Identification of MCAM/CD146 as the target antigen of a human monoclonal antibody that recognizes both epithelioid and sarcomatoid types of mesothelioma.
Identification of MCAM/CD146 as the target antigen of a human monoclonal antibody that recognizes both epithelioid and sarcomatoid types of mesothelioma.
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DOI：
10.1158/0008-5472.can-08-1363
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Bidlingmaier S;He J;Wang Y;An F;Feng J;Barbone D;Gao D;Franc B;Broaddus VC;Liu B
诊断为间皮瘤的患者的预后通常很差，目前可用的治疗方法通常无效。特异性靶向肿瘤细胞的疗法对于治疗对当前方法具有抗性的癌症具有很大的希望。我们先前已经选择了间皮瘤细胞系上的噬菌体抗体展示文库，以鉴定靶向间皮瘤相关的、临床上代表的细胞表面抗原的一组内化人单链（scFv）抗体，并进一步利用这些scFv的内化功能，以特异性地将致死剂量的脂质体封装的小分子药物递送至间皮瘤细胞的上皮样亚型和肉瘤亚型。在这里，我们报告的识别MCAM/MUC 18/CD 146的表面抗原结合的间皮瘤靶向单链抗体使用一种新的克隆策略的基础上酵母表面人类蛋白质组展示。间皮瘤组织微阵列的免疫组织化学分析证实，MCAM广泛表达上皮样和肉瘤型间皮瘤肿瘤细胞原位，但不正常间皮瘤细胞。此外，量子点标记的抗MCAM scFv靶向离体培养的肿瘤片段球状体中的原代间皮瘤细胞。作为评估MCAM靶向抗体的治疗潜力的第一步，我们使用抗MCAM scFv进行了单光子发射计算机断层扫描研究，发现它在体内识别间皮瘤器官型异种移植物。肿瘤细胞噬菌体抗体库筛选与酵母表面展示人蛋白质组快速鉴定靶抗原相结合，有望成为定位肿瘤细胞表面抗原表位的有效方法。
The prognosis for patients diagnosed with mesothelioma is generally poor, and currently available treatments are usually ineffective. Therapies that specifically target tumor cells hold much promise for the treatment of cancers that are resistant to current approaches. We have previously selected phage antibody display libraries on mesothelioma cell lines to identify a panel of internalizing human single chain (scFv) antibodies that target mesothelioma-associated, clinically represented cell surface antigens, and further exploited the internalizing function of these scFvs to specifically deliver lethal doses of liposome-encapsulated small molecule drugs to both epithelioid and sarcomatous subtypes of mesothelioma cells. Here we report the identification of MCAM/MUC18/CD146 as the surface antigen bound by one of the mesothelioma targeting scFvs using a novel cloning strategy based on yeast surface human proteome display. Immunohistochemical analysis of mesothelioma tissue microarrays confirmed that MCAM is widely expressed by both epithelioid and sarcomatous types of mesothelioma tumor cells in situ but not by normal mesothelial cells. In addition, quantum dot-labeled anti-MCAM scFv targets primary meosthelioma cells in tumor fragment spheroids cultured ex vivo. As the first step in evaluating the therapeutic potential of MCAM-targeting antibodies, we performed single-photon emission computed tomography studies using the anti-MCAM scFv and found that it recognizes mesothelioma organotypic xenografts in vivo. The combination of phage antibody library selection on tumor cells and rapid target antigen identification by screening the yeast surface displayed human proteome could be a powerful method for mapping the targetable tumor cell surface epitope space.