EPS8L2-derived neuronal peptide presented by HLA-A*02:01 (EPS8L2/HLA-A*02:01)

The EPS8L2-derived neuronal peptide presented by HLA-A*02:01 is a peptide-major histocompatibility complex (pMHC) that serves as a critical safety target in immunotherapy. The peptide, SAAELVHFL (residues 339-347 of EPS8L2), is derived from the Epidermal Growth Factor Receptor Kinase Substrate 8-Like Protein 2, which is highly expressed in the brain and inner ear (nih.gov). This complex is notorious for its cross-reactivity with T-cell receptors (TCRs) designed to target the MAGE-A3 cancer-testis antigen (bmj.com). In clinical trials, this off-target interaction led to fatal neurotoxicity as the engineered T cells attacked healthy brain tissue expressing EPS8L2 (nih.gov). Understanding and screening for this pMHC is now a standard part of de-risking TCR-based and TCR-mimetic therapies to ensure they do not cross-react with essential normal tissues (dntb.gov.ua). The high sequence similarity between the MAGE-A3 peptide (KVAELVHFL) and the EPS8L2 peptide (SAAELVHFL) facilitates this unintended immune activation.

Other names

EPS8L2 339-347 peptideSAAELVHFL/HLA-A*02:01 complexEPS8L2-HLA-A2 complexEPS8L2-derived peptide-MHCMAGE-A3 TCR off-target

Off-target T-cell receptor cross-reactivity