Peptide–Human Leukocyte Antigen A*0201 complex (pHLA-A*0201)

Peptide–Human Leukocyte Antigen A*0201 (HLA-A*0201) complexes presenting melanoma-associated antigens are specialized molecular structures on the surface of melanoma cells that serve as primary targets for T-cell-based immunotherapies. These complexes are formed when intracellular melanoma-specific proteins, such as gp100, MART-1, or MAGE-A4, are processed into short peptides and loaded onto the HLA-A*02:01 molecule for presentation to the immune system [PMID: 31040119]. The biological role of these complexes is to signal the presence of malignant transformation to CD8+ cytotoxic T cells via their T-cell receptors (TCRs) [PMID: 29374069]. In the context of drug development, these complexes are targeted by TCR-engineered T-cells and bispecific molecules like Tebentafusp, which bridge the tumor cell and T-cells to induce cell lysis [PMID: 35108470, PMID: 34551227]. Because these targets are highly specific to the peptide-HLA combination, they offer a way to target intracellular antigens that are otherwise inaccessible to traditional antibody therapies. However, their use is restricted to patients who carry the HLA-A*02:01 allele, which is a major limitation in patient eligibility [PMID: 31040119]. Safety concerns include cytokine release syndrome and potential on-target, off-tumor toxicity if the presented antigen is found in healthy tissues [PMID: 23940004]. Overall, these complexes represent a cornerstone of precision oncology in melanoma.

Other names

HLA-A*02:01-peptide complexMHC-peptide complexMelanoma antigen-MHC complexHLA-A2-peptide complexpMHC complex

These complexes are targeted by drugs that utilize engineered T-cell receptors (TCRs) or TCR-like bispecific molecules to recognize the specific peptide-MHC interface, thereby activating or redirecting T-cells to eliminate the antigen-presenting tumor cells.