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

The HLA-A*02:01 presenting MAGE-A3-derived epitopes is a peptide-major histocompatibility complex (pMHC) that serves as a critical target for cancer immunotherapy. MAGE-A3 (Melanoma-associated antigen 3) is a cancer-testis antigen that is highly expressed in various malignancies, including melanoma and non-small cell lung cancer, but is absent from normal adult tissues except for the testis and placenta (UniProt P43357). The HLA-A*02:01 allele, prevalent in many populations, presents specific MAGE-A3 peptides, such as the decamer KVAELVHFL, to the immune system (PubMed: 23552371). This complex is recognized by the T-cell receptors (TCRs) of CD8+ cytotoxic T cells, which can then initiate the destruction of the tumor cell. Therapeutic approaches targeting this complex have included cancer vaccines like the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) and adoptive T-cell therapies using engineered TCRs (Lancet Oncol. 2016; 17: 822-835). However, clinical development has been complicated by safety concerns, most notably a fatal cross-reactivity incident where an engineered TCR intended for MAGE-A3 also recognized a similar peptide from the muscle protein Titin, leading to severe cardiotoxicity (Blood. 2013; 122: 863-871). Despite these challenges, the high tumor specificity of MAGE-A3 continues to make this pMHC complex a significant focus for next-generation TCR-T and TCR-like antibody therapies.

Other names

MAGE-A3/HLA-A2 complexHLA-A*02:01-MAGE-A3(112-120)MAGE-A3-A2 complexMelanoma-associated antigen 3 presented by HLA-A*02:01

Recognition of the peptide-MHC complex by engineered or endogenous T-cell receptors (TCRs) to trigger cytotoxic T-lymphocyte (CTL) mediated lysis of tumor cells.