Premelanosome protein (gp100) peptide–Major Histocompatibility Complex (gp100-pMHC)

The Premelanosome protein (gp100) peptide–Major Histocompatibility Complex is a therapeutic target consisting of a specific peptide fragment derived from the PMEL protein presented on the cell surface by HLA molecules, typically HLA-A*02:01 (UniProt: P40967). PMEL is a transmembrane glycoprotein involved in the organization of melanosomes in melanocytes and is frequently overexpressed in melanoma cells (Restifo et al., 2012, Nature Reviews Cancer). This complex is recognized by the T-cell receptor (TCR), making it a primary target for immunotherapies designed to redirect the immune system against malignant melanocytes. The most prominent drug targeting this complex is tebentafusp, a bispecific protein that links the gp100-pMHC complex to T-cells via a CD3-binding domain (Nathan et al., 2021, NEJM). While highly effective in treating uveal melanoma, targeting this complex can result in off-tumor effects due to PMEL expression in healthy melanocytes located in the skin, eyes, and inner ear (FDA, 2022, Kimmtrak Label). Consequently, clinical monitoring for cytokine release syndrome and dermatological toxicities is essential during treatment. This target represents a significant advancement in TCR-based therapeutics, providing a bridge between intracellular protein expression and extracellular immune recognition.

Other names

gp100-HLA-A*02:01 complexPMEL-MHC complexMelanocyte protein PMEL peptide-MHCgp100-HLA complexgp100:280-288 peptide-HLA-A2gp100:209-217 peptide-HLA-A2

T-cell redirection via a bispecific T-cell receptor (TCR) fusion protein that binds the gp100 peptide-HLA-A*02:01 complex and the CD3 epsilon chain on T-cells (Nathan et al., 2021, NEJM).