Wilms tumor protein 1 (WT1) peptide 126-134–HLA-A*02:01 complex (WT1_126-134/HLA-A2 complex)

The Wilms tumor protein 1 (WT1) peptide 126-134–HLA-A*02:01 complex consists of the HLA-A*02:01 (HLA-A2) molecule presenting the WT1-derived nonapeptide RMFPNAPYL (residues 126-134), forming a conformational epitope recognized by CD8+ T cells. WT1, a transcription factor overexpressed in numerous hematologic malignancies like acute myeloid leukemia and solid tumors, makes this peptide–MHC complex a key tumor-associated antigen for immunotherapy. Crystal structures (PDB: 3HPJ) reveal the peptide in an extended conformation within the HLA-A2 groove, with solvent-exposed residues enabling T cell receptor (TCR) interaction, while variants like R1Y (YMFPNAPYL) enhance MHC affinity via electrostatic changes but risk altering TCR specificity. TCR-mimic antibodies targeting this complex, such as affinity-matured scFvs (e.g., Q2L), bind with high specificity to induce ADCC against WT1-expressing tumor cells, showing antitumor efficacy in preclinical models. Therapeutic strategies include peptide vaccines and TCR-like immunotherapies, though challenges like cross-reactivity with normal HLA-A2+ cells (e.g., PBMCs) and trial hypersensitivities necessitate careful epitope validation using platforms like PresentER. Overall, this complex holds promise as a precise target for HLA-A*02:01-restricted cancer immunotherapies targeting intracellular oncoproteins.

Other names

WT1 126 epitope–HLA-A*0201 complexWT1_126 (RMFPNAPYL)–HLA-A2 complexWT1 peptide–HLA-A02 complex

TCR-mimic antibody binding for antibody-dependent cellular cytotoxicity (ADCC); T cell receptor (TCR) engagement for immunotherapy