Tyrosinase-derived peptide–HLA-A*02:01 complex (TYR-pMHC)

Tyrosinase-derived peptide–MHC class I complexes are specialized cell-surface antigens consisting of a peptide fragment from the tyrosinase enzyme bound to a Major Histocompatibility Complex (MHC) class I molecule, typically HLA-A*02:01 (PMID: 7506951). Tyrosinase is a rate-limiting enzyme in melanin biosynthesis and is highly expressed in melanoma cells, while its expression in healthy tissue is restricted to melanocytes in the skin, eye, and inner ear (PMID: 12461158). These complexes are recognized by the T-cell receptors (TCRs) of CD8+ cytotoxic T lymphocytes, making them prime targets for cancer immunotherapies such as TCR-engineered T cells (TCR-T) and bispecific T-cell engagers like ImmTACs (PMID: 22908283). By targeting the specific peptide-MHC interface, these therapeutic agents can direct a potent immune response against melanoma tumors. However, the presence of tyrosinase in normal melanocytes poses a risk of on-target, off-tumor toxicities, which may manifest as vitiligo, uveitis, or hearing loss (PMID: 15150569). Clinical development of drugs targeting these complexes, such as IMC-F10V, focuses on maximizing anti-tumor efficacy while managing these autoimmune-like side effects (Immunocore Pipeline). Patient selection for these therapies requires screening for both the specific HLA genotype and the expression of the tyrosinase protein within the tumor.

Other names

Tyrosinase-derived peptide–MHC class I complexes on antigen-presenting cells and melanoma cellsTYR:369-377/HLA-A*02:01 complexTyrosinase peptide-MHC complexTYR-HLA-A2Tyrosinase-derived peptide–HLA-A*02:01 complex (TYR-pMHC)

T-cell redirection and activation via specific binding to the peptide-MHC complex, leading to granzyme/perforin-mediated lysis of target cells (PMID: 22908283).