Human Leukocyte Antigen A*02:01-Glycoprotein 100(209-217) peptide complex (HLA-A2-gp100(209-217))

The Human Leukocyte Antigen A*02:01-Glycoprotein 100(209-217) peptide complex is a specific peptide-major histocompatibility complex (pMHC) that serves as a critical target for melanoma immunotherapy (Nathan et al., 2021, NEJM). It consists of the HLA-A*02:01 molecule presenting a 9-amino acid epitope (ITDQVPFSV) derived from Glycoprotein 100 (gp100/PMEL), a lineage-specific protein involved in melanosome maturation (UniProt P40967). While gp100 is expressed in normal melanocytes, its significant overexpression in melanoma cells makes this pMHC complex an attractive target for T-cell receptor (TCR)-based therapies (Rosenberg et al., 1998, Nature Medicine). Tebentafusp, a first-in-class bispecific TCR-anti-CD3 fusion protein, specifically binds this complex to redirect T-cells to attack uveal melanoma cells (FDA Kimmtrak Label, 2022). Other therapeutic approaches include peptide vaccines, such as the modified g209-2M peptide, which aim to enhance the frequency of circulating cytotoxic T-lymphocytes specific to this epitope. Clinical use of drugs targeting this complex is restricted to patients who are HLA-A*02:01 positive, as confirmed by genomic testing. Potential safety concerns include on-target off-tumor toxicities affecting healthy melanocytes in the skin and eyes, as well as systemic cytokine release syndrome.

Other names

HLA-A*02:01-PMEL(209-217)gp100:209-217/HLA-A*02:01 complexITDQVPFSV-HLA-A*02:01HLA-A2-gp100HLA-A*0201 presenting gp100:209–217 peptides

T-cell redirection via bispecific T-cell receptor (TCR)-anti-CD3 fusion proteins and induction of antigen-specific CD8+ T-cell responses through vaccination.