Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

Abstract

<jats:p>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.</jats:p>

Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

“…In this regard, mesothelin and ASPH have shown the most promising characteristics. The expression of mesothelin is limited to mesothelial cells in the pleura, pericardium and peritoneum, and also according to the preclinical studies, mesothelin does not play a role in normal cell processes and development 38 , 81 , 82 , 114 . Similarly, ASPH is not expressed in healthy pancreatic tissue nor is it in many healthy tissues.…”

“…Mesothelin is a glycoprotein normally found on the surface of mesothelial cells in the pleura, pericardium and peritoneum 81 , 82 . It is a glycosylphosphatidylinositol-anchored membrane protein formed from a precursor which is further processed into the soluble serum mesothelin relative peptide (SMRP) 37 , 80 .…”

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

“…In mice, LMB-100 combined with nab-paclitaxel was well-tolerated and resulted in strong anti-tumor activity [121]. However, this combination was not well-tolerated in a phase I/II study [122], and different combinations and strategies are currently being explored [122,123].…”

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

“…Anetumab ravtansine, also known as BAY 94-9343, is another DM-4-based ADC targeted to mesothelin, a surface glycoprotein overexpressed in all mesotheliomas and in ovarian and pancreatic tumors, and with a limited expression in healthy tissues [ 29 , 30 ]. In this formulation, the maytansinoid DM-4 is conjugated to an anti-mesothelin-monoclonal antibody via a disulfide reducible linker.…”