Melanoma-associated antigen 3 peptide presented by HLA-A1 (MAGE-A3/HLA-A1)

Melanoma-associated antigen 3 (MAGE-A3) is a member of the cancer-testis antigen family, which is typically expressed in the testes and placenta but silenced in normal adult tissues. In many cancers, including melanoma and lung cancer, MAGE-A3 is aberrantly re-expressed and its peptides, such as EVDPIGHLY, are presented on the cell surface by HLA-A1 (specifically HLA-A*01:01) molecules [UniProt P43357, Lancet Oncol 2016]. This peptide-MHC complex serves as a specific target for the immune system, particularly for T-cell receptor (TCR) based therapies and cancer vaccines [ClinicalTrials.gov NCT00001434]. Biologically, MAGE-A3 acts as a scaffold for E3 ubiquitin ligases, facilitating the degradation of tumor suppressors like p53, thereby promoting tumor cell survival and proliferation [UniProt P43357]. Despite its potential as a highly specific target, clinical trials using high-affinity TCRs against MAGE-A3/HLA-A1 have encountered severe safety hurdles. Notable incidents include fatal cardiotoxicity caused by cross-reactivity with a similar peptide in the cardiac protein Titin, and lethal neurotoxicity due to cross-reactivity with MAGE-A12 expressed in the brain [Blood 2013, J Immunother 2013].

Other names

MAGE-A3/HLA-A*01:01MAGE-3/HLA-A1EVDPIGHLY/HLA-A1 complexAntigen MZ2-DCancer/testis antigen 1.3

T-cell receptor (TCR) binding to the peptide-MHC complex, triggering cytotoxic T-lymphocyte (CTL) activation and subsequent lysis of the target tumor cell.