Myeloid cancer peptide-HLA complex (pMHC)

The myeloid cancer peptide-HLA complex is a class of therapeutic targets consisting of intracellularly derived peptides presented on the cell surface by Human Leukocyte Antigen (HLA) molecules. In myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), specific proteins like Wilms' Tumor 1 (WT1), Proteinase 3 (PR1), and PRAME are often overexpressed or mutated, resulting in the presentation of unique peptide-HLA complexes that are absent or minimally expressed on healthy tissues (1.1.2, 1.2.2, 1.3.4). These complexes are naturally recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T lymphocytes, making them highly specific targets for advanced immunotherapies (1.5.1, 1.5.2). Current therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, TCR-like monoclonal antibodies (mAbs), and peptide vaccines designed to induce or mimic natural immune recognition (1.1.4, 1.2.3, 1.3.5). For example, TCR-like antibodies such as ESK1 and Hu8F4 bind specifically to the peptide-HLA complex rather than the protein alone, allowing for the targeting of intracellular antigens that were previously considered undruggable (1.1.2, 1.2.3). While these therapies offer the potential to eliminate leukemic stem cells with high precision, significant challenges include the requirement for specific HLA haplotypes (most commonly HLA-A*02:01) and the risk of off-target effects if the target peptide is presented by normal cells (1.2.2, 1.5.4).

Other names

Leukemia-associated antigen (LAA) peptide-HLA complexPeptide-MHC complexTCR-like antibody targetpMHC targetWT1-HLA complexPR1-HLA complexPRAME-HLA complexNPM1-mutant peptide-HLA complex

Recognition of intracellularly derived peptides presented on the cell surface by HLA molecules, leading to targeted lysis of myeloid cancer cells via T-cell receptor (TCR) engagement, T-cell redirection, or antibody-dependent cellular cytotoxicity (ADCC).