Melanoma-associated antigen A4 peptide-Human leukocyte antigen complex (MAGEA4-HLA complex)

The Melanoma-associated antigen A4 (MAGE-A4) peptide-Human leukocyte antigen (HLA) complex is a tumor-specific antigen complex used as a target for advanced immunotherapy, particularly in solid tumors (UniProt P43358). MAGE-A4 is a member of the cancer-testis antigen (CTA) family, which is normally restricted to immune-privileged sites like the testes but becomes highly expressed in various cancers such as synovial sarcoma, myxoid/round cell liposarcoma, and lung carcinoma (PMID: 31535351). Since normal germ cells do not express HLA molecules, the presentation of MAGE-A4 peptides on the cell surface via HLA (most commonly HLA-A*02:01) is exclusive to malignant cells. This makes the complex an ideal target for T-cell receptor (TCR) engineered therapies and bispecific T-cell engagers, which are designed to recognize the specific peptide-MHC interface (PMID: 38537145). The clinical utility of this target was validated by the FDA approval of afamitresgene autoleucel (Tecelra), the first TCR-T cell therapy for solid tumors (FDA, 2024). Patient selection requires screening for both MAGE-A4 protein expression and a compatible HLA allele. While highly promising, therapies targeting this complex must be carefully engineered to avoid cross-reactivity with other MAGE family proteins and to manage systemic inflammatory responses like cytokine release syndrome.

Other names

MAGE-A4/HLA-A*02 complexMAGE-A4 peptide-MHC complexMAGE-A4-HLA-A2Melanoma antigen family A 4 peptide-HLA complex

Engineered T-cell receptor (TCR) therapy and bispecific T-cell engagers designed to recognize and bind the specific MAGE-A4 peptide fragment presented by HLA molecules on the tumor cell surface, leading to T-cell activation and tumor cell lysis.