Mucin 1-derived peptide-Major Histocompatibility Complex (MUC1-pMHC) (MUC1-pMHC)

Mucin 1 (MUC1) is a high-molecular-weight transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in over 90% of breast, pancreatic, and ovarian cancers [PMID: 29158515]. While traditional monoclonal antibodies target the extracellular protein domain, a specialized class of therapeutics targets MUC1-derived peptide epitopes presented on the cell surface by Major Histocompatibility Complex (MHC) molecules [PMID: 26451618]. These peptide-MHC (pMHC) complexes represent a unique class of targets that allow the immune system to recognize intracellularly processed antigens. In cancer cells, MUC1 is processed into specific peptides, such as those from the tandem repeat or signal sequence, which are then loaded onto MHC Class I molecules, most commonly HLA-A*02:01 [PMID: 30552151]. Drugs targeting these complexes, including TCR-engineered T cells (TCR-T) and TCR-like CAR-T cells like ET1402L1, utilize the high specificity of T-cell receptor recognition to induce potent, antigen-specific lysis of malignant cells [Eureka Therapeutics, 2021]. This approach is particularly valuable for targeting the 'undruggable' intracellular proteome and overcoming the limitations of targeting the bulky, heavily glycosylated MUC1 protein directly.

Other names

MUC1 peptide-HLA complexMUC1-MHC complexMucin 1-derived epitopes on MHCMUC1-HLA-A2 complexMUC1-pMHC complex

Recognition of the MUC1 peptide-MHC complex by engineered T-cell receptors (TCR-T) or TCR-like chimeric antigen receptors (CAR-T), triggering cytotoxic T-lymphocyte (CTL) activity, cytokine release, and direct lysis of tumor cells expressing the specific MUC1 peptide-MHC complex.