Melanoma-associated antigen A4 peptide–Human leukocyte antigen A*02 complex (MAGE-A4/HLA-A*02)

The Melanoma-associated antigen A4 (MAGE-A4) peptide–Human leukocyte antigen A*02 (HLA-A*02) complex is a specific peptide-MHC (pMHC) target found on the surface of various malignant cells. MAGE-A4 is a member of the cancer-testis antigen (CTA) family, which is normally restricted to immune-privileged germ cells in the testis but is aberrantly expressed in numerous solid tumors, including synovial sarcoma and non-small cell lung cancer (UniProt P43358). The complex is formed when the intracellular MAGE-A4 protein is degraded by the proteasome into peptides, such as the GVYDGREHTV decamer, which are then loaded onto HLA-A*02:01 molecules and transported to the cell surface (PubMed: 32701377). This pMHC complex serves as a critical recognition site for engineered T-cell receptor (TCR) therapies and bispecific T-cell engagers (Nature Medicine, 2022). In August 2024, the FDA granted accelerated approval to afamitresgene autoleucel, the first TCR-T cell therapy targeting this complex for patients with unresectable or metastatic synovial sarcoma (FDA.gov). Clinical success depends on the dual requirement of the patient being HLA-A*02 positive and the tumor expressing the MAGE-A4 protein as determined by a companion diagnostic (ClinicalTrials.gov: NCT03132922). Therapeutic challenges include managing systemic inflammatory responses like cytokine release syndrome (CRS) and ensuring the engineered TCR does not cross-react with similar peptides in healthy tissues (Journal of Clinical Oncology, 2020).

Other names

MAGE-A4/HLA-A2MAGE-A4/HLA-A*02:01GVYDGREHTV/HLA-A*02:01 complexMAGE-A4 pMHCMelanoma-associated antigen 4 peptide-MHC complex

Engineered T-cell receptor (TCR) binding to the peptide-MHC complex, leading to T-cell activation and tumor cell lysis; Bispecific T-cell engagement (ImmTAC).