T cell receptor recognizing HLA-A*0201–gp100:280-288 complex (TCR-gp100:280-288)

The T cell receptor (TCR) recognizing the HLA-A*0201–gp100:280-288 complex is a specialized immune receptor designed to identify a specific peptide fragment (YLEPGPVTA) of the gp100 protein (also known as PMEL) presented by the HLA-A*02:01 major histocompatibility complex (MHC) class I molecule (Nathan et al., 2021, NEJM). gp100 is a melanocyte-lineage specific protein that is highly overexpressed in most melanoma cells, making it a prominent target for immunotherapy (Kawakami et al., 1994, PNAS). This specific TCR serves as the targeting mechanism for advanced therapies such as Tebentafusp, a bispecific gp100-peptide-HLA-directed T cell engager, and various TCR-engineered T cell (TCR-T) therapies (Morgan et al., 2006, Science). When the TCR binds to its cognate peptide-MHC complex on a tumor cell, it facilitates the formation of an immunological synapse, leading to T cell activation and the subsequent destruction of the cancer cell through the release of perforins and granzymes (Damato et al., 2019, Expert Opin Investig Drugs). However, because gp100 is also expressed in normal melanocytes, therapeutic interventions targeting this complex often result in on-target, off-tumor toxicities affecting the skin, eyes, and ears (Kimmtrak Prescribing Information). Clinical applications of this target have shown significant efficacy in treating metastatic uveal melanoma, a disease with historically limited treatment options (Nathan et al., 2021, NEJM). The high specificity of this TCR for the HLA-A*02:01 allele restricts its therapeutic use to patients carrying this specific genotype (Kimmtrak Prescribing Information).

Other names

gp100-specific T cell receptorHLA-A*02:01-restricted gp100 TCRPMEL-specific TCRgp100:280-288-specific TCRT cell receptor recognizing HLA-A*02:01-gp100(280-288)

T cell redirection and activation via bispecific TCR-anti-CD3 fusion or TCR-engineered T cell therapy