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

The Melanoma-associated antigen A4 (MAGE-A4) peptide–HLA complex is a tumor-specific antigen consisting of a peptide fragment derived from the intracellular MAGE-A4 protein presented by Human Leukocyte Antigen (HLA) class I molecules on the cell surface [6, 12]. MAGE-A4 is a member of the cancer-testis antigen family, which is typically expressed only in the germ cells of the testis and placenta—tissues that lack MHC class I expression—making the complex an ideal target for immunotherapy with minimal off-target effects on healthy tissues [8, 14]. This target is particularly prevalent in solid tumors such as synovial sarcoma, myxoid/round cell liposarcoma, and various carcinomas including lung and ovarian cancer [6, 11]. Therapeutic strategies targeting this complex primarily involve adoptive cell therapies, such as T-cell receptor (TCR)-engineered T-cells, which are designed to recognize the specific peptide-HLA configuration [1, 4]. Afamitresgene autoleucel (Tecelra) is the first FDA-approved TCR-T therapy targeting this complex for the treatment of synovial sarcoma [2, 15]. Patient eligibility for these therapies requires dual screening for MAGE-A4 protein expression via immunohistochemistry and a compatible HLA-A*02 genotype [11, 13].

Other names

MAGE-A4/HLA-A*02 complexMAGE-A4 pMHCMAGE-A4/HLA-A2 complexMAGE-A4/MHC complexMAGE-A4 peptide-MHC complex

Engineered T-cell receptor (TCR) binding to the MAGE-A4 peptide-HLA complex, which triggers T-cell activation, secretion of pro-inflammatory cytokines (e.g., IFN-gamma), and direct cytotoxic lysis of the tumor cell [1, 4, 5].