Melanoma-associated antigen 3 (MAGE-A3) peptide-HLA class I complex (MAGE-A3/HLA-I)

Melanoma-associated antigen 3 (MAGE-A3) is a prominent member of the cancer-testis antigen (CTA) family, characterized by its expression in various malignancies and restricted expression in immune-privileged tissues like the testis and placenta [3, 9]. In cancer cells, MAGE-A3 is processed into peptides that are presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules, such as HLA-A*01, HLA-A*02, and HLA-A*24, making it a highly specific target for CD8+ cytotoxic T cells [13, 14, 19]. Therapeutic strategies targeting this complex include cancer vaccines (e.g., GSK1572932A) and adoptive T-cell therapies using engineered T-cell receptors (TCR-T) [1, 15, 16]. Despite its potential as a tumor-specific target, clinical development has faced significant safety challenges. Affinity-enhanced TCRs targeting the MAGE-A3/HLA-A*01 complex resulted in fatal cardiac toxicity in clinical trials due to unexpected cross-reactivity with a similar peptide from the muscle protein titin [1, 7]. Furthermore, HLA-A*02-restricted TCRs have been associated with severe neurotoxicity caused by cross-reactivity with other MAGE family members unexpectedly expressed in the central nervous system [10, 12]. These events highlight the critical need for rigorous off-target screening when developing high-affinity therapies against peptide-MHC targets.

Other names

MAGE-A3MAGE3Melanoma-associated antigen 3Cancer/testis antigen 1.3CT1.3Melanoma antigen family A 3

T-cell receptor (TCR) mediated cell killing and active immunotherapy via vaccination