Human leukocyte antigen A*02:01 presenting Wilms' tumor 1 peptide RMFPNAPYL (HLA-A*02:01/WT1(126-134))

The HLA-A*02:01 presenting WT1 RMFPNAPYL peptide complex is a specific peptide-major histocompatibility complex (pMHC) class I molecule that serves as a critical target for cancer immunotherapy (Cheever et al., 2009, Clinical Cancer Research). The Wilms' tumor 1 (WT1) protein is an intracellular transcription factor that is highly overexpressed in various hematological malignancies, such as acute myeloid leukemia (AML), and several solid tumors, while maintaining low expression in normal tissues. Because WT1 is an intracellular protein, it cannot be targeted by traditional antibodies; however, its degradation products, such as the RMFPNAPYL epitope (residues 126-134), are presented on the cell surface by HLA molecules (Oka et al., 2000, Immunogenetics). This specific pMHC complex is recognized by specific T-cell receptors (TCRs), making it a focal point for the development of TCR-engineered T-cell therapies and peptide vaccines like Galinpepimut-S (Maslak et al., 2018, Blood Advances). Additionally, TCR-mimic antibodies like ESK1 have been engineered to bind this specific pMHC complex with high affinity, providing a way to target intracellular antigens with antibody-based modalities (Dao et al., 2013, Science Translational Medicine). Therapeutic engagement of this target aims to induce a potent cytotoxic T-lymphocyte response against tumor cells while sparing normal tissues. Clinical challenges include the potential for on-target off-tumor toxicity in tissues like the kidney or bone marrow where low levels of WT1 may be present.

Other names

HLA-A*02:01/WT1 RMFPNAPYL complexWT1-A2 complexHLA-A*02:01/WT1(126)pMHC HLA-A*02:01/WT1MHC-restricted WT1 epitope

T-cell receptor (TCR) binding leading to T-cell mediated cytotoxicity; TCR-mimic antibody binding leading to antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).