Preferentially expressed antigen in melanoma peptide-Human leukocyte antigen complex (PRAME-HLA complex)

The PRAME peptide-HLA complex is a tumor-associated antigen complex consisting of peptides derived from the Preferentially Expressed Antigen in Melanoma (PRAME) protein presented on the cell surface by Human Leukocyte Antigen (HLA) molecules, most commonly HLA-A*02:01 [1, 6, 12]. PRAME is a member of the cancer-testis antigen family, characterized by high expression in various malignancies—including melanoma, acute myeloid leukemia, and non-small cell lung cancer—while remaining largely absent in healthy adult tissues except for the testes and ovaries [1, 16]. Because PRAME is an intracellular protein, it cannot be targeted by traditional monoclonal antibodies; however, its proteasomal degradation products (such as the SLLQHLIGL or ALYVDSLFFL peptides) are displayed by HLA class I molecules, making the complex a viable target for T-cell receptor (TCR)-based therapies [4, 6, 13]. Therapeutic strategies targeting this complex include TCR-bispecific ImmTAC molecules like brenetafusp (IMC-F106C), which redirect T cells to kill tumor cells, and adoptive TCR-engineered T-cell therapies like IMA203 and MDG1011 [2, 10, 23, 29]. Clinical development of these agents has shown promise in treating advanced solid tumors and hematological malignancies, though challenges such as cytokine release syndrome and HLA downregulation remain [11, 24, 35].

Other names

PRAME-MHC complexPRAME pMHCPRAME-HLA-A*02:01 complexSLLQHLIGL-HLA-A*02:01 complexALYVDSLFFL-HLA-A*02:01 complexPRAME-HLA-A2 complex

T-cell redirection and activation through specific recognition of the peptide-HLA complex by engineered T-cell receptors (TCRs) or TCR-bispecific molecules, leading to targeted lysis of tumor cells.