Melanoma-associated antigen 3 (MAGE-A3) peptide 112–120 presented by HLA-A*02:01 (MAGE-A3/HLA-A*02:01)

Melanoma-associated antigen 3 (MAGE-A3) peptide 112–120 (sequence: KVAELVHFL) presented by HLA-A*02:01 is a specific peptide-major histocompatibility complex (pMHC) target found on the surface of various cancer cells (UniProt P43357). MAGE-A3 belongs to the cancer-testis antigen (CTA) family, which is characterized by high expression in malignant tissues but restricted expression in healthy tissues like the testes, where MHC Class I molecules are typically absent (PubMed: 23550147). This restricted expression profile makes the MAGE-A3:112-120/HLA-A*02:01 complex a highly sought-after target for immunotherapy, including cancer vaccines and T-cell receptor (TCR) engineered T-cell therapies. However, clinical development has been hindered by significant safety concerns. Early TCR-T trials targeting this epitope resulted in fatal neurotoxicity due to cross-reactivity with MAGE-A12 in the brain and fatal cardiotoxicity due to unexpected cross-reactivity with the muscle protein Titin (PubMed: 23918952). These events highlighted the critical importance of rigorous specificity testing for TCR-based therapies. Despite these setbacks, MAGE-A3 remains a prototype for studying pMHC-targeted precision medicine in oncology. Current research focuses on improving the specificity of TCRs to avoid such off-target effects while maintaining potent anti-tumor activity (PubMed: 26034044). The target is primarily relevant in patients who are HLA-A*02:01 positive and whose tumors express the MAGE-A3 protein. It represents a key example of the challenges and potential of targeting intracellular antigens via the MHC presentation pathway.

Other names

MAGE-A3:112–120/HLA-A2KVAELVHFL-HLA-A*02:01 complexMAGE-A3 epitopeMAGE-A3 p112-120

T-cell receptor (TCR) mediated recognition and cytotoxic T-cell activation