Glycoprotein 100 peptide-HLA-A*0201 complex (gp100/HLA-A*0201)

The gp100/HLA-A*0201 complex is a specific peptide-major histocompatibility complex (pMHC) that serves as a critical therapeutic target in melanoma, particularly uveal melanoma. Glycoprotein 100 (gp100), also known as PMEL, is a melanocyte-lineage protein involved in melanosome biogenesis and is highly overexpressed in malignant melanoma cells (UniProt P40967). A specific 9-amino acid peptide from gp100 (YLEPGPVTA) is processed and presented on the cell surface by the HLA-A*02:01 allele, a common human leukocyte antigen (NIH.gov). This complex is recognized by specialized T-cell receptors (TCRs), which can be engineered into soluble bispecific molecules or used in TCR-engineered T-cell (TCR-T) therapies. The most prominent drug targeting this complex is Tebentafusp, an ImmTAC (Immune mobilizing monoclonal TCR Against Cancer) that consists of a high-affinity TCR fused to an anti-CD3 effector domain (Nathan et al., 2021, NEJM). By binding the gp100/HLA-A*0201 complex on tumor cells and CD3 on T cells, these therapies redirect polyclonal T cells to exert cytotoxic activity against melanoma cells. Clinical use of these agents requires patients to be HLA-A*02:01 positive, making the HLA genotype a mandatory companion diagnostic biomarker (FDA Label: Kimmtrak). Safety concerns primarily involve cytokine release syndrome and skin-related toxicities due to the presence of gp100-expressing melanocytes in healthy skin (Damato et al., 2023, J. Hematol. Oncol.).

Other names

PMEL/HLA-A*0201gp100-HLA complexYLEPGPVTA/HLA-A*02:01 complexMelanocyte protein PMEL peptide-MHC complex

T-cell redirection via bispecific TCR-anti-CD3 fusion protein