Melanoma-associated antigen 3 peptide–HLA-A*02:01 complex (MAGE-A3/HLA-A*02:01)

The Melanoma-associated antigen 3 (MAGE-A3) peptide–HLA-A*02:01 complex is a specific peptide-major histocompatibility complex (pMHC) presented on the surface of various malignant cells (UniProt P43357). MAGE-A3 is a member of the cancer-testis antigen family, which is typically expressed only in immune-privileged germ cells but is aberrantly upregulated in cancers such as melanoma and non-small cell lung cancer (Morgan et al., 2013). The complex consists of a processed MAGE-A3 intracellular peptide (most commonly the 112-120 sequence KVAELVHFL) bound to the HLA-A*02:01 allele, serving as a target for T-cell receptor (TCR)-engineered T-cell therapies and bispecific engagers (Linette et al., 2013). While highly specific to tumor cells in theory, clinical development has been hindered by severe safety events. Notable trials were halted due to lethal off-target cross-reactivity where the engineered TCRs recognized the muscle protein Titin in cardiac tissue or MAGE-A12 in the brain (Linette et al., 2013; Morgan et al., 2013). Current research focuses on utilizing advanced TCR screening to ensure high specificity for the MAGE-A3/HLA-A*02:01 complex while avoiding these life-threatening toxicities (ClinicalTrials.gov NCT03907852).

Other names

MAGE-A3/HLA-A2MAGE-A3:HLA-A*02:01MAGE-A3 peptide-MHC complexAntigen MAGE-A3 presented by HLA-A*02:01KVAELVHFL-HLA-A*02:01 complex

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex, leading to T-cell activation, cytokine release, and targeted granzyme/perforin-mediated lysis of tumor cells.