Melanoma-associated antigen A4-derived peptide–HLA-A*02:01 complex (MAGE-A4/HLA-A*02:01)

The MAGE-A4-derived peptide–MHC complex is a highly specific therapeutic target in oncology, consisting of a peptide fragment from the Melanoma-associated antigen A4 (MAGE-A4) presented by the Human Leukocyte Antigen (HLA) Class I molecule, most commonly HLA-A*02:01 (1.1.4, 1.2.5). MAGE-A4 is a cancer-testis antigen that is typically restricted to immune-privileged tissues like the testis and placenta but is frequently overexpressed in various solid tumors, including synovial sarcoma and non-small cell lung cancer (1.1.3, 1.5.1). In these tumor cells, the MAGE-A4 protein is processed intracellularly and its peptides are displayed on the cell surface via MHC molecules (1.3.1, 1.3.2). This complex is recognized by engineered T-cell receptor (TCR) therapies, such as afamitresgene autoleucel, or TCR-bispecific engagers (1.1.3, 1.3.1). Upon binding, these therapies trigger a potent immune response, leading to the activation of cytotoxic T lymphocytes and the subsequent destruction of the tumor cells (1.3.1, 1.4.2). The high tumor specificity of MAGE-A4 makes this complex an ideal target for minimizing damage to healthy tissues while effectively treating advanced malignancies (1.1.3, 1.5.1). Clinical applications of targeting this complex have shown significant efficacy in patients with synovial sarcoma, leading to the first FDA approval of an engineered TCR-T cell therapy (1.1.3, 1.5.1).

Other names

MAGE-A4 pMHCMAGE-A4/HLA-A2 complexGVYDGREHTV-HLA-A*02:01 complexMAGE-A4-derived peptide–MHC complex

Engineered T-cell receptors (TCRs) or TCR-mimic antibodies specifically bind to the MAGE-A4 peptide-HLA complex on the surface of tumor cells, leading to T-cell activation, cytokine release, and cytotoxic lysis of the target cell.