Identification of MCAM/CD146 as the Target Antigen of a Human Monoclonal Antibody that Recognizes Both Epithelioid and Sarcomatoid Types of Mesothelioma

Abstract

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. [Cancer Res 2009;69(4):1570-7]

Immunocytochemistry of CD146 is useful to discriminate between malignant pleural mesothelioma and reactive mesothelium

“…2 and 7) were CD146 positive by OJ79. These results show that CD146 is a marker capable of discriminating between malignant pleural mesothelioma and reactive mesothelium, in agreement with the recent findings by Bidlingmaier et al 27 that CD146 has been detected in mesothelioma with high frequency but not in one case of normal mesothelium using tissue microarrays.…”

“…Bidlingmaier et al 27 have recently identified CD146 as the surface antigen recognized by the targeting single-chain antibody that was capable of internalizing epitopes on the plasma membrane of mesothelioma cells. Using a mesothelioma xenograft model, the single-chain antibody against CD146 was shown to possess the potential for targeting therapy of mesothelioma.…”

CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer

“…Although previous reports have shown that CD146 significantly correlates with advanced tumor stage in malignant melanoma (13), prostate cancer (14), epithelial ovarian cancer (15), and mesothelioma (27,28), little is known about the underlying mechanisms. Here, we report a unique role for CD146; the induction of EMTs to promote breast cancer progression.…”

Utility of Immunohistochemistry in the Diagnosis of Pleuropulmonary and Mediastinal Cancers: A Review and Update

“…80,83 Initial exploration of the possibility of using CD146, a cell adhesion molecule, as a diagnostic marker for distinguishing MM from reactive mesothelial proliferation started a couple years ago, and few studies have been published. 84,85 One study performed by Sato et al 84 evaluated the expression of 2 clones of CD146 (OJ79 and EPR3208) in 23 pleural MMs and 28 reactive mesothelial proliferation cases. They found that the sensitivities of OJ79 and EPR3208 were 94% and 90%, respectively, and the …”