gp100-specific T-cell receptor (gp100 TCR)

The gp100-specific T-cell receptor (TCR) is a specialized immune receptor engineered to recognize the melanocyte protein PMEL (gp100), a lineage-specific antigen highly expressed in melanoma (Liddy et al., 2012). This TCR is utilized in advanced immunotherapies, most notably as the targeting domain of tebentafusp (a bispecific T-cell engager) and in adoptive TCR-T cell therapies (Middleton et al., 2020). It specifically binds to a gp100-derived peptide (typically gp100:209-217) presented by the HLA-A*02:01 MHC class I molecule on the surface of tumor cells (Nathan et al., 2021). Upon binding, the TCR facilitates the formation of an immunological synapse, leading to T-cell activation and the subsequent release of cytotoxic molecules like perforin and granzymes to kill the cancer cells (FDA, 2022). While effective, particularly in uveal melanoma, these therapies are restricted to patients with the HLA-A*02:01 genotype and can cause on-target, off-tumor toxicities in normal melanocyte-containing tissues such as the skin and eyes (NIH).

Other names

gp100-specific T-cell receptor on CD4+/CD8+ T cellsgp100 TCRPMEL-specific T-cell receptorHLA-A*02:01-restricted gp100-specific TCRIMCgp100

Tebentafusp is a bispecific fusion protein that redirects T cells to kill gp100-expressing tumor cells by binding the gp100 peptide-HLA-A*02:01 complex via a high-affinity TCR domain and activating T cells via an anti-CD3 domain. Adoptive TCR-T therapies utilize T cells engineered to express this TCR for direct antigen-specific cytotoxicity.