Melanoma-associated antigen 3 – HLA-A*02:01 peptide complex (MAGE-A3 – HLA-A2 complex)

The MAGE-A3 – HLA-A2 peptide complex is a specific peptide-major histocompatibility complex (pMHC) presented on the surface of various malignant cells. MAGE-A3 (Melanoma-associated antigen 3) is a cancer-testis antigen that is highly expressed in tumors such as melanoma, non-small cell lung cancer, and multiple myeloma, but is absent from normal adult tissues except for the testis (1.4.1, 1.4.3). The complex forms when MAGE-A3-derived peptides, such as the nonamers KVAELVHFL (residues 112-120) or FLWGPRALV (residues 271-279), are processed and loaded onto the HLA-A*02:01 molecule (1.3.2, 1.3.5). This complex serves as a critical target for T-cell-based immunotherapies, particularly T-cell receptor (TCR) engineered T-cells and bispecific TCR molecules (1.1.2, 1.5.1). By targeting this specific pMHC, therapies aim to induce a potent cytotoxic T-lymphocyte response against tumor cells while sparing healthy tissue. However, clinical development has been complicated by safety concerns, most notably severe neurotoxicity observed in early trials (1.5.1). This toxicity was linked to TCR cross-reactivity with similar peptides found in the central nervous system, such as those from MAGE-A12 or EPS8L2 (1.5.1).

Other names

MAGE-A3 – HLA-A*02:01MAGE3 – HLA-A2Melanoma-associated antigen 3 – HLA-A2 complexMAGE-A3 peptide-MHC complexKVAELVHFL – HLA-A*02:01 complexFLWGPRALV – HLA-A*02:01 complex

T-cell receptor (TCR) recognition of the peptide-MHC complex leading to cytotoxic T-lymphocyte (CTL) activation and tumor cell lysis.