Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity
Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity
复制标题
DOI：
10.1158/1078-0432.ccr-04-2653
复制
发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Johns, TG
中科院分区：
文献类型：
--
作者：
Perera, RM;Narita, Y;Johns, TG
单抗(MAb)806是一种新型的具有显著抗肿瘤活性的表皮生长因子受体(EGFR)抗体，它识别在胶质瘤中常见的突变的EGFR，称为delta2-7 EGFR(de2-7 EGFR或EGFRvIII)和在过度表达该受体的细胞中发现的野生型(Wt)EGFR的子集。我们使用了两个人异种移植小鼠模型来检测mAb806与mAb528的联合疗效，mAb528是一种典型的抗EGFR抗体，具有类似于西妥昔单抗的特异性。荷瘤裸鼠的治疗。或者国际刑事法院。表达wt或de2-7 EGFR的肿瘤人移植瘤与mAb806和528联合使用，具有相加的抗肿瘤活性，在某些情况下还具有协同抗肿瘤活性。有趣的是，mAb528单独使用时对表达非配体依赖的de2-7 EGFR的异种移植瘤也有效，表明其抗肿瘤活性不仅仅是通过抑制配体结合来实现的。当单抗806或528单独使用时，无论在体外还是在体内，mAb806和528都不能诱导de2-7 EGFR的下调。相反，抗体的组合在体外和异种移植中都产生了细胞表面de2-7 EGFR的快速和戏剧性的减少。与总细胞表面de2-7 EGFR的下降一致，我们观察到当抗体在体内联合使用时，细胞周期抑制物p27(KIP1)上调，Ki-67免疫染色检测到肿瘤细胞增殖减少。因此，mAb806可以与其他EGFR特异性抗体协同作用，从而为其进入临床提供理论基础。
Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor, We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.