Melanoma-associated antigen 3 (MAGE-A3) peptide presented by Human Leukocyte Antigen A*01:01 (HLA-A*01:01) (MAGE-A3/HLA-A*01:01)

The MAGE-A3 peptide presented by HLA-A*01:01 is a specific peptide-major histocompatibility complex (pMHC) target used in cancer immunotherapy. Melanoma-associated antigen 3 (MAGE-A3) is a member of the cancer-testis antigen family, which is typically expressed in various malignancies but restricted to immune-privileged sites like the testes in healthy individuals (Gjerstorff et al., 2015, PMID: 25726288). When MAGE-A3 proteins are degraded within cancer cells, specific peptides, such as the EVDPIGHLY sequence, are loaded onto HLA-A*01:01 molecules and displayed on the cell surface (van der Bruggen et al., 1994, PMID: 7524368). This complex serves as a target for T-cell receptors (TCRs), allowing the immune system to distinguish malignant cells from healthy tissue. Therapeutic strategies targeting this complex include TCR-engineered T-cell (TCR-T) therapies and cancer vaccines (Vansteenkiste et al., 2016, PMID: 27030077). However, drug development has faced significant challenges due to off-target cross-reactivity; for instance, early TCR-T trials targeting this complex resulted in fatal cardiotoxicity and neurotoxicity because the engineered TCRs recognized similar peptides in Titin and MAGE-A12 (Linette et al., 2013, PMID: 23733940; Morgan et al., 2013, PMID: 23917459). Consequently, precise TCR engineering and rigorous specificity testing are critical for safely targeting this pMHC complex.

Other names

MAGE-A3:A0101MAGE-A3 168-176 peptide/HLA-A*01:01 complexMAGE-A3/HLA-A1MAGE-A3-A1EVDPIGHLY/HLA-A*01:01

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex on the surface of tumor cells, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of the target cell (Linette et al., 2013, PMID: 23733940).