LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

单克隆抗体 癌症研究 抗原 抗体 细胞毒性 卵巢癌 体内 补体依赖性细胞毒性 生物 癌症 体外 医学 免疫学 内科学 抗体依赖性细胞介导的细胞毒性 生物化学 生物技术
作者
Kosuke Hiramatsu,Satoshi Serada,Takayuki Enomoto,Yusuke Takahashi,Satoshi Nakagawa,Satoshi Nojima,Akiko Morimoto,Shinya Matsuzaki,Takuhei Yokoyama,Tsuyoshi Takahashi,Minoru Fujimoto,Hiroshi Takemori,Yutaka Ueda,Kiyoshi Yoshino,Eiichi Morii,Tadashi Kimura,Tetsuji Naka
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (2): 516-527 被引量:47
标识
DOI:10.1158/0008-5472.can-17-0910
摘要

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR+ EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro, and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment. Significance: These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. Cancer Res; 78(2); 516–27. ©2017 AACR.
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