Wilms tumor protein 1-derived peptide–MHC complex (WT1-MHC complex) (WT1-MHC complex)

The Wilms tumor protein 1 (WT1)-derived peptide–MHC complex is a tumor-associated antigen (TAA) presented on the surface of malignant cells. It consists of short peptide fragments derived from the intracellular WT1 transcription factor, bound to Major Histocompatibility Complex (MHC) class I molecules, most frequently HLA-A*02:01 (UniProt P19544). While WT1 is essential for embryonic development, its expression in healthy adults is restricted to low levels in specific tissues like the kidney and bone marrow (Cheever et al., 2009). In contrast, WT1 is highly overexpressed in various leukemias and solid tumors, making the peptide-MHC complex a specific target for immunotherapy. Therapeutic strategies include peptide vaccines like Galinpepimut-S and DSP-7888, which aim to induce an endogenous cytotoxic T-lymphocyte response (SELLAS Life Sciences; Sumitomo Pharma). Additionally, advanced modalities such as TCR-engineered T-cells (TCR-T) and TCR-mimic (TCRm) antibodies are designed to recognize the complex with high affinity (Dao et al., 2013). These therapies aim to bypass the limitations of targeting intracellular proteins by focusing on the surface-presented peptide fragments. The primary clinical challenge involves HLA restriction, which limits these therapies to patients with compatible MHC alleles. There is also a potential for on-target off-tumor toxicity in tissues where WT1 is expressed at low levels. Overall, the WT1-MHC complex represents a high-priority target for precision oncology.

Other names

WT1-HLA complexWilms tumor 1 peptide-MHC complexWT1-pMHCWT1-HLA-A*02:01 complexWilms tumor protein 1-derived peptide–HLA-A*02:01 complex

Binding of T-cell receptors or TCR-mimic antibodies to the specific peptide-MHC interface to induce targeted cytotoxicity.