Glycoprotein 100 peptide–Major Histocompatibility Complex class I complex (gp100–MHC I complex)

The Glycoprotein 100 (gp100) peptide–Major Histocompatibility Complex (MHC) class I complex is a cell-surface molecular assembly primarily found on melanocytes and melanoma cells. It is formed when the intracellular protein gp100 (also known as PMEL) is proteolytically processed into peptides and presented on the cell surface by MHC class I molecules, most commonly the HLA-A*02:01 allele (UniProt P40967). This complex acts as a specific epitope for T-cell receptor (TCR) recognition, making it a critical target for cancer immunotherapy. In melanoma, particularly uveal melanoma, the overexpression of gp100 provides a therapeutic window for drugs like tebentafusp, a bispecific gp100-peptide-HLA-directed T-cell engager (Nathan et al., 2021). Tebentafusp bridges the gp100–MHC complex on tumor cells with CD3 on T-cells, triggering a potent cytotoxic immune response against the cancer (Dammeijer et al., 2020). Because gp100 is also expressed in healthy melanocytes in the skin and eye, treatment can lead to on-target, off-tumor toxicities such as rash, pruritus, and vitiligo (Middleton et al., 2020). Patient selection for therapies targeting this complex requires confirmation of the specific HLA allele to ensure the drug can recognize the peptide-MHC assembly.

Other names

gp100–HLA-A*02:01 complexPMEL peptide–MHC complexMelanocyte protein PMEL–HLA-A2 complexgp100(209-217)–HLA-A*02:01gp100–HLA complex

Bispecific T-cell engager (ImmTAC) that binds the gp100–MHC complex via a high-affinity TCR domain and recruits T-cells via an anti-CD3 effector domain to induce tumor cell lysis.