MAGE-A3-specific T-cell receptor (MAGE-A3 TCR)

The MAGE-A3-specific T-cell receptor (TCR) is an engineered or naturally occurring protein complex designed to recognize peptides derived from the Melanoma-associated antigen 3 (MAGE-A3) presented by specific Human Leukocyte Antigen (HLA) molecules [1][2]. MAGE-A3 is a cancer-testis antigen that is highly expressed in various tumors, including melanoma and non-small cell lung cancer, but is restricted in normal tissues, making it a compelling target for adoptive cell therapy [2][3]. When T cells are modified to express this TCR, they can specifically identify and eliminate MAGE-A3-positive malignant cells through the release of perforin and granzymes [1]. The clinical development of MAGE-A3-specific TCRs has been significantly impacted by severe off-target toxicities discovered in early trials [1][4]. Notable instances include cross-reactivity with the cardiac protein Titin, which led to fatal cardiotoxicity, and cross-reactivity with MAGE-A12 in the central nervous system, resulting in neurological damage [1][4]. Current research focuses on improving the affinity and specificity of these receptors to avoid cross-reactivity with similar peptides in healthy tissues while maintaining potent anti-tumor activity [3]. (Citations: [1] Linette GP, et al. Blood. 2013;122(6):863-871; [2] Morgan RA, et al. J Clin Oncol. 2013;31(26):3328-3339; [3] Dhodapkar MV, et al. Front Immunol. 2020;11:590461; [4] Raman MC, et al. J Biol Chem. 2016;291(21):11051-11066).

Other names

Melanoma-associated antigen 3-specific T-cell receptorAnti-MAGE-A3 TCRMAGE-A3-specific TCRMAGE-A3-targeted T-cell receptor

Recognition of MAGE-A3 peptide-HLA complexes (typically HLA-A*01 or HLA-A*02) on the surface of tumor cells, which triggers T-cell activation, cytokine secretion, and the release of cytotoxic granules (perforin and granzymes) to induce target cell lysis.