Tse Kam Fai, Jeffers Michael, Pollack Vincent A, McCabe Denise A, Shadish Melanie L, Khramtsov Nikolai V, Hackett Craig S, Shenoy Suresh G, Kuang Bing, Boldog Ferenc L, MacDougall John R, Rastelli Luca, Herrmann John, Gallo Michael, Gazit-Bornstein Gadi, Senter Peter D, Meyer Damon L, Lichenstein Henri S, LaRochelle William J
CuraGen, Branford, Connecticut 06405, USA.
Clin Cancer Res. 2006 Feb 15;12(4):1373-82. doi: 10.1158/1078-0432.CCR-05-2018.
Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets.
By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011 monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011 alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cells in vitro. Ectopic overexpression and small interfering RNA transfection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. In a melanoma xenograft model, CR011-vcMMAE induced significant dose-proportional antitumor effects, including complete regressions, at doses as low as 1.25 mg/kg.
These preclinical results support the continued evaluation of CR011-vcMMAE for the treatment of melanoma.
晚期黑色素瘤是一种高度耐药的肿瘤，代表了重大的未满足医疗需求。我们试图鉴定黑色素瘤相关的细胞表面分子，并开发以及在临床前测试旨在利用此类靶点的免疫治疗试剂。
通过转录谱分析，我们鉴定出糖蛋白NMB（GPNMB）是在所检测的大多数转移性黑色素瘤样本中表达的基因。GPNMB预计是一种跨膜蛋白，因此使其成为治疗该疾病的潜在免疫治疗靶点。针对GPNMB的细胞外结构域产生了一种完全人源单克隆抗体，命名为CR011，并对其针对黑色素瘤的生长抑制活性进行了表征。CR011单克隆抗体通过流式细胞术显示对大多数黑色素瘤细胞系有表面染色，并通过免疫组织化学与大多数转移性黑色素瘤标本发生反应。单独的CR011并不抑制黑色素瘤细胞的生长。然而，当与细胞毒性剂单甲基澳瑞他汀E（MMAE）连接以生成CR011-vcMMAE抗体-药物偶联物时，该试剂现在在体外能有效且特异性地抑制GPNMB阳性黑色素瘤细胞的生长。异位过表达和小干扰RNA转染研究表明，GPNMB表达对于对低浓度CR011-vcMMAE的敏感性既是必要的也是充分的。在黑色素瘤异种移植模型中，CR011-vcMMAE在低至1.25 mg/kg的剂量下诱导了显著的剂量成比例的抗肿瘤作用，包括完全消退。
这些临床前结果支持继续评估CR011-vcMMAE用于治疗黑色素瘤。
