Wilms' tumor 1-derived peptide–Major Histocompatibility Complex (WT1-pMHC)

The Wilms' tumor 1 (WT1)-derived peptide–Major Histocompatibility Complex (MHC) is a cell-surface target formed when intracellular WT1 proteins are processed and presented by MHC class I molecules, most commonly HLA-A*02:01 [1]. WT1 is a zinc-finger transcription factor that is highly overexpressed in a variety of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors like mesothelioma and ovarian cancer [2][3]. In healthy adults, WT1 expression is limited to specific tissues such as the renal podocytes, mesothelial cells, and a subset of hematopoietic stem cells, providing a therapeutic window for targeting [1][4]. Because the target is an intracellular protein presented as a peptide fragment, it is inaccessible to standard monoclonal antibodies and instead requires specialized modalities like T-cell receptor (TCR)-engineered T-cells or TCR-like antibodies [5]. These therapies are designed to recognize the specific conformational shape of the WT1 peptide nestled within the MHC groove, triggering a potent and directed cytotoxic immune response against the cancer cell [5][6]. Clinical development of agents targeting this complex aims to harness this specificity to treat refractory cancers while monitoring for potential on-target toxicities in the kidneys and bone marrow [4][6]. Sources: [1] UniProt (P19544); [2] NCI Priority List (2009); [3] Journal of Hematology & Oncology (2021); [4] Blood (2018); [5] Science Translational Medicine (2013); [6] Nature Medicine (2019).

Other names

WT1-HLA complexWT1 peptide-MHCWT1-MHC class I complexWT1-HLA-A*02:01

Recognition and binding of the peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-like antibodies, leading to T-cell activation and targeted lysis of tumor cells.