Preferentially expressed antigen in melanoma (PRAME) presented on human leukocyte antigen (HLA) (PRAME/HLA complex)

Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen (CTA) that is predominantly expressed in the testis but aberrantly overexpressed in a wide range of solid and hematological malignancies, including melanoma, synovial sarcoma, and acute myeloid leukemia [1.2.1, 1.2.4]. Intracellularly, PRAME acts as a transcriptional repressor of retinoic acid receptor (RAR) signaling, thereby inhibiting cell differentiation and apoptosis while promoting tumor cell proliferation [1.1.1, 1.2.2]. Because PRAME is an intracellular protein, it is not accessible to conventional monoclonal antibodies; however, its proteasomally processed peptides are presented on the cell surface by human leukocyte antigen (HLA) class I molecules [1.4.1, 1.4.3]. The most common target epitope is the ALYVDSLFFL peptide presented in the context of HLA-A*02:01 [1.4.1, 1.4.2]. This peptide-HLA complex serves as a highly specific target for T-cell-based immunotherapies, such as TCR-engineered T cells (TCR-T) and TCR-bispecific engagers like ImmTACs and TCERs [1.3.1, 1.3.4]. These therapies, including candidates like IMA203 and IMC-F106C, are designed to redirect the patient's immune system to recognize and eliminate PRAME-positive tumor cells [1.3.1, 1.3.5]. While PRAME is highly tumor-selective, potential safety concerns include on-target, off-tumor toxicity due to low-level expression in healthy tissues such as the ovaries, adrenals, and kidney tubules [1.4.4, 1.5.1]. Clinical trials have demonstrated promising anti-tumor activity across multiple indications, though challenges such as HLA downregulation and cytokine release syndrome remain [1.3.1, 1.3.5].

Other names

PRAME peptide-HLA complexPRAME-HLA-A*02Melanoma antigen preferentially expressed in tumorsMAPEOIP4Opa-interacting protein 4CT130Cancer-testis antigen 130

T-cell receptor (TCR)-mediated recognition of the PRAME peptide-HLA complex, leading to T-cell activation, recruitment, and cytotoxic lysis of the target tumor cell [1.3.1, 1.4.1].