Genentech, Inc., South San Francisco, California 94080, USA.
Clin Cancer Res. 2011 Mar 1;17(5):965-75. doi: 10.1158/1078-0432.CCR-10-2340. Epub 2011 Jan 18.
To identify and evaluate targets amenable to antibody therapy in melanoma.
We searched for mRNA transcripts coding for cell-surface proteins with expression patterns similar to that of the melanoma oncogene MITF. One such candidate, the endothelin B receptor (EDNBR), was first analyzed for a functional contribution to tumor growth by conditional induction of shRNA. Second, antibodies were raised to the receptor, conjugated with monomethyl auristatin E, and tested for efficacy against melanoma tumor models generated from cell lines.
Conditional knockdown of the receptor in tumor xenograft models resulted in only a modest impact on tumor growth. A monoclonal antibody reactive with the N-terminal tail of EDNBR was found to internalize rapidly into melanoma cells. When conjugated with monomethyl auristatin E, the antibody-drug conjugate (ADC) showed remarkable efficacy against human melanoma cell lines and xenograft tumor models that was commensurate with levels of receptor expression. Comparative immunohistochemistry revealed a range of EDNBR expression across a panel of human melanomas, with the majority expressing levels equivalent to or greater than that in the models responsive to the ADC.
An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma.
鉴定和评估可用于黑色素瘤抗体治疗的靶点。
我们搜索了表达模式与黑色素瘤致癌基因 MITF 相似的细胞表面蛋白的 mRNA 转录本。候选蛋白之一是内皮素 B 受体 (EDNBR)，首先通过条件性诱导 shRNA 分析其对肿瘤生长的功能贡献。其次，针对该受体产生了抗体，并与单甲基奥瑞他汀 E 缀合，用于测试针对细胞系生成的黑色素瘤肿瘤模型的疗效。
在肿瘤异种移植模型中，受体的条件性敲低仅对肿瘤生长产生适度影响。发现一种与 EDNBR N 端尾巴反应的单克隆抗体可迅速内化进入黑色素瘤细胞。当与单甲基奥瑞他汀 E 缀合时，抗体药物偶联物 (ADC) 对人黑色素瘤细胞系和异种移植肿瘤模型显示出显著疗效，与受体表达水平相当。比较免疫组织化学显示，一组人黑色素瘤中存在 EDNBR 表达范围，大多数表达水平与对 ADC 有反应的模型相当或更高。
针对 EDNBR 的 ADC 在黑色素瘤的临床前模型中具有高度疗效。
