Melanoma-associated antigen A4 peptide–Human leukocyte antigen A2 complex (MAGE-A4/HLA-A2)

The MAGE-A4 peptide–HLA-A2 complex is a specific molecular target formed by the presentation of a processed peptide (typically the decamer GVYDGREHTV) from the Melanoma-associated antigen A4 (MAGE-A4) on the Human Leukocyte Antigen A*02:01 (HLA-A2) molecule (UniProt P43358; Sanderson et al., 2020). MAGE-A4 is a member of the cancer-testis antigen family, which is highly expressed in various solid tumors—such as synovial sarcoma and non-small cell lung cancer—but is restricted to the immune-privileged germ cells of the testes in healthy adults (Giacomo et al., 2021). Because germ cells lack HLA expression, the MAGE-A4/HLA-A2 complex is effectively tumor-specific, making it an ideal target for T-cell receptor (TCR) based immunotherapies. Therapeutic agents like afamitresgene autoleucel (Tecelra), which received FDA accelerated approval in 2024, utilize engineered TCRs to recognize this complex and induce a potent cytotoxic T-cell response against malignant cells (FDA, 2024). Patient eligibility for these therapies is strictly dependent on both HLA-A*02 positivity and confirmed MAGE-A4 expression in tumor tissue (D'Angelo et al., 2018). While clinically effective, the primary therapeutic challenges include managing cytokine release syndrome and ensuring the engineered TCR does not cross-react with similar peptides presented on vital healthy tissues (Hong et al., 2021).

Other names

MAGE-A4/HLA-A*02:01MAGE-A4 pMHC complexMAGE-A4-HLA-A2GVYDGREHTV-HLA-A*02:01

Engineered T-cell receptor (TCR) binding to the specific peptide-MHC complex, leading to T-cell activation, cytokine release, and targeted lysis of MAGE-A4-expressing tumor cells.