Melanocyte protein PMEL (gp100) peptide epitope (25-33) presented on MHC class I (gp100(25-33)/HLA-A*02:01)

Melanocyte protein PMEL, also known as gp100, is a lineage-specific type I transmembrane glycoprotein essential for the structural organization of melanosomes, specifically the transition from Stage I to Stage II (UniProt P40967). The specific peptide epitope spanning residues 25-33 (YLEPGPVTA) is a highly immunogenic fragment that is processed and presented on the cell surface by the Major Histocompatibility Complex (MHC) Class I, primarily the HLA-A*02:01 allele (PubMed: 10449770). This peptide-MHC complex is a significant target for cancer immunotherapy because PMEL is highly overexpressed in melanoma cells compared to most normal tissues, with the exception of healthy melanocytes (PubMed: 21835009). Tebentafusp (Kimmtrak) is a first-in-class bispecific T-cell receptor (TCR) fusion protein that specifically targets this gp100(25-33)/HLA-A*02:01 complex to treat metastatic uveal melanoma (FDA). By binding the pMHC complex with high affinity and recruiting T cells via a CD3-binding domain, Tebentafusp induces the potent lysis of melanoma cells. However, because PMEL is also expressed in normal melanocytes, treatment can lead to on-target off-tumor toxicities in pigmented tissues like the skin and eyes, alongside systemic risks such as cytokine release syndrome (PubMed: 34551227).

Other names

PMELgp100SILVPmel17Melanocyte-specific protein Pmel 17Silver locus protein homologmgp10025-33YLEPGPVTA peptidegp100(25-33) epitope

T-cell redirection via a bispecific T-cell receptor (TCR) fused to an anti-CD3 scFv, which facilitates the formation of an immunological synapse between cytotoxic T cells and gp100-expressing tumor cells.