T cell receptor specific for gp100 peptide-HLA-A*02:01 complex (gp100/HLA-A*02:01 TCR)

The T cell receptor (TCR) specific for the gp100 peptide-HLA-A*02:01 complex is a specialized immune receptor used to target melanoma cells. gp100, also known as PMEL, is a protein involved in melanosome biogenesis and is highly expressed in both cutaneous and uveal melanoma (PMID: 34554482). This TCR specifically recognizes the YLEPGPVTA epitope of gp100 presented by the HLA-A*02:01 major histocompatibility complex (MHC) (FDA Label: Kimmtrak). It serves as the basis for Tebentafusp, a first-in-class bispecific T-cell engager (ImmTAC) that redirects T cells to kill gp100-positive tumor cells. By binding the peptide-MHC complex with high affinity, the TCR domain of the drug facilitates the formation of an immunological synapse between the tumor and T cells, leading to tumor cell lysis (PMID: 31019007). Clinical applications are primarily focused on HLA-A*02:01-positive patients with metastatic uveal melanoma. Because gp100 is also expressed in healthy melanocytes, treatment can lead to on-target off-tumor effects like vitiligo or skin rashes. The therapeutic use of this TCR represents a significant advancement in treating cancers with low mutational burdens that are typically resistant to checkpoint inhibitors.

Other names

gp100-specific T cell receptorPMEL-specific TCRgp100(280-288)-specific TCRYLEPGPVTA-specific TCR

Tebentafusp is a bispecific gp100 peptide-HLA-directed T cell receptor (TCR) CD3-directed T cell engager that binds to the gp100 peptide presented by HLA-A*02:01 on tumor cells and to the CD3 receptor on T cells, resulting in T cell activation and lysis of melanoma cells (FDA Label: Kimmtrak).