Antibody-Dependent Cell-Mediated Cytotoxicity Effector-Enhanced EphA2 Agonist Monoclonal Antibody Demonstrates Potent Activity against Human Tumors
Antibody-Dependent Cell-Mediated Cytotoxicity Effector-Enhanced EphA2 Agonist Monoclonal Antibody Demonstrates Potent Activity against Human Tumors
复制标题
DOI：
10.1593/neo.81578
复制
发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Coats, Steven
中科院分区：
文献类型：
--
作者：
Bruckheimer, Elizabeth M.;Fazenbaker, Christine A.;Coats, Steven
EphA 2是一种受体酪氨酸激酶，已显示在多种人类肿瘤类型中过表达。先前的研究表明，靶向EphA 2的激动剂单克隆抗体诱导受体的内化和降解，从而消除其致癌作用。在本研究中，评价了EphA 2效应增强的激动剂单克隆抗体的体外和体内抗体依赖性细胞介导的细胞毒性（ADCC）活性。对于肿瘤细胞系和健康人外周血单核细胞，EphA 2抗体显示出类似于80%的肿瘤细胞杀伤。以剂量依赖性方式，自然杀伤（NK）细胞是体外ADCC活性所必需的，并通过诱导CD 107 a的细胞表面表达而被激活。为了评估NK细胞对体内抗肿瘤功效的作用，在严重受损免疫缺陷（SCID）小鼠（其具有功能性NK细胞和单核细胞）和SCID非肥胖糖尿病（NOD）小鼠（其很大程度上缺乏功能性NK细胞和单核细胞）的异种移植物模型中评估EphA 2抗体。在SCID鼠肿瘤模型中给予EphA 2抗体导致肿瘤体积减少6.2倍，而SCID/非肥胖糖尿病模型显示出相对于同种型对照减少1.6倍。总之，这些结果证明抗EphA 2单克隆抗体可以通过至少两种作用机制发挥作用：EphA 2受体活化和ADCC介导的活性。这些新的EphA 2单克隆抗体提供了额外的手段，通过该手段可以激活宿主效应机制以选择性破坏表达EphA 2的肿瘤细胞。
EphA2 is a receptor tyrosine kinase that has been shown to be overexpressed in a variety of human tumor types. Previous studies demonstrated that agonist monoclonal antibodies targeting EphA2 induced the internalization and degradation of the receptor, thereby abolishing its oncogenic effects. In this study, the in vitro and in vivo antibody-dependent cell-mediated cytotoxicity (ADCC) activity of EphA2 effector-enhanced agonist monoclonal antibodies was evaluated. With tumor cell lines and healthy human peripheral blood monocytes, the EphA2 antibodies demonstrated similar to 80% tumor cell killing. In a dose-dependent manner, natural killer (NK) cells were required for the in vitro ADCC activity and became activated as demonstrated by the induction of cell surface expression of CD107a. To assess the role of NK cells on antitumor efficacy in vivo, the EphA2 antibodies were evaluated in xenograft models in severe compromised immunodeficient (SCID) mice (which have functional NK cells and monocytes) and SCID nonobese diabetic (NOD) mice (which largely lack functional NK cells and monocytes). Dosing of EphA2 antibody in the SCID murine tumor model resulted in a 6.2-fold reduction in tumor volume, whereas the SCID/nonobese diabetic model showed a 1.6-fold reduction over the isotype controls. Together, these results demonstrate that the anti-EphA2 monoclonal antibodies may function through at least two mechanisms of action: EphA2 receptor activation and ADCC-mediated activity. These novel EphA2 monoclonal antibodies provide additional means by which host effector mechanisms can be activated for selective destruction of EphA2-expressing tumor cells.