Shimazaki Kaori, Lepin Eric J, Wei Bo, Nagy Agnes K, Coulam Catherine P, Mareninov Sergey, Fu Maoyong, Wu Anna M, Marks James D, Braun Jonathan, Gordon Lynn K, Wadehra Madhuri
Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Clin Cancer Res. 2008 Nov 15;14(22):7367-77. doi: 10.1158/1078-0432.CCR-08-1016.
Endometrial cancer is the most common gynecologic malignancy. One promising biomarker is epithelial membrane protein 2 (EMP2), and its expression is an independent prognostic indicator for tumors with poor clinical outcome expression. The present study assesses the suitability of EMP2 as a therapeutic target.
Human monovalent anti-EMP2 antibody fragments were isolated from a human phage display library and engineered as bivalent antibody fragments (diabodies) with specificity and avidity to both EMP2 peptides and native cell-surface EMP2 protein. Diabodies were assessed using cell death and apoptosis assays. In addition, the efficacy of EMP2 diabodies on endometrial cancer tumors was determined using mouse xenograft models.
Treatment of human endometrial adenocarcinoma cell lines with anti-EMP2 diabodies induced significant cell death and caspase-3 cleavage in vitro. These responses correlated with cellular EMP2 expression and were augmented by progesterone, which physiologically induces EMP2 expression. In vivo, treatment of subcutaneous human xenografts of HEC-1A cell lines with anti-EMP2 diabodies suppressed tumor growth and induced cell death in the xenograft.
These findings suggest that EMP2 may be a potential pharmacologic target for human endometrial cancer.
子宫内膜癌是最常见的妇科恶性肿瘤。一种有前景的生物标志物是上皮膜蛋白2（EMP2），其表达是临床预后不良肿瘤的独立预后指标。本研究评估EMP2作为治疗靶点的适用性。
从人噬菌体展示文库中分离出单价抗EMP2抗体片段，并将其工程化为对EMP2肽和天然细胞表面EMP2蛋白具有特异性和亲和力的双价抗体片段（双抗体）。使用细胞死亡和凋亡试验评估双抗体。此外，使用小鼠异种移植模型确定EMP2双抗体对子宫内膜癌肿瘤的疗效。
用抗EMP2双抗体处理人子宫内膜腺癌细胞系在体外诱导了显著的细胞死亡和半胱天冬酶-3切割。这些反应与细胞EMP2表达相关，并因生理上诱导EMP2表达的孕酮而增强。在体内，用抗EMP2双抗体处理HEC-1A细胞系的皮下人异种移植物可抑制肿瘤生长并诱导异种移植物中的细胞死亡。
这些发现表明EMP2可能是人类子宫内膜癌的潜在药理学靶点。
