Abstract
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.
Highlights
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed on serosal tissues such as pleura, pericardium, and peritoneum, but is not in the parenchyma of any vital organs [1,2]
It is commonly expressed on a number of solid tumors, such as mesothelioma, pancreatic adenocarcinoma, ovarian cancer and others [1,3,4,5,6,7,8,9]
It was found that selective lymphodepletion with the chemotherapy drugs pentostatin and cyclophosphamide (P+C) could combat anti-drug antibody (ADA) formation in mice immunized with iTox [90]
Summary
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed on serosal tissues such as pleura, pericardium, and peritoneum, but is not in the parenchyma of any vital organs [1,2]. InofiTox, the native domain is replaced a novel targeting molecule, such as anti-Lewis-y antibody, to direct the poison to cancer cells. Truncated PE is inactive outside of the cell, In iTox, the native binding domain is replaced with a novel targeting molecule, such as antibut highly lethal if even a few molecules reach the cytosol, making precise targeting extremely important. Truncated PE is inactive outside of Pancreatic adenocarcinoma (PDAC) is a lethal disease, with a five-year overall survival of just the cell, but highly lethal if even a few molecules reach the cytosol, making precise targeting. Pancreatic adenocarcinoma (PDAC) is a lethal disease, with a five-year overall survival of just Systemic therapy for such patients has limited efficacy, with response rates ranging between 6 and. Targeted therapies that have shown benefit in other solid tumors, such as Similar to PDAC, metastatic disease virtually eliminates any reasonable hope for cure. We review existing data on those drugs and explore strategies for harnessing and enhancing their activity
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