A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells
A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells
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DOI：
10.1158/1078-0432.ccr-11-1029
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发表时间：
2011-11-01
影响因子：
11.5
通讯作者：
Mekada, Eisuke
中科院分区：
文献类型：
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作者：
Miyamoto, Shingo;Iwamoto, Ryo;Mekada, Eisuke
目的：肝素结合表皮生长因子样生长因子(HB-EGF)是EGF家族的一员，在卵巢癌的发生发展中起关键作用。我们研制了抗HB-EGF的单抗，并研究了其体内外的抗肿瘤活性，以评价其作为卵巢癌治疗性抗体的潜力。实验设计：以重组人可溶性HB-EGF免疫HB-EGF基因缺陷小鼠，制备单抗，并评价其结合和中和HB-EGF的活性。结果：制备了两株小鼠抗HB-EGF单抗，其中一株KM3566与细胞表面表达的膜锚定HB-EGF(Pro-HB-EGF)具有较高的结合活性，并能中和可溶性HB-EGF的促生长活性。KM3566(CKM3566)的人-鼠嵌合抗体(CKM3566)体外对表达HB-EGF的癌细胞具有剂量依赖性的抗体依赖性细胞毒作用(ADCC)，并能显著抑制MCAS或ES-2人卵巢癌细胞的生长。结论：新型抗HB-EGF嵌合抗体cKM3566具有中和和ADCC两种抗肿瘤机制。这些结果表明cKM3566是一种很有前途的抗卵巢癌治疗性抗体。临床癌症资源；17(21)；6733-41。(C)2011年AACR。
Purpose: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family and plays a pivotal role in tumor progression in ovarian cancer. We developed an anti-HB-EGF monoclonal antibody (mAb) and investigated its antitumor activities in vitro and in vivo to evaluate its potential as a therapeutic antibody against ovarian cancer.Experimental Design: We prepared mAbs from HB-EGF null mice immunized with recombinant human soluble HB-EGF and evaluated their binding and neutralizing activity against HB-EGF. Next, we generated a mouse-human chimeric antibody and examined its in vitro and in vivo antitumor activities.Results: Two murine anti-HB-EGF mAbs were developed, and one of them, KM3566, was revealed to have a high binding reactivity for membrane-anchored HB-EGF (pro-HB-EGF) expressed on the cell surface, as well as neutralizing activity against growth promoting activity of soluble HB-EGF. The mouse-human chimeric counterpart for KM3566 (cKM3566) induced dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against cancer cells expressing HB-EGF in vitro, and significantly inhibited tumor growth in severe combined immunodeficient mice inoculated with MCAS or ES-2 human ovarian cancer cells.Conclusions: A novel anti-HB-EGF chimeric antibody, cKM3566, with two antitumor mechanisms, neutralization and ADCC, exhibits potent in vivo antitumor activity. These results indicate that cKM3566 is a promising antiovarian cancer therapeutic antibody. Clin Cancer Res; 17(21); 6733-41. (C)2011 AACR.