T-cell receptor recognizing Gp100-derived peptide–MHC complexes (Gp100-specific TCR)

The T-cell receptor recognizing Gp100-derived peptide–MHC complexes is a specialized immune receptor designed to target the Gp100 protein, also known as PMEL (UniProt P40967). Gp100 is a lineage-specific antigen highly expressed in melanocytes and overexpressed in most melanoma tissues, including uveal and cutaneous melanoma (Nathan et al., 2021). The TCR specifically binds to Gp100-derived peptides, most commonly the YLEPGPVTA sequence, when presented by the Major Histocompatibility Complex (MHC) class I molecule HLA-A*02:01 (Liddy et al., 2012). This interaction is the basis for advanced immunotherapies, such as Tebentafusp, a bispecific TCR-anti-CD3 fusion protein (FDA, 2022). By binding the Gp100-MHC complex on tumor cells and CD3 on T-cells, these therapies redirect T-cell cytotoxicity toward the cancer. Clinical studies have demonstrated that targeting this complex can significantly improve overall survival in patients with metastatic uveal melanoma (Nathan et al., 2021). However, because Gp100 is also expressed in healthy melanocytes, treatment can result in on-target off-tumor toxicities in the skin and eyes (FDA, 2022). Monitoring for cytokine release syndrome is also critical during the administration of drugs targeting this receptor complex.

Other names

PMEL-specific T-cell receptorGp100-TCRMelanocyte protein PMEL-specific TCRGp100-peptide-MHC complexGp100-HLA-A*02:01

The drug (e.g., Tebentafusp) uses a soluble TCR to bind the Gp100 peptide-MHC complex on the tumor cell surface and an anti-CD3 domain to recruit and activate T-cells, leading to direct lysis of the tumor cell.