Melanoma gp100-specific T-cell receptor (recognizing HLA-A*02:01–gp100:280-288) (gp100 TCR)

The Melanoma gp100-specific T-cell receptor (TCR) is an engineered or naturally derived immune receptor designed to recognize a specific epitope of the gp100 protein (also known as PMEL). This TCR specifically targets the gp100:280-288 peptide (YLEPGPVTA) when presented by the Human Leukocyte Antigen (HLA)-A*02:01 molecule on the surface of cells (PubMed: 10449770). gp100 is a lineage-specific protein involved in melanosome maturation and is highly overexpressed in most melanoma tissues, making it a viable target for immunotherapy (UniProt: P40967). The most prominent therapeutic application of this TCR is Tebentafusp, a bispecific gp100-specific TCR-anti-CD3 fusion protein approved for the treatment of HLA-A*02:01-positive metastatic uveal melanoma (FDA: Kimmtrak). By bridging T-cells and melanoma cells, the TCR facilitates directed lysis of the tumor through the release of perforins and granzymes. Clinical use requires patients to be HLA-A*02:01 positive, as the TCR recognition is strictly MHC-restricted. Common safety concerns include cytokine release syndrome and on-target off-tumor effects such as vitiligo and skin rash, resulting from the presence of gp100 in normal melanocytes. This TCR represents a breakthrough in targeting intracellular antigens, which are typically inaccessible to conventional monoclonal antibodies.

Other names

gp100-specific TCRHLA-A*02:01-restricted gp100 TCRPMEL-specific T-cell receptorgp100:280-288 TCRMelanoma gp100-specific T-cell receptors recognizing HLA-A*0201–gp100:280-288

T-cell redirection and activation via binding of the TCR domain to the HLA-A*02:01-gp100 peptide complex on tumor cells and the CD3 domain to T-cells.