Melanocyte protein PMEL-derived peptide presented by Human Leukocyte Antigen (HLA) class I (gp100/HLA complex)

Melanocyte protein PMEL (also known as gp100 or PMEL17) is a lineage-specific transmembrane glycoprotein involved in the maturation of melanosomes in melanocytes (UniProt P40967). In melanoma, gp100 is frequently overexpressed, and its intracellular degradation products are presented as short immunogenic peptides on the cell surface by Human Leukocyte Antigen (HLA) class I molecules, most notably HLA-A*02:01. This specific peptide-MHC complex, such as the one containing the gp100:280-288 (YLEPGPVTA) peptide, serves as a validated target for T-cell-based immunotherapies. Therapeutic agents like Tebentafusp, a bispecific T-cell receptor (TCR)-anti-CD3 fusion protein, are designed to bind this complex with high affinity, thereby redirecting T-cells to lyse melanoma cells (Nathan et al., 2021, NEJM). Because gp100 is also expressed in healthy melanocytes, targeting this complex can lead to off-tumor effects such as vitiligo or uveitis. However, its high prevalence in both cutaneous and uveal melanoma makes it a critical target for patients who are HLA-A*02:01 positive.

Other names

gp100 peptide-MHC complexPMEL17 peptide-HLA complexgp100:209-217/HLA-A*02:01gp100:280-288/HLA-A*02:01Silver locus protein peptide-HLA complexME20-M/HLA complex

T-cell redirection and activation through specific binding of a T-cell receptor (TCR) or TCR-fusion protein to the peptide-MHC complex on the target cell surface.