Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors

Abstract

BackgroundMonoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers).MethodsMesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside.ResultsNovel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained.ConclusionThese antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.

Novel systemic therapy against malignant pleural mesothelioma

“…There are currently three different antibody-drug conjugates targeting mesothelin expressing cells in clinical trials (141). The concept of a "magic bullet" delivering a potent chemotherapeutic to cancer cells and not normal healthy cells was first proposed over a century ago (142).…”

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

“…Intracellularly, MSLN can activate NFkB, MAPK, and PI3K signaling pathways, thereby promoting cell proliferation and resistance to apoptosis (15). The restricted expression of MSLN on healthy tissues, combined with the high expression on several solid cancers renders it an attractive tumor antigen for targeted cancer therapy and several preclinical and clinical approaches are currently being pursued including CAR-T cells, vaccines, antibodies (amatuximab), recombinant immunotoxins (SS1P, and RG7787) as well as antibody drug conjugates (anetumab ravtansine/BAY 94-9343; aMSLN-MMAE (h7D9.v3), and MDX-1204 (14,(16)(17)(18).…”

Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings

“…Clinical trials include an open‐label phase I clinical trial of escalating doses of anetumab ravtansine in patients with advanced solid tumors (https://clinicaltrials.gov/ct2/show/NCT01439152) and a phase I study to evaluate the safety and pharmacokinetics of anetumab ravtansine in patients with advanced solid tumors in Japan (https://clinicaltrials.gov/ct2/show/NCT02485119). Elevated AST, ALT, ALP and bilirubin were commonly noted, with AST elevations being grade 3 in two patients (Zhao, Subramanyam, Sarapa, Golfier, & Dinter, ). AST elevations were also considered dose limiting in a few patients.…”

“…gov/ct2/show/NCT02485119). Elevated AST, ALT, ALP and bilirubinwere commonly noted, with AST elevations being grade 3 in two patients(Zhao, Subramanyam, Sarapa, Golfier, & Dinter, 2016). AST elevations were also considered dose limiting in a few patients.…”