gp100 (PMEL) and MART-1 (Melan-A) peptides presented on MHC class I (gp100/MART-1 pMHC)

gp100 (also known as PMEL or PMEL17) and MART-1 (also known as Melan-A) are melanocyte differentiation antigens that are highly expressed in the majority of melanoma tumors (UniProt P40967, Q16655). These intracellular proteins are processed into short peptide fragments and presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01, where they can be recognized by CD8+ cytotoxic T lymphocytes (PubMed: 35068520). Because these peptide-MHC (pMHC) complexes are highly specific to the melanocytic lineage, they serve as critical therapeutic targets for melanoma immunotherapies, including T-cell receptor (TCR) engineered T-cell therapies and bispecific T-cell engagers. For example, the drug tebentafusp (Kimmtrak) is a bispecific protein that redirects T cells to target the gp100 peptide-HLA-A*02:01 complex on melanoma cells (FDA, 2022). While these targets allow for potent anti-tumor activity, they also carry the risk of on-target, off-tumor toxicities due to the presence of normal melanocytes in the skin, uvea, and inner ear, which can result in conditions such as vitiligo or uveitis (NCI, 2023).

Other names

PMEL17Melan-AMelanoma-associated antigengp100-HLA complexMART-1-HLA complexAntigen LB39-AAAntigen SK29-AAPremelanosome proteinMelanoma antigen recognized by T cells 1

T-cell redirection and activation via T-cell receptor (TCR) recognition of specific peptide-MHC complexes, leading to the release of perforins and granzymes and subsequent lysis of the target melanoma cell (PubMed: 35068520).