Melanocyte protein PMEL (PMEL17) (PMEL)

Melanocyte protein PMEL, also known as gp100, is a type I transmembrane glycoprotein primarily expressed in melanocytes and melanoma cells, where it plays a vital role in melanosome biogenesis (UniProt P40967). It is processed into several fragments that self-assemble into amyloid fibrils within the melanosome lumen, providing a structural scaffold for melanin sequestration and protection against oxidative stress (PubMed: 11544171). Due to its high expression in malignant melanoma and limited expression in normal tissues, PMEL is a major target for cancer immunotherapy (PubMed: 22446637). The most notable therapeutic targeting PMEL is tebentafusp, a bispecific T-cell engager that targets a gp100 peptide presented by HLA-A*02:01 (FDA: Kimmtrak). Other strategies include peptide vaccines and CAR-T/TCR-T cell therapies aimed at inducing a robust anti-tumor immune response. Potential safety concerns include on-target, off-tumor toxicities such as vitiligo and uveitis due to the presence of PMEL in healthy melanocytes (PubMed: 35196439). Clinical monitoring for cytokine release syndrome is also required for certain PMEL-targeted therapies, particularly bispecifics.

Other names

gp100Pmel17Silver locus protein homologSILVME20Premelanosome protein

Tebentafusp acts as a bispecific T-cell receptor (TCR) fusion protein that redirects T cells to kill gp100-expressing melanoma cells by binding to the gp100 peptide-HLA-A*02:01 complex (FDA: Kimmtrak). Other mechanisms include antibody-drug conjugates (ADCs) that deliver cytotoxic payloads directly to PMEL-expressing cells and vaccines that stimulate endogenous T-cell responses against gp100 epitopes (PubMed: 22446637).