Melanoma-associated antigen A4-derived peptide presented by MHC class I (MAGE-A4/MHC-I)

Melanoma-associated antigen A4 (MAGE-A4) is a member of the cancer-testis antigen family, characterized by high expression in various solid tumors and restricted expression in normal tissues, primarily the immune-privileged germ cells of the testis (UniProt P43358). The therapeutic target is a specific complex formed when MAGE-A4-derived peptides, such as the decamer GVYDGREHTV, are processed intracellularly and presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01. This peptide-MHC complex serves as a tumor-specific epitope that can be recognized by high-affinity, engineered T-cell receptors (TCRs). In August 2024, the FDA approved afamitresgene autoleucel, the first TCR-engineered T-cell therapy targeting this complex for patients with advanced synovial sarcoma (FDA, 2024). Because MAGE-A4 is not expressed in healthy adult somatic tissues, targeting this complex allows for the selective destruction of malignant cells while minimizing damage to normal tissue. Successful treatment is contingent upon both the presence of the MAGE-A4 antigen in the tumor and the patient possessing the specific HLA allele required for peptide presentation (Adaptimmune, 2024).

Other names

MAGE-A4/HLA-A*02 complexMAGE-A4 peptide-HLA complexMelanoma antigen family A, 4 peptide-MHCGVYDGREHTV-HLA-A*02:01 complex

Therapeutic agents, primarily engineered T-cell receptors (TCRs), bind specifically to the MAGE-A4 peptide when it is presented by MHC class I molecules (typically HLA-A*02:01) on the surface of tumor cells (FDA, 2024). This interaction mimics natural immune recognition, triggering the activation and expansion of the engineered T cells, which then release cytotoxic molecules such as perforin and granzymes to induce apoptosis in the target cancer cell (PMID: 32814720).