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

The Preferentially expressed antigen in melanoma (PRAME)–Human leukocyte antigen (HLA) peptide complex is a critical therapeutic target in immuno-oncology, enabling the immune system to recognize intracellular tumor-associated antigens. PRAME is a member of the cancer-testis antigen family, which is normally expressed in immune-privileged sites like the testes but is aberrantly overexpressed in a wide range of malignancies, including melanoma, uveal melanoma, acute myeloid leukemia, and various solid tumors. Intracellular PRAME proteins are degraded into short peptides, such as SLLQHLIGL or ALYVDSLFFL, which are then presented on the cell surface by HLA class I molecules, particularly HLA-A*02:01. This complex serves as a specific flag for T-cell receptors (TCRs), allowing for the development of therapies that bypass the limitations of conventional antibodies restricted to surface proteins. Current therapeutic strategies targeting this complex include TCR-engineered T-cell therapies (e.g., IMA203) and bispecific T-cell engagers known as ImmTACs (e.g., brenetafusp), which redirect cytotoxic T cells to kill PRAME-expressing cells. Clinical trials have shown promising efficacy, including durable responses and reductions in circulating tumor DNA across multiple tumor types. However, safety concerns such as cytokine release syndrome and potential off-target reactivity in normal tissues with low PRAME expression, such as kidney tubules, are significant considerations in drug development. Successful targeting requires precise patient selection based on both PRAME expression and the presence of the specific HLA restriction element.

Other names

PRAME-pHLAPRAME-MHC complexPRAME-HLA-A2 complexPRAME-derived peptide-HLA complexPRAME-HLA-A*02:01 peptide complex

T-cell redirection and activation via TCR-mediated recognition of the peptide-HLA complex on tumor cells, leading to targeted cytolysis.