gp100 peptide-HLA-A*02:01 complex (gp100/HLA-A2)

The target is a specific peptide-major histocompatibility complex (pMHC) consisting of epitopes derived from the melanocyte protein PMEL (also known as gp100) presented by MHC class I molecules, most notably HLA-A*02:01, and the cognate T-cell receptors (TCRs) that recognize them (Cancers 2021, 13(23), 5968; Ther Adv Med Oncol 2022, 14). PMEL is a transmembrane glycoprotein essential for the structural organization of melanosomes and is highly overexpressed in melanoma and uveal melanoma cells (UniProt P40967). This pMHC complex serves as a specific tumor-associated antigen, making it a key target for immunotherapies such as tebentafusp (Kimmtrak). Tebentafusp is a first-in-class bispecific fusion protein (ImmTAC) that uses an engineered high-affinity TCR domain to bind the gp100/HLA-A*02:01 complex on tumor cells and an anti-CD3 domain to redirect and activate polyclonal T cells for tumor lysis (Ther Adv Med Oncol 2022, 14). Clinical efficacy is restricted to patients who are HLA-A*02:01 positive, which serves as a mandatory biomarker for treatment. Common safety concerns include cytokine release syndrome and dermatological reactions, such as rash and pruritus, which occur because gp100 is also expressed in normal melanocytes.

Other names

PMEL peptide-MHC complexgp100/HLA-A*02:01 complexMelanocyte protein PMELgp100SILVSilver locus protein homologME20-M

Tebentafusp is a bispecific T-cell engager (ImmTAC) that redirects T cells to tumor cells by binding the gp100 peptide-HLA-A*02:01 complex via an engineered high-affinity T-cell receptor (TCR) domain and engaging CD3 on T cells via an anti-CD3 scFv domain.