Major histocompatibility complex class I presenting Wilms' tumor 1 peptide (WT1-pMHC)

The MHC peptide-binding groove presenting Wilms' tumor 1 (WT1)-derived epitopes is a specialized molecular target for cancer immunotherapy, particularly for T-cell based interventions. WT1 is a zinc-finger transcription factor that plays a crucial role in cell growth and differentiation, and it is highly overexpressed in a wide range of hematological malignancies and solid tumors, leading to its ranking by the National Cancer Institute as a top priority cancer antigen (Cheever et al., Clin Cancer Res, 2009; UniProt P19544). As an intracellular protein, WT1 is not accessible to standard monoclonal antibodies; instead, it is degraded into peptides, such as the immunodominant RMFPNAPYL sequence, which are then presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01 (Dao et al., Sci Transl Med, 2013; Sugiyama, Jpn J Clin Oncol, 2010). This peptide-MHC (pMHC) complex acts as a specific marker for malignant cells, allowing them to be targeted by engineered T-cell receptors (TCR-T) or TCR-mimetic antibodies that recognize the complex with high specificity (Sellas Life Sciences; Astellas Pharma). Current therapeutic developments targeting this complex include peptide vaccines like Galinpepimut-S, which aim to stimulate an endogenous immune response, and advanced cellular therapies designed to bypass immune tolerance. However, safety remains a concern due to low-level WT1 expression in normal tissues such as renal podocytes and hematopoietic stem cells, which can lead to on-target off-tumor toxicities (Oka et al., Sci Rep, 2017).

Other names

WT1-HLA complexHLA-A*02:01/WT1(RMFPNAPYL) complexWilms' tumor 1 peptide-MHC complexpMHC-WT1WT1-HLA-A*02:01 complex

Recognition of the peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to trigger cytotoxic immune responses against tumor cells.