Melanocyte protein PMEL (gp100) peptide-MHC complex (PMEL/gp100-MHC)

Melanocyte protein PMEL (also known as gp100) is a lineage-specific transmembrane glycoprotein essential for the formation of stage II melanosomes and the transition from stage I to stage II melanosomes (UniProt P40967). While its physiological role is restricted to pigment-producing cells, it is highly overexpressed in the majority of cutaneous and uveal melanomas, making it a significant melanoma-associated antigen. The therapeutic target specifically refers to short peptide fragments derived from PMEL, such as the gp100:209-217 or gp100:280-288 epitopes, which are processed and presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01 (PubMed: 10427670). Drugs like tebentafusp utilize a high-affinity T-cell receptor (TCR) domain to recognize this specific peptide-MHC complex, redirecting T-cells to kill melanoma cells regardless of their natural TCR specificity (FDA: Kimmtrak). Because PMEL is also expressed in healthy melanocytes in the skin, eye, and inner ear, targeting this complex can lead to autoimmune-like side effects such as vitiligo or ocular inflammation.

Other names

gp100PMEL17Silver locus protein homologMelanoma-associated antigen gp100ME20gp100:209-217 epitopegp100:280-288 epitope

T-cell redirection via bispecific T-cell engagers (BiTEs), TCR-engineered T-cell therapy (TCR-T), and therapeutic vaccination to induce peptide-specific cytotoxic T-lymphocyte responses.