Human epidermal growth factor receptor 2 peptide-major histocompatibility complex (HER2 pMHC)

The Human epidermal growth factor receptor 2 (HER2) peptide-major histocompatibility complex (pMHC) is a therapeutic target consisting of intracellularly processed HER2 fragments presented on the cell surface by HLA molecules [1][2]. While traditional monoclonal antibodies like trastuzumab target the extracellular domain of the HER2 protein, TCR-based approaches recognize these specific peptide-HLA complexes, enabling the immune system to target cells with lower HER2 density or specific processed epitopes [3]. This target is central to the development of TCR-engineered T-cell (TCR-T) therapies and TCR-bispecific molecules designed to treat HER2-positive malignancies, including breast, gastric, and lung cancers [2][4]. By mimicking natural T-cell recognition, these therapies can bypass some resistance mechanisms associated with antibody-based treatments [3]. However, clinical development requires stringent screening for cross-reactivity, as HER2 is expressed at low levels in vital organs such as the heart and lungs, posing a risk for severe on-target off-tumor adverse events [5]. Sources: [1] UniProt (P04626, ERBB2_HUMAN) [2] Frontiers in Immunology (2020, "TCR-Like Antibodies: A New Hope for Cancer Therapy") [3] Journal of Immunology (1995, "Identification of a HER-2/neu peptide... HLA-A2") [4] Nature Communications (2022, "Engineered TCR-T cells targeting HER2") [5] Journal of Clinical Oncology (Safety of HER2-targeted T-cell therapies)

Other names

HER2-derived peptide-HLA complexErbB2 peptide-MHCHER2/HLA-A*02:01 complexHER2 pMHC complexHER2-derived peptide-HLA-A2 complex

Recognition of HER2-derived peptides (such as the HLA-A*02:01-restricted KIFGSLAFL epitope) presented by MHC Class I molecules by engineered T-cell receptors (TCRs). This binding triggers the formation of an immunological synapse, leading to T-cell activation, the release of cytotoxic granules (perforin and granzymes), and the secretion of pro-inflammatory cytokines (IFN-gamma, TNF-alpha) to induce apoptosis in the target tumor cell.