HLA-A*02:01-presented peptidome (excluding WT1) (HLA-A*02:01 peptidome)

The term "Non-WT1 peptides presented by HLA-A*02:01" refers to the diverse collection of endogenous peptides, derived from the normal cellular proteome, that are displayed on the cell surface by the Human Leukocyte Antigen (HLA) allele A*02:01. While the Wilms Tumor 1 (WT1) protein is a highly validated tumor-associated antigen, its specific epitopes (such as RMFPNAPYL) represent only a minute fraction of the total HLA-A*02:01 peptidome. In the development of immunotherapies like TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers, these non-WT1 peptides constitute the primary source of off-target safety risks. If a drug designed to target the WT1/HLA-A*02:01 complex cross-reacts with a similar-looking non-WT1 peptide expressed in vital organs, it can lead to severe or fatal autoimmune-like toxicities. Consequently, the characterization of this background peptidome is essential for the specificity screening and lead optimization of any WT1-targeted therapeutic agent.

Other names

Non-WT1 HLA-A*02:01 ligandsHLA-A*02:01 self-peptidomeOff-target HLA-A*02:01 epitopesCross-reactive HLA-A*02:01 peptidesHLA-A*02:01-peptide complex

These peptides serve as potential off-targets for T-cell receptors (TCRs) or TCR-mimic antibodies designed to recognize the WT1/HLA-A*02:01 complex; therapeutic agents must distinguish between the target WT1 epitope and this background peptidome to avoid cross-reactivity.