Melanoma-associated antigen 3-derived peptide–MHC complex (MAGE-A3/MHC)

Melanoma-associated antigen 3 (MAGE-A3) is a member of the cancer-testis antigen (CTA) family, which is typically expressed only in the immune-privileged germ cells of the testis but is frequently upregulated in various malignancies, including melanoma, non-small cell lung cancer, and bladder cancer [1, 2]. The therapeutic target is the specific complex formed when MAGE-A3-derived peptides are presented on the tumor cell surface by Major Histocompatibility Complex (MHC) class I molecules, most notably HLA-A*01:01 [3]. This peptide-MHC complex serves as a highly specific tumor antigen that can be targeted by T-cell receptor (TCR) engineered T-cell therapies and cancer vaccines to induce a potent cytotoxic immune response [4, 5]. However, the clinical development of MAGE-A3-targeted therapies has been significantly hindered by severe safety issues, including fatal neurotoxicity and cardiotoxicity resulting from TCR cross-reactivity with similar sequences in MAGE-A12 (expressed in the brain) and Titin (expressed in the heart) [6, 7]. Consequently, modern drug discovery efforts emphasize the use of high-affinity, highly specific TCRs and rigorous preclinical screening to mitigate off-target risks while leveraging the tumor-restricted presentation of the MAGE-A3/MHC complex [8]. Citations: [1] UniProt (P43357). [2] Gjerstorff et al. (2015) PMID: 25710477. [3] van der Bruggen et al. (1991) PMID: 1840698. [4] ClinicalTrials.gov (NCT03159585). [5] Kruit et al. (2013) PMID: 23532113. [6] Morgan et al. (2013) PMID: 23943301. [7] Linette et al. (2013) PMID: 23776243. [8] Sanderson et al. (2020) PMID: 32814744.

Other names

MAGE-A3 peptide-HLA complexHLA-A*01:01/MAGE-A3 complexMelanoma antigen family A 3 peptide-MHCMAGE3/MHCMAGE-A3/HLA complex

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