Preferentially expressed antigen in melanoma-derived peptide-MHC complex (PRAME-MHC) (PRAME-MHC)

Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen (CTA) that is highly expressed in a wide range of solid tumors and hematological malignancies, while its expression in normal tissues is largely restricted to the testis (UniProt P78395). Because PRAME is an intracellular protein, it is not accessible to conventional antibody-based therapies; instead, it is processed into peptides and presented on the cell surface in complex with Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01 (PubMed: 33055371). These PRAME-peptide-MHC complexes serve as specific targets for T-cell receptor (TCR)-based immunotherapies, including TCR-engineered T cells (TCR-T) and TCR-bispecific molecules. Drugs like IMA203 are designed to recognize these complexes with high affinity, triggering a potent cytotoxic immune response against the tumor cells (Immatics, 2023). This targeting strategy allows for the precision of cellular therapy to be applied to intracellular oncogenic drivers that were previously considered undruggable. The clinical success of targeting PRAME-MHC complexes depends on both the high expression of the PRAME protein in tumor cells and the presence of the specific HLA restriction element in the patient.

Other names

PRAME-HLA complexPRAME-peptide-HLA-A*02:01 complexPRAME-MHC class I complexCancer-testis antigen PRAME-MHC

Recognition of the PRAME peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-bispecific molecules, leading to T-cell activation, secretion of cytotoxic cytokines, and direct lysis of tumor cells (PubMed: 33055371).