gp100 peptide-MHC class I complex (gp100-MHC-I)

The gp100 peptide-MHC class I complex is a molecular assembly consisting of a peptide fragment derived from the melanocyte-specific protein gp100 (also known as PMEL) bound to a Major Histocompatibility Complex (MHC) class I molecule, typically HLA-A*02:01 (UniProt P16623; NCI Dictionary). gp100 is a transmembrane glycoprotein essential for the formation and maturation of melanosomes in melanocytes (UniProt P16623). In the context of oncology, gp100 is classified as a tumor-associated antigen because it is significantly overexpressed in melanoma cells, including both cutaneous and uveal melanoma (Nathan et al., NEJM 2021). The presentation of gp100 peptides on the cell surface allows the immune system to identify and target malignant cells through T-cell receptor (TCR) recognition (FDA Kimmtrak Label). Modern therapeutic approaches, such as the bispecific ImmTAC molecule tebentafusp, are designed to bind this specific peptide-MHC complex with extremely high affinity (Nathan et al., NEJM 2021). By bridging the gp100-MHC complex on tumor cells with the CD3 receptor on T cells, these drugs trigger a potent cytotoxic immune response regardless of the natural TCR specificity (FDA Kimmtrak Label). This target is particularly significant in uveal melanoma, where it has provided the first survival benefit for a systemic therapy in the metastatic setting (Nathan et al., NEJM 2021). Safety concerns associated with targeting this complex include cytokine release syndrome and skin-related toxicities due to the presence of gp100 in normal melanocytes (FDA Kimmtrak Label).

Other names

PMELPMEL17Melanocyte protein PMELSilver locus protein homologgp100-HLA-A*02:01 complexgp100-HLA-A2 complex

T-cell redirection via a bispecific fusion protein consisting of a high-affinity T-cell receptor (TCR) fused to an anti-CD3 scFv (FDA Kimmtrak Label; Nathan et al., NEJM 2021)