Melanocyte protein PMEL peptide-MHC complex (gp100-MHC)

The gp100 peptide–MHC complex is a tumor-associated antigen consisting of a specific peptide fragment derived from the Melanocyte protein PMEL (also known as gp100 or Pmel17) presented on the cell surface by Major Histocompatibility Complex (MHC) Class I molecules, most commonly HLA-A*02:01 (UniProt P17667). gp100 is a transmembrane glycoprotein involved in the structural organization of melanosomes, and its expression is largely restricted to melanocytes and melanoma cells (PubMed: 11087664). Because of this restricted expression and high prevalence in melanoma, the gp100 peptide-MHC complex serves as a primary target for T-cell-based immunotherapies. Therapeutic targeting of this complex is exemplified by tebentafusp (Kimmtrak), a first-in-class bispecific T-cell receptor (TCR) fusion protein. Tebentafusp utilizes a high-affinity TCR domain to recognize the gp100 peptide presented by HLA-A*02:01 and an anti-CD3 effector domain to recruit and activate polyclonal T cells against the tumor (FDA Label: Kimmtrak). While effective in treating uveal melanoma, targeting this complex can lead to 'off-tumor, on-target' toxicities such as vitiligo and skin rashes due to the presence of gp100 in healthy melanocytes, as well as systemic cytokine release syndrome resulting from T-cell activation (PubMed: 34554639).

Other names

gp100-HLA-A*02:01 complexPMEL-MHC complexSilver locus protein-MHC complexgp100-HLA-A2 complexMelanocyte-specific protein Pmel 17 peptide-MHC complex

T-cell redirection via bispecific TCR-CD3 fusion proteins (ImmTACs) that bind the peptide-MHC complex, or direct T-cell activation via peptide-based vaccines and TCR-engineered T-cell therapies (PubMed: 34554639, 21632993).