Premelanosome protein (PMEL) peptide–Major Histocompatibility Complex (MHC) class I complex (PMEL-MHC I)

The Premelanosome protein (PMEL), also known as gp100, is a type I transmembrane glycoprotein primarily involved in the maturation of melanosomes (UniProt: P17683). While it is expressed in normal melanocytes, it is significantly upregulated in cutaneous and uveal melanoma, making it a prominent tumor-associated antigen (PubMed: 22553348). The therapeutic target is the complex formed when intracellularly processed PMEL peptides, such as the immunodominant gp100:209-217 epitope, are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, typically HLA-A*02:01 (PubMed: 34554650). This peptide-MHC (pMHC) complex serves as a specific molecular signature recognized by T-cell receptors (TCRs), facilitating the immune-mediated destruction of melanoma cells. Tebentafusp (Kimmtrak) is a first-in-class bispecific T-cell engager that binds this complex with high affinity to redirect T-cell cytotoxicity toward the tumor (FDA: Kimmtrak Label). Because PMEL is also present in healthy melanocytes, safety concerns include on-target off-tumor toxicities such as vitiligo and uveitis, alongside systemic risks like cytokine release syndrome (PubMed: 34554650). This target is currently the only pMHC complex with an FDA-approved therapeutic specifically designed for its recognition.

Other names

gp100-HLA-A*02:01 complexPMEL-MHC complexgp100-MHC class I complexMelanocyte-specific protein Pmel 17 peptide-MHC complex

T-cell redirection via a bispecific fusion protein (ImmTAC) that binds the PMEL-MHC complex and the CD3 receptor on T cells.