Mesothelin (MSLN) is a cell-surface-bound glycosylphosphatidylinositol (GPI)-anchored protein. The membrane-anchored form may play a role in cell adhesion. Also known as megakaryocyte potentiating factor (MPF), MSLN promotes megakaryocyte colony formation in vitro. While MSLN is normally localized to the mesothelial surface of the body, it is significantly overexpressed in a wide range of solid tumors. Therefore, MSLN has become an important target for the development of novel immunotherapies.
Expression distribution of MSLN
MSLN is primarily expressed in mesothelial cells of the peritoneum, pleural cavity, and pericardium. It is highly overexpressed in a variety of solid tumors, including mesothelioma, epithelial ovarian cancer, pancreatic cancer, bile duct cancer, gastric cancer, lung cancer, esophageal cancer, cervical cancer, and ovarian cancer. In mesothelioma, its expression level is particularly significant and correlates with the malignancy of the tumor.
(Data source: Uniprot)
Structure and maturation of MSLN
MSLN is a 71 kDa precursor protein that is hydrolyzed by furin protease into two components: the 40 kDa GPI-anchored membrane-bound protein mesothelin and the 31 kDa secreted fragment megakaryocyte colony-stimulating factor (MPF). MSLN is shed from the cell membrane by sheddases, such as members of the ADAM family. There are three types of MSLN in the body: the precursor protein, mature MSLN and MPF, and soluble MSLN.
(Data source: Pastan I, et al. Cancer Res. 2014)
MSLN signaling in cancer
Mesothelin lacks a kinase domain but activates downstream oncogenic pathways through unknown mechanisms, promoting cell proliferation, survival, invasion, and metastasis . In OC, PDAC, epithelial mesothelial cells, adenomatous NSCLC, CRC, and GC, CA125 binds to the N-terminus of mesothelin on mesothelial cells, leading to SGK3/FOXO3 activation and subsequent inhibition of DKK1. In PDAC models, CA125/MSLN interaction also increases MMP7 expression through the p38/MAPK pathway.
The binding of SMRP to membrane-associated mesothelin upregulates MMPs by activating the ERK1/2, AKT, and JNK pathways, leading to loss of cell adhesion and acquisition of a fibroblastic phenotype by tumor cells, which marks the occurrence of endothelial-mesenchymal transition and is associated with cell invasion, migration, and resistance to chemotherapy.
(Data source: Chu Q. Curr Oncol Rep . 2023）
MSLN-targeted therapy
The limited expression of MSLN in normal tissues and its overexpression in various tumors make MSLN an attractive and promising therapeutic target. Various types of anti-mesothelin therapies have been developed, including antibodies, antibody-drug conjugates (ADCs), immunotoxins, cancer vaccines, and CAR-T cell immunotherapy.
(Data source: Montemagno C, et al. Int J Mol Sci. 2020)
Amatuximab (MORAb-009) is a chimeric, high-affinity monoclonal antibody that targets MSLN and inhibits the MUC16/MSLN interaction. Amatuximab eradicates tumor cells through antibody-dependent cellular cytotoxicity.
Anetumab ravtansine is an ADC, a fully human IgG1 monoclonal antibody linked to DM4 via a disulfide bond. It specifically binds to the N-terminus of MSLN without interfering with its interaction with CA125. At nanomolar concentrations, it is preferentially taken up by tumor cells that overexpress MSLN. Following endocytosis, DM4 disrupts tubulin formation, inducing tumor cell apoptosis. Simultaneously, DM4 or its metabolites can diffuse to neighboring cells, producing a bystander killing effect. A phase I clinical trial showed that anetumab ravtansine exhibited modest antitumor activity in patients with mesothelin-positive malignant pleural mesothelioma and ovarian cancer, but it also caused adverse reactions such as fatigue, nausea, and diarrhea. In a randomized phase II clinical trial, anetumab ravtansine did not demonstrate a significant improvement in metastatic progression-free survival (mPFS) or overall survival (mOS) compared to Vinorelbine in previously treated patients with mesothelin-positive malignant pleural mesothelioma. However, a post-hoc analysis showed that patients with high MSLN expression had a better prognosis in the anetumab ravtansine group.
ABBV-428 simultaneously targets MSLN and CD40, a member of the tumor necrosis factor receptor superfamily. In clinical trials, ABBV-428 demonstrated some anti-tumor activity in some patients, but its clinical development was terminated because the maximum tolerated dose was not reached and no significant changes in immune activation were observed.
(Data source: Chu Q. Curr Oncol Rep . 2023）
CAR-T cell therapy has become an effective strategy for treating solid tumors with high expression of MSLN. Currently, the safety, effects and maximum tolerated doses of more than a dozen CAR-T and CAR-NK cell therapies for MSLN are being evaluated in clinical trials.
(Data source: Klampatsa A , et al. Expert Opin Biol Ther. 2021)
