Melanocyte protein PMEL peptide–HLA class I complex (gp100–HLA complex) (gp100–HLA complex)

The gp100 peptide–HLA class I complex is a specific molecular target formed by the presentation of intracellularly processed fragments of the melanocyte protein PMEL (gp100) on the cell surface via Human Leukocyte Antigen (HLA) molecules, typically HLA-A*02:01 (UniProt P37301). This complex is highly expressed in melanoma, including both cutaneous and uveal subtypes, where it serves as a neoantigen-like target for the cellular immune system (Nathan et al., NEJM 2021). Under normal physiological conditions, gp100 is involved in the maturation of melanosomes, and its expression is restricted to melanocytes in the skin, retina, and inner ear. Because the complex is presented on the cell surface, it can be targeted by specialized immunotherapies such as T-cell receptor (TCR) bispecifics and TCR-engineered T cells. The most prominent drug targeting this complex is tebentafusp, a bispecific protein that redirects T cells to kill gp100-positive tumor cells (Damato et al., 2019). Therapeutic efficacy is often limited to patients with the specific HLA-A*02:01 genotype, making HLA typing a prerequisite for treatment. Safety concerns associated with targeting this complex include cytokine release syndrome and inflammatory reactions in healthy melanocyte-containing tissues, such as the skin and eyes. Despite these challenges, targeting the gp100–HLA complex has shown significant clinical benefit in patients with metastatic uveal melanoma, a disease with historically poor outcomes. Ongoing research continues to explore more potent TCR-based therapies and combinations to overcome resistance mechanisms. Overall, the gp100–HLA complex represents a validated and clinically significant target in the landscape of melanoma immunotherapy.

Other names

gp100-HLA-A2 complexPMEL-HLA-A*02:01 complexgp100 peptide-MHC complexMelanocyte protein PMEL peptide-HLA-A*02:01 complex

T-cell redirection and activation via bispecific fusion proteins or engineered T-cell receptors that specifically bind the peptide-HLA complex, leading to the release of perforins and granzymes and subsequent tumor cell lysis.