Melanocyte protein PMEL (gp100) epitopes presented by HLA-A2, HLA-DR53, and HLA-DQw6 (gp100/HLA complex)

Melanocyte protein PMEL (gp100) is a lineage-specific protein involved in the formation of melanosomes in melanocytes and is highly overexpressed in melanoma (UniProt P17683). This target refers to specific gp100-derived peptides (epitopes) that are processed and presented on the cell surface by a combination of Human Leukocyte Antigen (HLA) molecules: HLA-A2 (Class I), HLA-DR53 (Class II), and HLA-DQw6 (Class II). Presentation by HLA-A2 (specifically HLA-A*02:01) is a well-characterized target for CD8+ cytotoxic T-cell responses, while presentation by HLA-DR53 (HLA-DRB4) and HLA-DQw6 (HLA-DQB1*06) facilitates CD4+ helper T-cell activation, which is crucial for a sustained and effective anti-tumor immune response (PubMed 11015561, 7522232). Therapeutic strategies targeting these complexes include the bispecific TCR-CD3 fusion protein tebentafusp (Kimmtrak), which is FDA-approved for HLA-A*02:01-positive patients with uveal melanoma, as well as various peptide vaccines and TCR-engineered T-cell therapies. Because gp100 is also expressed in normal melanocytes, therapeutic targeting can lead to on-target, off-tumor toxicities such as vitiligo, uveitis, and hearing loss. Clinical efficacy is strictly dependent on the patient's HLA genotype and the expression level of gp100 within the tumor.

Other names

PMELSilver locus proteingp100Melanocyte-specific antigen gp100ME20-MME20-SHLA-A*02:01/gp100 complexHLA-DRB4/gp100 complexHLA-DQB1*06/gp100 complex

T-cell receptor (TCR) mediated recognition of peptide-MHC complexes leading to T-cell activation and directed lysis of gp100-expressing cells.