Melanoma-associated antigen A4 (MAGE-A4) peptide–Major histocompatibility complex class I (HLA-A*02:01) complex (MAGE-A4/HLA-A*02:01)

The Melanoma-associated antigen A4 (MAGE-A4) peptide–HLA-A*02:01 complex is a specific molecular target consisting of a peptide fragment (typically GVYDGREHTV) derived from the MAGE-A4 protein presented on the cell surface by the Human Leukocyte Antigen (HLA) allele A*02:01 (UniProt P43358). MAGE-A4 is a member of the cancer-testis antigen family, which is characterized by high expression in various malignancies—such as synovial sarcoma, myxoid/round cell liposarcoma, and non-small cell lung cancer—while being restricted to the immune-privileged germ cells of the testes in healthy adults (PubMed: 30199034). This highly tumor-specific expression profile makes the pMHC complex an ideal target for precision immunotherapies, including T-cell receptor (TCR) engineered T-cells and bispecific T-cell engagers. Drugs like afamitresgene autoleucel (Tecelra) are designed to recognize this specific complex, triggering a potent cytotoxic T-lymphocyte response against the tumor cells (FDA, 2024). The therapeutic mechanism involves the binding of an engineered TCR to the MAGE-A4/HLA-A2 complex, which induces T-cell activation, cytokine secretion, and direct cell lysis (PubMed: 32778524). Patient selection for these therapies requires screening for both the HLA-A*02:01 genotype and MAGE-A4 protein expression via immunohistochemistry. Safety considerations primarily include cytokine release syndrome (CRS) and the potential for off-target toxicity if the TCR cross-reacts with similar peptides in healthy tissues. Clinical trials have demonstrated significant objective response rates in patients with advanced solid tumors, leading to the first regulatory approval of a TCR-T therapy targeting this complex.

Other names

MAGE-A4/HLA-A2 complexMAGE-A4 pMHCGVYDGREHTV-HLA-A*02:01 complexMAGEA4-HLA-A2

T-cell receptor (TCR) mediated recognition of the specific peptide-MHC complex, leading to T-cell activation, cytokine release, and directed lysis of the target tumor cell (PubMed: 32778524).