gp100 melanoma-associated antigen-derived peptides presented by HLA-A*0201 (gp100/HLA-A*02:01)

The gp100 melanoma-associated antigen-derived peptides presented by HLA-A*0201 represent a specific peptide-major histocompatibility complex (pMHC) target used in cancer immunotherapy. gp100, also known as PMEL or PMEL17, is a transmembrane glycoprotein primarily expressed in melanocytes and overexpressed in most melanoma cells, where it plays a crucial role in the maturation of melanosomes (UniProt P37803). Because gp100 is a lineage-specific protein, its derived peptides are presented on the cell surface by HLA-A*0201, making them ideal targets for T-cell-based interventions in patients carrying this specific HLA allele. Therapeutic strategies targeting this complex include bispecific T-cell engagers, such as tebentafusp, and various peptide vaccines or TCR-engineered T-cell therapies. Tebentafusp, for instance, utilizes a high-affinity T-cell receptor (TCR) to bind the gp100/HLA-A*02:01 complex and a CD3 effector domain to redirect T cells to kill melanoma cells (FDA, 2022). While effective, targeting this complex can lead to on-target, off-tumor toxicities due to gp100 expression in healthy melanocytes, resulting in side effects like vitiligo or skin rashes. This target is particularly significant in uveal melanoma, where it has provided the first survival benefit for a systemic therapy in the metastatic setting. Patient selection for these therapies requires screening for the HLA-A*02:01 genotype to ensure the target complex can be formed and recognized.

Other names

PMELPMEL17Melanocyte protein PMELgp100-HLA-A2 complexSilver locus protein homologMelanoma-associated antigen gp100

T-cell redirection and activation via TCR-mediated recognition of the peptide-MHC complex