Mesothelin targeted cancer immunotherapy

Abstract

Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium. It is, however, highly expressed in several human cancers including malignant mesothelioma, pancreatic, ovarian and lung adenocarcinoma. The normal biologic function of mesothelin is unknown but recent studies have shown that it binds to CA-125 and may play a role in the peritoneal spread of ovarian cancer. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. Three mesothelin targeted agents are in various stages of clinical evaluation in patients. These include SS1P (CAT-5001) a recombinant immunotoxin targeting mesothelin, MORAb-009 a chimeric anti-mesothelin monoclonal antibody and CRS-207 a live-attenuated Listeria monocytogenes vector encoding human mesothelin. These ongoing clinical trials will help define the utility of mesothelin as a target for cancer therapy.

Figure 1

Schematic of mesothelin. The human mesothelin (MSLN) gene encodes a precursor protein of 622 amino acids. On translocation into the endoplasmic reticulum (ER) the N-terminal signal peptide (red; residues 1–33) and the C-terminal glycosyl-phosphatidylinositol (GPI) anchor addition signal (blue; a predicted cleavage site: Ser598) are removed and the latter replaced with a GPI anchor. The MSLN precursor is cleaved into two products, mature megakaryocyte potentiating factor (MPF; residues Ser34 – Arg286) and the GPI-anchored membrane-bound mature MSLN (orange) starting from Glu296. The proteolytic cleavage region (green) contains a furin cleavage site at Arg295, and other protease cleavage sites including a trypsin cleavage site at Arg286. The four N-linked glycans (black lollipops; Asn57, Asn388, Asn488 and Asn515) are indicated.

Figure 2

Mesothelin expression in human tumors. Mesothelin expression was detected by immunohistochemistry using monoclonal antibody (mAb) 5B2 in tissue specimens of patients with mesothelioma (A); ovarian cancer (B); pancreatic adenocarcinoma (C); and lung adenocarcinoma (D).