Human epidermal growth factor receptor 2 intracellular domain-derived peptide-major histocompatibility complex (HER2-ICD pMHC)

The Human epidermal growth factor receptor 2 (HER2) intracellular domain (ICD)-derived peptide-MHC complex is a specialized tumor-associated antigen used in advanced immunotherapy. While traditional HER2-targeted therapies like trastuzumab bind to the extracellular domain, this target consists of short peptides (e.g., HER2 369-377) derived from the internal portion of the HER2 protein that are processed and presented by Major Histocompatibility Complex (MHC) Class I molecules, typically HLA-A*02:01 (1). This presentation occurs on both tumor cells overexpressing HER2 and antigen-presenting cells (APCs) that have cross-presented tumor antigens (2). Targeting the pMHC complex allows the immune system to recognize intracellular oncogenic drivers that are otherwise inaccessible to standard monoclonal antibodies (3). This approach is particularly relevant for overcoming resistance to extracellular-targeted agents and for targeting tumors with low surface protein density but high internal protein turnover (4). Current therapeutic strategies include T-cell receptor (TCR)-engineered T cells and TCR-like antibodies (TCRm) designed to bind the specific peptide-HLA interface with high affinity (5). These therapies aim to induce potent, antigen-specific T-cell mediated cytotoxicity against HER2-positive malignancies (6).

Other names

HER2 peptide-HLA complexERBB2 peptide-MHCHER2 ICD-derived peptide/HLA-A*02:01 complexHER2 pMHCHER2(369-377)/HLA-A2 complex

T-cell mediated cytotoxicity and immune redirection via specific recognition of the HER2 peptide-MHC complex