Premelanosome protein (PMEL) gp100 peptide gp209-2M presented by HLA-A*02:01 (gp209-2M/HLA-A*02:01)

The gp209-2M epitope is a synthetic, heteroclitic peptide derived from the premelanosome protein (PMEL/gp100), a lineage-specific protein involved in melanosome biogenesis (UniProt P40967). While the native gp100:209-217 peptide (ITDQVPFSV) binds weakly to HLA-A*02:01, the gp209-2M variant (IMDQVPFSV) incorporates a threonine-to-methionine substitution at the second position to significantly increase MHC binding affinity and T-cell activation (Parkhurst et al., 1996, Journal of Immunology). This complex is a prominent target in melanoma immunotherapy, particularly for peptide-based vaccines and adoptive cell transfer using TCR-engineered T-cells. Because PMEL expression is largely restricted to melanocytes and melanoma, it provides a relatively specific target, though it can result in on-target off-tumor toxicities in the skin and eyes. Clinical trials have demonstrated that vaccination with gp209-2M can induce significant expansion of tumor-reactive T-cells in HLA-A*02:01-positive patients (Rosenberg et al., 1998, Nature Medicine).

Other names

gp100:209-217(210M)IMDQVPFSVMelanocyte protein PMELSilver locus protein homologgp100 peptide

The gp209-2M peptide is presented by HLA-A*02:01 on the surface of melanoma cells, where it is recognized by specific T-cell receptors (TCRs) on CD8+ cytotoxic T lymphocytes. Therapeutic vaccines or TCR-engineered T-cells utilize this recognition to trigger the release of perforins and granzymes, leading to tumor cell lysis (Rosenberg et al., 1998, Nature Medicine; Parkhurst et al., 1996, Journal of Immunology).