Proteins (mesothelin)

Mesothelin is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein present on the surface of many malignant cells originally identified as the target of a monoclonal antibody raised against a human ovarian cancer cell line (Chang and Pastan 1996). Normal expression of mesothelin is primarily restricted to mesothelial cells lining the pericardium, peritoneum, and pleura. However, mesothelin is expressed on nearly all mesotheliomas and pancreatic adenocarcinomas; commonly on ovarian cancers, non-small-cell lung cancers, squamous cell carcinomas, and acute myeloid leukemias; and less frequently on other cancer cells including colorectal, esophageal, and gastric cancers (Chang and Pastan 1996; Hassan et al. 2004; Hassan and Ho 2008; Steinbach et al. 2007). In total, mesothelin is expressed on nearly a third of human malignancies. The mesothelin gene consists of 17 exons located on the human chromosome 16p13.3 (Chang and Pastan 1996; Hassan et al. 2004). It encodes a 71-kDa precursor protein that is proteolytically processed into a shed 31-kDa N-terminal fragment - megakaryocyte-potentiating factor (MPF), a protein shown to stimulate megakaryocyte colony-forming activity of IL-3 in mouse bone marrow cell culture (Kojima et al. 1995), and the surface-bound 40-kDa C-terminal fragment - mesothelin. Elevated levels of soluble mesothelin have been detected in the sera of patients with mesotheliomas and ovarian and pancreatic cancers (Scholler et al. 1999; Hassan et al. 2006; Johnston et al. 2009). Studies are underway to determine if serum levels of mesothelin can serve as a marker of tumor burden or as a marker for diagnosis and follow-up of patients with mesothelin-expressing tumors. Spontaneous mesothelin-specific antibody responses have been detected in patients with mesotheliomas and ovarian cancers and less commonly in patients with pancreatic cancers (Johnston et al. 2009; Hellstrom et al. 2008; Ho et al. 2005). Although antibody responses are less common in pancreatic cancer patients, spontaneous mesothelin-specific T cell responses have been measured in approximately 50% of patients with pancreatic cancers (Johnston et al. 2009). Furthermore, early studies suggest that enhanced post-immunotherapy mesothelin-specific T cell responses may be associated with improved survival in pancreatic cancer patients receiving a whole tumor cell vaccine (Thomas et al. 2004; Laheru et al. 2008; Lutz et al. 2011). Due to the immunogenicity of mesothelin, its restricted expression in normal tissues and high expression on the surface of multiple cancers, mesothelin is considered an attractive target for immunotherapy (Hassan et al. 2004; Hassan and Ho 2008). For this reason, both T cell-mediated and antibody-mediated treatment strategies specifically targeting mesothelin are under clinical development.