically synthesized. Doxorubicin (DOX)-conjugate of the antibody was produced by chemical conjugation. The effects of the antibody and the conjugate on cell growth were examined using a midkine-secreting tumor cell, i.e. human hepatocellular carcinoma cell (HepG2).Results: The monoclonal antibody bound to the N-terminal half of midkine. The antibody did not inhibit the growth of HepG2 cells probably because the active domain of midkine is in the C-terminal half. We produced the antibody conjugated with DOX with the hope that the conjugate would be internalized accompanied with midkine. Indeed, the antibody-DOX conjugate significantly inhibited the growth of HepG2 cells compared with DOX-conjugated control IgG.Conclusion: The result raises the possibility of using anti-midkine antibody conjugated with DOX for cancer therapy.