Melanoma-associated antigen 3 (MAGE-A3) peptide-HLA-A*02 complex (MAGE-A3/HLA-A2)

Melanoma-associated antigen 3 (MAGE-A3) is a member of the cancer-testis antigen family, which is characterized by restricted expression in male germ cells and aberrant re-expression in various histological types of tumors (UniProt P43357). The target specifically refers to a processed peptide fragment of the MAGE-A3 protein presented on the cell surface by the Human Leukocyte Antigen A2 (HLA-A*02) MHC class I molecule (PubMed: 7507011). This peptide-MHC complex is a critical target for cancer immunotherapy because it is absent from normal somatic tissues, providing a window for tumor-specific T-cell recognition. Therapeutic approaches targeting this complex include recombinant protein vaccines, such as GSK1572932A, and adoptive cell therapies using T-cells engineered with high-affinity T-cell receptors (TCRs). However, clinical development has encountered significant safety challenges; for instance, a TCR-T cell trial was halted after fatal neurotoxicity occurred due to unexpected cross-reactivity with the MAGE-A12 protein expressed in human brain tissue (PubMed: 23478461). Consequently, successful targeting of the MAGE-A3/HLA-A2 complex requires stringent patient screening for both the HLA-A*02 allele and confirmed MAGE-A3 expression within the tumor.

Other names

MAGE-3MAGEA3Antigen MZ2-DCancer/testis antigen 1.3CT1.3MAGE-A3 peptide-MHC complex

Recognition of the specific MAGE-A3 peptide presented by HLA-A*02 by the T-cell receptor (TCR) of cytotoxic T lymphocytes, leading to targeted lysis of tumor cells.