Preferentially expressed antigen in melanoma (PRAME) peptide–major histocompatibility complex (PRAME peptide–MHC complex)

The Preferentially expressed antigen in melanoma (PRAME) peptide–major histocompatibility complex (MHC) is a specialized therapeutic target used to address intracellular oncogenic proteins through the immune system [1, 15]. PRAME is a cancer-testis antigen that normally represses retinoic acid receptor (RAR) signaling to prevent cell differentiation, a function it exploits in various malignancies to drive proliferation and survival [3, 10, 21]. As an intracellular protein, PRAME is processed into specific peptide fragments—most notably VLDGLDVLL, SLLQHLIGL, and ALYVDSLFFL—which are then presented on the cell surface by MHC Class I molecules, typically HLA-A*02:01 [6, 9, 15]. This presentation allows the complex to be recognized by T-cell receptors (TCRs), enabling the development of TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (ImmTACs) like brenetafusp (IMC-F106C) [2, 7, 14]. These therapies redirect the patient's immune system to specifically lyse PRAME-expressing tumor cells in cancers such as melanoma, uveal melanoma, and acute myeloid leukemia [8, 19, 20]. While the target offers high tumor selectivity, therapeutic development must carefully manage potential on-target off-tumor effects in tissues like the testis and adrenal glands, as well as off-target cross-reactivity with similar human peptides [1, 12, 19].

Other names

PRAME/HLA-A*02:01 complexPRAME pMHCMelanoma antigen preferentially expressed in tumors peptide complexOpa-interacting protein 4 (OIP4) peptide complexCancer testis antigen 130 (CT130) peptide complexVLDGLDVLL/HLA-A*02:01SLLQHLIGL/HLA-A*02:01ALYVDSLFFL/HLA-A*02:01

T-cell redirection and TCR-mediated cytotoxicity via recognition of intracellularly derived peptides presented on the cell surface by MHC Class I molecules.