Melanocyte protein PMEL peptide-Major Histocompatibility Complex (PMEL peptide-MHC complex) (PMEL-pMHC)

The PMEL peptide-MHC complex is a therapeutic target in melanoma, consisting of a peptide derived from the premelanosome protein (PMEL, also known as gp100) presented by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01. PMEL is a lineage-specific protein involved in melanosome maturation and is highly expressed in melanocytes and malignant melanoma cells. Because it is an intracellular protein, its fragments are presented on the cell surface via the MHC pathway, making them accessible to T-cell receptors (TCRs). Drugs targeting this complex, such as the bispecific T-cell engager tebentafusp (Kimmtrak), utilize engineered TCR domains to redirect T cells to kill tumor cells. This target is particularly significant in uveal melanoma, where it has provided the first survival benefit for a TCR-based therapeutic. Other therapeutic approaches include gp100 peptide vaccines and adoptive cell transfer using T cells engineered with PMEL-specific TCRs. Safety concerns primarily involve on-target, off-tumor effects on normal melanocytes, leading to dermatological toxicities like rash and pruritus. Systemic cytokine release syndrome is also a common adverse event associated with T-cell redirecting therapies targeting this complex. Patient selection for these therapies requires both PMEL expression and the presence of the specific HLA allele, typically HLA-A*02:01.

Other names

gp100 peptide-MHC complexPMEL17 peptide-MHC complexgp100-HLA-A2 complexPMEL-HLA complexMelanocyte protein Pmel 17 peptide-MHC complexSilver protein peptide-MHC complex

Tebentafusp is a bispecific protein that redirects T cells to target cells expressing the PMEL peptide-MHC complex, leading to T-cell activation and tumor cell lysis. TCR-T therapies involve the adoptive transfer of T cells engineered to express PMEL-specific TCRs that recognize the complex on tumor cells.