Melanoma-associated antigen 4 peptide-major histocompatibility complex (MAGE-A4 pMHC)

The MAGE-A4 peptide-MHC complex is a specific molecular target formed by the presentation of a processed peptide from the Melanoma-associated antigen 4 (MAGE-A4) protein on the surface of cancer cells via Major Histocompatibility Complex (MHC) Class I molecules, typically HLA-A*02:01 (UniProt P43358). MAGE-A4 is a cancer-testis antigen, meaning its expression is restricted to immune-privileged germ cells in the testes under normal conditions but is highly upregulated in various solid tumors, including synovial sarcoma and lung cancer (PubMed: 31535357). This restricted expression pattern makes the MAGE-A4 pMHC an ideal target for precision immunotherapy, as it allows for the selective destruction of malignant cells while sparing healthy tissue. Current therapeutic approaches primarily utilize engineered T-cell receptor (TCR-T) therapies, such as afamitresgene autoleucel (Tecelra), which was FDA-approved in 2024 for the treatment of synovial sarcoma (FDA, 2024). These therapies are designed to recognize the specific peptide-HLA configuration with high affinity and trigger a potent immune response. Beyond TCR-T cells, bispecific molecules like IMC-C103C are also in development to recruit endogenous T-cells to the tumor site (ClinicalTrials.gov: NCT03973333). The primary challenge in targeting this complex is ensuring high specificity to avoid cross-reactivity with similar peptides presented on healthy cells, which requires rigorous preclinical screening.

Other names

MAGE-A4/HLA-A*02 complexMAGEA4-HLA-A2MAGE-A4 peptide-HLA complexMelanoma antigen family A 4 peptide-MHC

T-cell receptor (TCR) engineered T-cell therapy and bispecific T-cell engagers (ImmTACs) that specifically bind the peptide-MHC complex to trigger T-cell mediated lysis of tumor cells.