Human leukocyte antigen class I complexed with melanoma-associated antigen peptides (HLA-I/Melanoma Peptide Complex)

Human leukocyte antigen (HLA) class I molecules presenting melanoma-derived peptides are specialized protein complexes that display intracellular tumor antigens on the cell surface for recognition by the immune system (PMID: 31913352). These complexes are composed of an HLA heavy chain, beta-2 microglobulin, and a short peptide fragment derived from melanoma-associated antigens such as gp100, MART-1, or MAGE-A3 (UniProt P01889, P40306). In oncology, these peptide-MHC (pMHC) complexes serve as highly specific targets for T-cell receptor (TCR) based therapies, including engineered T-cells and bispecific T-cell engagers (PMID: 34554662). A prominent example is Tebentafusp, a bispecific protein that redirects T cells to kill melanoma cells by binding specifically to the HLA-A*02:01/gp100 complex (FDA Label: Kimmtrak). This targeting strategy allows the immune system to bypass traditional cell-surface protein requirements, accessing the intracellular proteome of the cancer cell (PMID: 33441437). However, therapeutic success depends on the patient's HLA genotype, most commonly requiring the HLA-A*02:01 allele for current approved therapies (PMID: 34554662). Safety concerns include on-target off-tumor toxicities, such as skin and ocular inflammation, because the targeted peptides may be expressed in healthy melanocytes (PMID: 33441437). Additionally, tumors may develop resistance through the downregulation of HLA molecules or mutations in the antigen processing and presentation pathway (PMID: 29242105).

Other names

pMHC complexHLA-A*02:01/gp100HLA-A*02:01/MART-1MHC class I-peptide complexMelanoma antigen-presenting HLA

T-cell receptor (TCR) mediated recognition and bispecific T-cell engagement