Mesothelin-derived peptide-HLA complex (MSLN-pHLA)

Mesothelin-derived peptide-HLA complexes represent a critical class of therapeutic targets in solid tumors, particularly mesothelioma and pancreatic ductal adenocarcinoma (PDAC). Mesothelin is a cell-surface glycoprotein that is highly overexpressed in these malignancies while maintaining limited expression in normal mesothelial cells of the pleura, pericardium, and peritoneum (PMID: 32810091). In the context of immunotherapy, intracellularly processed mesothelin proteins are degraded into short peptides and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules, most commonly HLA-A*02:01. These peptide-HLA (pHLA) complexes serve as the specific ligands for T-cell receptors (TCRs), allowing the immune system to distinguish malignant cells from healthy tissue (PMID: 34251641). Drugs targeting these complexes, such as TCR-engineered T-cells (TCR-T) and TCR-mimic antibodies, are designed to bypass the limitations of traditional CAR-T cells by recognizing internal protein fragments rather than just surface-bound proteins. This approach is currently being explored in clinical trials to improve outcomes for patients with refractory PDAC and mesothelioma, where traditional therapies often fail (PMID: 36109515).

Other names

Mesothelin peptide-HLA-A*02:01 complexMSLN-HLA complexMeso-associated tumor antigen-HLA complexPDAC-associated tumor antigen-HLA complex

Therapeutic agents such as TCR-T cells or TCR-mimic antibodies specifically recognize the processed mesothelin peptide fragments displayed by HLA molecules on the tumor cell surface, leading to targeted T-cell mediated cytotoxicity and tumor lysis.