Cytotoxic activity of immunotoxin SS1P is modulated by TACE-dependent mesothelin shedding.
Cancer Res. 2011 Jul 20;
Authors: Zhang Y, Chertov O, Zhang J, Hassan R, Pastan I
Mesothelin is a cell-surface tumor-associated antigen expressed in several human cancers. The limited expression of mesothelin on normal tissues and its high expression in many cancers make it an attractive candidate for targeted therapies utilizing monoclonal antibodies, immunoconjugates and immunotoxins. Mesothelin is actively shed from the cell surface and is present in the serum of patients with malignant mesothelioma, which could negatively affect the response to these therapies. We have found that mesothelin sheddase activity is mediated by a tumor necrosis factor-? converting enzyme (TACE), a member of the MMP/ADAM family. We showed that EGF and TIMP-3 act through TACE as endogenous regulators of mesothelin shedding. We also found that reducing shedding significantly improved the in vitro cytotoxicity of immunotoxin SS1P, which targets mesothelin and is currently in clinical trials for the treatment of patients with mesothelioma and lung cancer. Our findings provide a mechanistic understanding of mesothelin shedding and could help improve mesothelin-based targeted therapies.
PMID: 21775520 [PubMed - as supplied by publisher]
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