Premelanosome protein (gp100) peptide 209-217 presented by HLA-A*02:01 (PMEL/HLA-A*02:01)

Premelanosome protein (PMEL), also known as gp100, is a type I transmembrane glycoprotein essential for the formation of stage II melanosomes in melanocytes (UniProt P40967). It functions by forming intralumenal amyloid fibrils that provide a scaffold for melanin deposition (PubMed: 11544351). In the context of oncology, gp100 is a well-characterized tumor-associated antigen (TAA) frequently overexpressed in cutaneous and uveal melanoma (PubMed: 34554650). The specific peptide fragment consisting of amino acids 209-217 (ITDQVPFSV) is a dominant epitope that, when presented by the HLA-A*02:01 major histocompatibility complex (MHC) class I molecule, can be recognized by the cellular immune system (PubMed: 11544351). This pMHC complex is the primary target for tebentafusp, a first-in-class bispecific T-cell receptor (TCR) fusion protein (ImmTAC) approved for the treatment of HLA-A*02:01-positive metastatic uveal melanoma (FDA: Kimmtrak Label). By binding both the gp100:209-217/HLA-A*02:01 complex and the CD3 receptor on T cells, these therapies induce targeted lysis of melanoma cells. However, because gp100 is also expressed in healthy melanocytes, clinical use is often associated with on-target off-tumor toxicities such as vitiligo and ocular inflammation (PubMed: 34554650).

Other names

gp100PMEL17Silver locus protein homologMelanocyte lineage-specific antigen gp100gp100:209-217ITDQVPFSVME20SILV

T-cell redirection via bispecific T-cell receptor (TCR) fusion proteins (ImmTACs) that bind the gp100:209-217/HLA-A*02:01 complex and the CD3 receptor on T cells, leading to T-cell activation and tumor cell lysis (FDA: Kimmtrak Label; PubMed: 34554650).