Melanocyte protein PMEL peptide-HLA-A*0201 complex (gp100/HLA-A*0201)

Melanocyte protein PMEL, also known as gp100, is a lineage-specific type I transmembrane glycoprotein essential for the structural organization and maturation of melanosomes (UniProt P16623). While its expression is normally restricted to melanocytes in the skin and eye, it is frequently overexpressed in cutaneous and uveal melanoma, serving as a prominent tumor-associated antigen (PubMed: 11544352). The therapeutic target specifically refers to immunogenic gp100-derived peptides, such as the g209-2M (IMDQVPFSV) or YLEPGPVTA sequences, when presented on the cell surface by the Human Leukocyte Antigen (HLA)-A*02:01 molecule (PubMed: 20689521). This peptide-MHC complex is the recognition site for tebentafusp (Kimmtrak), a first-in-class bispecific T-cell engager (ImmTAC) that redirects polyclonal T cells to attack melanoma cells (FDA: 214828). Because the target involves a specific HLA allele, its clinical utility is restricted to HLA-A*02:01-positive patients. Safety concerns primarily involve on-target, off-tumor effects on healthy melanocytes, leading to skin-related toxicities and uveitis, as well as systemic cytokine release syndrome (PubMed: 34554662).

Other names

gp100PMELPMEL17Silver locus protein homologMelanocyte-specific protein gp100ME20gp100:HLA-A*02:01 complex

T-cell redirection and activation through a bispecific fusion protein (ImmTAC) or engineered T-cell receptors (TCR-T) that specifically bind the gp100 peptide presented by HLA-A*02:01.