Melanoma-associated antigen A4 peptide-HLA-A*02 complex (MAGE-A4/HLA-A*02)

The Melanoma-associated antigen A4 (MAGE-A4) peptide-HLA-A*02 complex is a specific peptide-major histocompatibility complex (pMHC) found on the surface of various malignant cells (PubMed: 32718944). MAGE-A4 belongs to the cancer-testis antigen (CTA) family, meaning it is typically expressed only in immune-privileged germ cells but becomes aberrantly re-expressed in numerous solid tumors, including synovial sarcoma and lung cancer (UniProt: P43358). In these tumor cells, MAGE-A4 proteins are degraded by the proteasome into short peptides, such as the decamer GVYDGREHTV, which are then loaded onto HLA-A*02 molecules and transported to the cell surface (PubMed: 31911568). This specific pMHC serves as a highly selective target for adoptive T-cell therapies, such as afamitresgene autoleucel (Tecelra), which utilize engineered T-cell receptors (TCRs) to recognize the complex (FDA, 2024). Upon binding, these engineered T cells initiate a potent cytotoxic immune response against the tumor. Because MAGE-A4 is not present on healthy adult somatic tissues, targeting this complex minimizes the risk of on-target, off-tumor toxicity, though careful screening for cross-reactivity with other MAGE family members is required (PubMed: 34161334).

Other names

MAGE-A4/HLA-A2 complexMAGE-A4 peptide-MHCGVYDGREHTV-HLA-A*02:01MAGEA4-HLA-A2

Engineered T-cell receptors (TCRs) or TCR-mimetic antibodies specifically recognize and bind the MAGE-A4 peptide presented by HLA-A*02 on the surface of tumor cells, leading to T-cell activation, cytokine release, and direct lysis of the cancer cell.