Human epidermal growth factor receptor 2-derived peptide-Major Histocompatibility Complex (HER2-pMHC) (HER2-pMHC)

The Human epidermal growth factor receptor 2-derived peptide-Major Histocompatibility Complex (HER2-pMHC) is a specialized therapeutic target consisting of short peptide fragments of the HER2 protein bound to MHC Class I molecules on the cell surface (Rock et al., 2016). While traditional HER2 therapies like trastuzumab target the extracellular domain of the intact protein, HER2-pMHC targets allow for the recognition of tumor cells by the cellular immune system, specifically CD8+ cytotoxic T-lymphocytes (Sears et al., 2008). Common epitopes include E75 (KIFGSLAFL) and GP2, which are frequently presented by HLA-A*02:01 (Mittendorf et al., 2012). This target is the basis for several immunotherapeutic strategies, including peptide vaccines like Nelipepimut-S, TCR-engineered T-cells, and TCR-like antibodies (Liu et al., 2023). These therapies are designed to overcome the limitations of monoclonal antibodies by engaging the potent killing mechanisms of T-cells. Clinical applications are primarily focused on HER2-positive breast and gastric cancers, though efficacy can be limited by MHC downregulation or the requirement for specific patient HLA genotypes (Schmittling et al., 2008). The target is particularly valuable for addressing tumors with low HER2 expression that may not respond to standard antibody-drug conjugates or monoclonal antibodies.

Other names

HER2 peptide-HLA complexHER2/neu peptide-MHCE75-HLA-A*02:01 complexGP2-HLA-A*02:01 complexHER2-derived epitope-MHC

Recognition of the peptide-MHC complex by T-cell receptors (TCRs) to induce cytotoxic T-lymphocyte-mediated lysis of tumor cells.