Preferentially expressed antigen in melanoma (PRAME)-derived peptide presented by HLA-A*02:01 (PRAME/HLA-A*02:01)

Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is highly expressed in various solid and hematological malignancies but has restricted expression in normal tissues, primarily the testes and ovaries [2, 3, 16, 20]. As an intracellular protein, PRAME is not accessible to traditional antibody therapies; instead, it is processed into peptides and presented on the cell surface by Major Histocompatibility Complex (MHC) Class I molecules, such as HLA-A*02:01 [3, 16, 27]. The specific peptide-MHC (pMHC) complex, particularly the PRAME 425-433 (SLLQHLIGL) epitope presented by HLA-A*02:01, serves as a potent target for T-cell receptor (TCR)-based immunotherapies [3, 22, 25, 27]. Drugs targeting this complex, including TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (ImmTACs), are designed to recognize the pMHC with high affinity and redirect T-cell cytotoxicity against tumor cells [1, 9, 11, 18, 20]. This target is currently being evaluated in clinical trials for a range of solid tumors, including cutaneous and uveal melanoma, ovarian cancer, and synovial sarcoma [9, 11, 14, 15, 28]. Therapeutic strategies often involve the use of soluble TCRs fused to anti-CD3 domains or the genetic modification of autologous T cells to express PRAME-specific TCRs [1, 11, 18, 20]. Clinical efficacy has been demonstrated through objective tumor responses and reductions in circulating tumor DNA in heavily pretreated patient populations [11, 14, 15]. Safety considerations for therapies hitting this target include managing cytokine release syndrome and potential neurotoxicity, as well as ensuring high specificity to prevent off-target reactivity with similar peptides in healthy tissues [11, 14, 17, 27].

Other names

PRAME 425-433/HLA-A*02:01 complexSLLQHLIGL/HLA-A*02:01PRAME-A2 complexPRAME pMHCPRAME-derived peptide/HLA-A*02:01 complex

T-cell redirection and TCR-mediated cytotoxicity via recognition of the peptide-MHC complex