HLA-A*01:01-restricted Melanoma-associated antigen 3 (MAGE-A3) peptide complex (HLA-A1/MAGE-A3)

The HLA-A1 presenting MAGE-3 epitope is a specific peptide-major histocompatibility complex (pMHC) found on the surface of various malignant cells. MAGE-A3 (Melanoma-associated antigen 3) is a member of the cancer-testis antigen family, which is typically expressed only in immune-privileged male germ cells but becomes aberrantly expressed in a wide range of cancers, including melanoma and lung carcinoma (UniProt P43357). The specific epitope, often the nonamer EVDPIGHLY, is loaded onto the HLA-A*01:01 molecule and presented to the immune system. This complex has been a primary target for adoptive T-cell therapies, particularly T-cell receptor (TCR) engineered T-cells, designed to redirect the patient's immune system to kill tumor cells. However, clinical development of therapies targeting this complex has faced significant hurdles; most notably, a high-affinity TCR (a3a) caused fatal cardiotoxicity in clinical trials because it cross-reacted with a similar peptide sequence found in the cardiac protein Titin (Linette et al., 2013; Cameron et al., 2013). Consequently, this target remains a high-interest but high-risk area for precision immunotherapy, requiring rigorous screening for potential cross-reactivity with healthy tissues.

Other names

MAGE-A3/HLA-A1 complexHLA-A*01:01/EVDPIGHLY complexMelanoma-associated antigen 3 presented by HLA-A1MAGE-3/HLA-A1

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex on the tumor cell surface, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of the target cell.