Preferentially expressed antigen in melanoma-derived peptide–Human leukocyte antigen class I complex (PRAME-HLA-I complex)

The PRAME-derived peptide–Human leukocyte antigen (HLA) class I complex is a molecular target consisting of a peptide fragment from the Preferentially Expressed Antigen in Melanoma (PRAME) protein bound to an HLA class I molecule, most commonly HLA-A*02:01 (UniProt P78395). PRAME is a cancer-testis antigen that is highly expressed in various malignancies—including melanoma, acute myeloid leukemia, and uveal melanoma—while remaining largely absent in healthy adult tissues except for the testes (PubMed: 10359808). This differential expression makes the PRAME-HLA complex an ideal target for immunotherapy, as it allows for the selective destruction of cancer cells by the immune system (Immatics, 2024). Therapeutic strategies targeting this complex include T-cell receptor (TCR) engineered T-cell therapies, such as IMA203, and bispecific TCR molecules like IMC-F106C that redirect T-cells to recognize and kill cells presenting these specific peptide-MHC complexes (Immunocore, 2024; ClinicalTrials.gov: NCT03686124). By utilizing natural immune recognition mechanisms, these drugs aim to overcome the limitations of traditional antibody-based therapies which cannot target intracellular proteins like PRAME. The complex serves as a critical bridge between the intracellular proteome of the cancer cell and the extracellular recognition machinery of the immune system. Its role in disease is primarily as a tumor-associated antigen that facilitates immune recognition when targeted by synthetic receptors. Safety concerns associated with targeting this complex include cytokine release syndrome (CRS) and potential on-target off-tumor toxicity if the target peptide is expressed at low levels in vital tissues. Overall, the PRAME-HLA complex represents a cornerstone of modern precision oncology in the field of TCR-based therapeutics.

Other names

PRAME-MHC class I complexPRAME/HLA-A*02 complexPRAME-peptide-HLA complexPRAME-HLA-A2PRAME-HLA-A*02:01

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex, leading to T-cell activation, cytokine release, and targeted lysis of the tumor cell.