Premelanosome protein (PMEL) peptide-MHC complex (PMEL-MHC)

The target consists of peptides derived from the Premelanosome protein (PMEL), also known as gp100, presented by Major Histocompatibility Complex (MHC) Class I molecules—specifically HLA-A*02:01 in humans and H-2Db in mice—to cognate CD8+ T cells [1]. PMEL is a transmembrane glycoprotein primarily expressed in melanocytes and is highly overexpressed in most melanoma cells, serving as a key tumor-associated antigen [1, 2]. The interaction between the PMEL peptide-MHC complex and the T-cell receptor (TCR) is the basis for several immunotherapy strategies, including TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers [3]. For instance, Tebentafusp is a bispecific protein that targets the gp100 peptide presented by HLA-A*02:01, redirecting T cells to kill melanoma cells [2, 4]. Clinical use of these therapies requires patients to be HLA-A*02:01 positive and often results in on-target, off-tumor effects in healthy melanocytes, such as vitiligo or uveitis [4, 5]. This target complex remains a cornerstone of research into T-cell mediated regression of metastatic melanoma [3, 5]. [1] UniProt (P40967); [2] NCI Drug Dictionary; [3] Overwijk et al., J Exp Med (2003); [4] Nathan et al., NEJM (2021); [5] FDA Label for Kimmtrak (Tebentafusp).

Other names

gp100PMEL17Silver locus proteinMelanocyte-specific protein gp100HLA-A*02:01/gp100 complexH-2Db/gp100 complexgp100:209-217 peptidegp100:25-33 peptide

T-cell redirection via bispecific T-cell receptor (TCR)-anti-CD3 fusion protein; TCR-engineered T-cell mediated cytotoxicity