Premelanosome protein (gp100) peptide–MHC class I complex (gp100–MHC I)

The gp100/PMel17 peptide–MHC class I complex is a clinically validated therapeutic target primarily used in the treatment of melanoma (PMID: 35081293). gp100, also known as PMEL or PMEL17, is a transmembrane glycoprotein expressed in melanocytes and melanoma cells, where it is involved in the formation of the fibrillar matrix in melanosomes (UniProt: P40967). Intracellular processing of gp100 generates specific peptides, such as gp100:209-217, which are presented on the cell surface by MHC class I molecules, most commonly HLA-A*02:01 (PMID: 12135425). This complex is recognized by the T-cell receptor (TCR) of cytotoxic T lymphocytes, making it a target for various immunotherapies. The most prominent drug targeting this complex is tebentafusp, a bispecific TCR-anti-CD3 fusion protein that redirects T cells to lyse gp100-expressing tumor cells (FDA: Kimmtrak). Other therapeutic approaches include peptide-based vaccines and adoptive T-cell therapies using engineered TCRs. Because gp100 is also expressed in normal melanocytes, targeting this complex can lead to on-target, off-tumor toxicities such as vitiligo, skin rash, and uveitis (PMID: 35081293).

Other names

gp100/PMel17 peptide–MHC class I complexPMEL17 peptide–MHC complexgp100–HLA-A*02:01 complexMelanocyte protein PMEL peptide–MHC complexSilver locus protein peptide–MHC complexME20 peptide–MHC complex

Tebentafusp is a bispecific T-cell receptor (TCR) fusion protein that redirects CD3+ T cells to the gp100 peptide–MHC complex on tumor cells, leading to T-cell activation and tumor cell lysis (PMID: 35081293). Peptide vaccines aim to stimulate the expansion of endogenous gp100-specific cytotoxic T lymphocytes (PMID: 15096515).