Human epidermal growth factor receptor 2-derived HLA-A*02:01-restricted peptide-MHC complex (HER2/HLA-A2 epitope)

The ERBB2-derived HLA-A2-restricted epitope is a specific peptide fragment, most commonly the E75 peptide (KIFGSLAFL), derived from the HER2/neu protein and presented on the cell surface by the Human Leukocyte Antigen (HLA) A*02:01 molecule. This peptide-MHC complex serves as a critical target for cancer immunotherapy, as HER2 is frequently overexpressed in various malignancies, including breast, gastric, and ovarian cancers, while its expression in normal adult tissues is relatively limited. Unlike monoclonal antibodies that target the extracellular domain of the intact HER2 protein, therapies targeting this epitope utilize the cellular immune system to identify and destroy cells processing internal HER2 proteins. Clinical development focusing on this target includes peptide-based vaccines designed to stimulate a patient's own immune system and adoptive T-cell therapies, such as TCR-engineered T cells, which are programmed to recognize the specific peptide-HLA configuration. Because this target is restricted to patients with the HLA-A*02:01 haplotype, patient selection requires both HER2 positivity and genetic HLA typing. While promising, therapeutic challenges include the potential for 'on-target, off-tumor' toxicities if the T cells react to low levels of HER2 in healthy tissues, as well as the risk of tumor escape through the downregulation of MHC molecules (Source: National Cancer Institute, PubMed PMID: 22490303, 30545895).

Other names

ERBB2-derived HLA-A2-restricted epitopeHER2-derived HLA-A2 epitopeHER2(369-377) peptideE75 peptide-HLA-A2 complexKIFGSLAFL-HLA-A*02:01 complexHER2 p369-377

The target acts as a specific molecular signature on the surface of cancer cells that is recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T lymphocytes. Therapeutic interventions such as peptide vaccines (e.g., Nelipepimut-S) aim to expand the endogenous T-cell population specific for this epitope, while TCR-T cell therapies provide exogenously engineered T cells to directly bind the peptide-MHC complex, leading to targeted lysis of HER2-expressing tumor cells (Source: PubMed PMID: 25103457, 26903155).