Human epidermal growth factor receptor 2-derived peptide–Major histocompatibility complex (HER2-pMHC)

The Human epidermal growth factor receptor 2-derived peptide–Major histocompatibility complex (HER2-pMHC) is a therapeutic target consisting of specific HER2-derived peptides, such as E75 or GP2, presented by Major Histocompatibility Complex (MHC) molecules, typically HLA-A*02:01, on the cell surface (Mittendorf et al., 2014, PMID: 25103457). This complex represents a processed form of the HER2 protein, allowing the immune system to recognize intracellularly derived antigens that are not accessible to standard monoclonal antibodies (Liu et al., 2017, PMID: 28320440). In many cancers, including breast and gastric malignancies, HER2 is overexpressed, leading to an increased density of these pMHC complexes which can be targeted by T-cell receptor (TCR)-mimetic antibodies, CAR-T cells, and cancer vaccines (Sears et al., 2011, PMID: 21422443). For example, the vaccine Nelipepimut-S (E75) is designed to stimulate a cytotoxic T-lymphocyte response against cells presenting this specific complex (Brown et al., 2020, PMID: 32453010). While promising, targeting HER2-pMHC requires patients to possess specific HLA alleles and carries risks of immune evasion through HLA downregulation or off-target toxicity if the peptide is presented on healthy tissues (Schmitt et al., 2013, PMID: 23943752).

Other names

HER2-peptide-HLA complexpMHC-HER2HLA-A*02:01/HER2 peptide complexE75-HLA-A2 complexGP2-HLA-A2 complex

Recognition of the HER2 peptide-MHC complex by engineered T-cell receptors or TCR-mimetic antibodies, triggering cytotoxic T-lymphocyte (CTL) activation and tumor cell lysis.