Melanocyte protein PMEL (gp100) – HLA-A*02:01-restricted epitopes (PMEL/HLA-A*02:01)

Melanocyte protein PMEL, also known as gp100, is a type I transmembrane glycoprotein primarily expressed in melanocytes and highly overexpressed in melanoma cells (UniProt P40967). Its physiological role involves the formation of the fibrillar matrix within stage II melanosomes, which is essential for melanin deposition. In the context of oncology, specific peptide fragments of PMEL are processed and presented on the cell surface by the Human Leukocyte Antigen (HLA) system, specifically the HLA-A*02:01 allele (PubMed: 10426705). These PMEL/HLA-A*02:01 complexes serve as potent targets for immunotherapies, including T-cell receptor (TCR) engineered cells and bispecific T-cell engagers. The most notable therapeutic targeting this complex is tebentafusp, a bispecific protein that redirects T cells to kill gp100-positive melanoma cells in HLA-A*02:01-positive patients (FDA Label: Kimmtrak). While effective, targeting this lineage-specific antigen can lead to off-tumor effects in healthy pigmented tissues, such as the skin and eyes, resulting in vitiligo or uveitis (PubMed: 34554650).

Other names

gp100Silver locus protein homologPmel17ME20SILVMelanocyte-specific lineage antigen gp100

T-cell redirection via bispecific TCR-anti-CD3 fusion proteins or direct T-cell recognition of peptide-MHC complexes by TCR-engineered T cells, leading to the release of perforins and granzymes and subsequent cytotoxic lysis of PMEL-expressing tumor cells (FDA Label: Kimmtrak; PubMed: 34554650).