Wilms' tumor protein (WT1) peptide-Human leukocyte antigen (HLA) A*02:01 complex (WT1-HLA-A*02:01)

Wilms' tumor protein (WT1) is a zinc-finger transcription factor that plays a crucial role in the normal development of the urogenital system but is frequently overexpressed in various hematological malignancies and solid tumors (UniProt P19544). Although WT1 is primarily an intracellular protein, it is processed by the proteasome into peptide fragments, such as the RMFPNAPYL decamer, which are subsequently presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules, specifically HLA-A*02:01 (Dao et al., 2013). The ESK1 BiTE is a bispecific T-cell engager designed to recognize this specific WT1 peptide-HLA complex using a T-cell receptor (TCR)-mimetic antibody fragment. By simultaneously binding the WT1-HLA complex on tumor cells and the CD3 receptor on T cells, the BiTE molecule facilitates the formation of an immunological synapse, leading to T-cell activation and the targeted lysis of cancer cells (Veomett et al., 2014). This therapeutic approach is significant because it allows for the targeting of an 'undruggable' intracellular oncogenic protein using antibody-based technology. Clinical development focuses on HLA-A*02:01-positive patients with WT1-expressing cancers, such as acute myeloid leukemia and mesothelioma, where the target is highly prevalent.

Other names

WT1-A2 complexRMFPNAPYL-HLA-A*02:01Wilms tumor 1WT1

T-cell redirection and activation via bispecific binding to the WT1 peptide-HLA complex on target cells and the CD3 receptor on T-cells