Premelanosome protein peptide–MHC class I complex (PMEL-MHC I complex)

The Premelanosome protein (PMEL) peptide–MHC class I complex is a molecular assembly consisting of a processed peptide fragment from the PMEL protein (also known as gp100) presented by a Major Histocompatibility Complex (MHC) class I molecule, most commonly HLA-A*02:01 (UniProt: P40967). PMEL is a transmembrane glycoprotein primarily expressed in melanocytes and is highly overexpressed in melanoma cells, making it a significant tumor-associated antigen (PubMed: 15150569). This complex is presented on the cell surface and serves as a specific target for the immune system, particularly CD8+ T cells. In oncology, this complex is targeted by advanced immunotherapies such as Tebentafusp, a bispecific T-cell engager that bridges the PMEL-MHC complex on tumor cells with CD3 on T cells (FDA: Kimmtrak). While effective in treating uveal melanoma, targeting this complex can lead to off-tumor effects in healthy melanocytes, resulting in skin rashes or pigment loss (PubMed: 34554660). The therapeutic success of targeting this complex depends on the patient's HLA type, specifically requiring the HLA-A*02:01 allele for recognition by current approved agents.

Other names

gp100 peptide–MHC complexPmel17 peptide–MHC complexgp100-HLA-A*02:01 complexMelanocyte-specific protein Pmel 17 peptide–MHC complexSilver locus protein peptide–MHC complex

T-cell redirection via bispecific T-cell engagers or T-cell receptor (TCR) engineered T-cells that recognize the specific peptide-MHC complex to induce cytotoxic cell death.