Melanoma-associated antigen A4-derived peptide–major histocompatibility complex (MAGEA4-pMHC)

Melanoma-associated antigen A4-derived peptide–major histocompatibility complex (MAGEA4-pMHC) is a therapeutic target formed when the intracellular cancer-testis antigen MAGE-A4 is processed and presented on the cell surface by HLA molecules, typically HLA-A*02:01 [1]. MAGE-A4 is highly expressed in various solid tumors but is restricted to immune-privileged germ cells in healthy adults, providing a wide therapeutic window for oncology [2]. Because MAGE-A4 is an intracellular protein, it is inaccessible to standard antibody therapies; however, the pMHC complex can be recognized by specialized T-cell receptors (TCRs) [3]. Current therapeutic strategies involve TCR-engineered T-cell therapies (TCR-T) and bispecific TCR-based T-cell engagers that redirect the immune system to kill MAGE-A4-positive cancer cells [4]. The clinical relevance of this target was recently validated by the FDA approval of afamitresgene autoleucel for the treatment of advanced synovial sarcoma [5]. (Sources: [1] UniProt P43358; [2] PMID: 32603453; [3] Adaptimmune Therapeutics; [4] PMID: 37353561; [5] FDA News Release 2024).

Other names

MAGE-A4/HLA-A2 complexMAGE-A4 peptide-MHCGVYDGREHTV-HLA-A*02 complexMAGE-A4-HLA-A*02:01

Engineered T-cell receptor (TCR) binding to the peptide-MHC complex, leading to T-cell activation, cytokine release, and directed lysis of MAGE-A4-expressing tumor cells.