Glycoprotein 100 peptide presented by Human Leukocyte Antigen A*02:01 (gp100/HLA-A*02:01)

The gp100 peptide presented by HLA-A*02:01 is a peptide-major histocompatibility complex (pMHC) that serves as a critical neoantigen target in melanoma immunotherapy (Nathan et al., 2022, NEJM). Glycoprotein 100 (gp100), encoded by the PMEL gene, is a transmembrane glycoprotein essential for the formation of melanosomes in melanocytes (UniProt P40967). In melanoma cells, gp100 is proteolytically processed into peptides, such as the immunodominant gp100(280-288) epitope, which are presented on the cell surface by the HLA-A*02:01 molecule (Liddy et al., 2012, Nature Medicine). This specific pMHC complex is the target for tebentafusp (Kimmtrak), the first T-cell receptor (TCR) therapeutic approved by the FDA for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (FDA, 2022). Tebentafusp functions as an Immune Mobilizing Monoclonal TCR Against Cancer (ImmTAC), binding the gp100/HLA complex with high affinity while simultaneously engaging CD3 on T cells to trigger an anti-tumor immune response. Because gp100 is also expressed in normal melanocytes in the skin and eye, therapeutic targeting can result in on-target off-tumor toxicities, including rash and pigmentary changes (Middleton et al., 2020, Clinical Cancer Research). The clinical success of targeting this complex highlights the potential of TCR-based therapies to address intracellular antigens that are otherwise inaccessible to traditional antibody-based approaches.

Other names

gp100:280-288/HLA-A*02:01PMEL peptide/HLA-A*02:01 complexMelanocyte protein PMEL peptide/HLA-A*02:01gp100-HLA-A2 complexYLEPGPVTA/HLA-A*02:01

Redirection of T cells to target cells expressing the gp100 peptide-HLA complex via bispecific T-cell receptor (TCR) fusion proteins.