T cell receptor specific for MAGE-3.A1–HLA-A*01 or NA17.A2–HLA-A*02:01 complexes (MAGE-3/NA17 TCR)

The T cell receptor specific for MAGE-3.A1–HLA-A*01 or NA17.A2–HLA-A*02:01 complexes is a therapeutic target used in the development of adoptive T-cell therapies for metastatic melanoma. This target encompasses engineered TCRs that recognize specific peptide-MHC complexes: the MAGE-A3 peptide (EVDPIGHLY) presented by HLA-A*01 and the NA17-A peptide (VLPDVFIRC) presented by HLA-A*02:01. These antigens are members of the cancer-testis antigen family, which are typically expressed in immune-privileged germline tissues and overexpressed in various cancers, particularly melanoma, making them ideal for targeted immunotherapy. In clinical practice, patients' T cells are genetically modified to express these TCRs, enabling them to specifically identify and eliminate tumor cells expressing the cognate antigen. However, the use of MAGE-A3-specific TCRs has been complicated by severe off-target toxicities, most notably fatal neurotoxicity caused by cross-reactivity with the MAGE-A12 protein expressed in the human brain. Consequently, while these TCRs demonstrate potent anti-tumor activity, their clinical application requires rigorous screening for potential cross-reactivity and careful patient selection based on HLA typing and antigen expression.

Other names

MAGE-3.A1/NA17.A2-specific T-cell receptorAnti-MAGE-3.A1 TCRAnti-NA17.A2 TCRMAGE-A3-specific HLA-A*01-restricted T-cell receptorNA17-A-specific HLA-A*02:01-restricted T-cell receptorT-cell receptor specific for MAGE-3.A1/NA17.A2 complexes

The engineered T-cell receptor (TCR) recognizes and binds to specific peptide-MHC complexes (MAGE-3 peptide on HLA-A*01 or NA17-A peptide on HLA-A*02:01) on the surface of tumor cells. This binding triggers the activation of the engineered T cell, leading to the release of cytotoxic granules (perforin and granzymes) and cytokines (IFN-gamma, TNF-alpha), which induce apoptosis and lysis of the target cancer cell.