Melanoma-associated antigen A4 (MAGE-A4) peptide presented by Human Leukocyte Antigen A*02 (HLA-A*02) (MAGE-A4/HLA-A*02)

Melanoma-associated antigen A4 (MAGE-A4) is a member of the cancer-testis antigen family, which is characterized by restricted expression in the immune-privileged germ cells of the testes and placenta, but frequent aberrant expression in various solid tumors (UniProt P43358). The therapeutic target is a specific peptide fragment of MAGE-A4, typically the 10-mer GVYDGREHTV, which is processed and presented on the tumor cell surface by the Human Leukocyte Antigen (HLA)-A*02 molecule (PubMed: 32814720). This peptide-MHC (pMHC) complex acts as a highly specific tumor-associated antigen, allowing the immune system to distinguish malignant cells from healthy somatic tissues that lack both MAGE-A4 expression and MHC Class I expression in germ cells. Drugs targeting this complex, such as the FDA-approved Afamitresgene autoleucel, utilize engineered T-cell receptors (TCRs) to recognize and bind the pMHC with high affinity (FDA, 2024). Upon binding, the engineered T-cells are activated to release cytotoxic granules, such as perforin and granzymes, leading to the selective destruction of MAGE-A4-positive tumor cells. This target is particularly significant in the treatment of synovial sarcoma and other soft tissue sarcomas where MAGE-A4 is highly prevalent (PubMed: 38537575).

Other names

MAGE-A4 peptide-MHC complexMAGE-A4/HLA-A*02:01MAGE-A4 230-239 peptideGVYDGREHTV-HLA-A*02 complexMAGE-A4 pMHC

Engineered T-cell receptor (TCR) therapy or bispecific molecules bind specifically to the MAGE-A4 peptide/HLA-A*02 complex, triggering T-cell activation, cytokine release, and direct lysis of the tumor cell (PubMed: 32814720).