Mesothelin-derived peptide presented by HLA-A*02:01 (MSLN-HLA-A*02:01)

Mesothelin (MSLN) is a 40 kDa cell-surface glycoprotein that is highly overexpressed in several aggressive malignancies, including malignant mesothelioma, ovarian cancer, and pancreatic adenocarcinoma (Hassan et al., 2004). While the full-length protein is a target for CAR-T cells, specific peptide fragments derived from MSLN, such as the 9-amino acid sequence SLLFLLFSL (residues 547–555), are processed intracellularly and presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules, most notably HLA-A*02:01 (Sato et al., 2014). This peptide-MHC (pMHC) complex serves as a critical target for T-cell receptor (TCR)-based therapies, which can recognize lower antigen densities and intracellularly derived epitopes that are inaccessible to standard antibodies. The most extensively studied epitope is the MSLN 547-555 peptide, which exhibits high binding affinity for the HLA-A*02:01 allele (Sato et al., 2014). Drugs targeting this complex, such as TCR-engineered T-cells (TCR-T), are designed to bind the MSLN-HLA complex with high affinity, triggering a potent cytotoxic immune response against the tumor cells (NCT03545815). However, therapeutic development faces challenges such as on-target off-tumor toxicity due to low-level MSLN expression in normal mesothelial linings, as well as the risk of cytokine release syndrome (CRS) following T-cell activation (Klampatsa et al., 2017).

Other names

MSLN(547-555)/HLA-A*02:01Mesothelin peptide-MHC complexMSLN pMHCMesothelin-derived peptide presented by HLA class IMSLN-HLA complex

T-cell receptor (TCR) mediated cytotoxicity via adoptive T-cell transfer and targeted cell lysis.