Terminal deoxynucleotidyl transferase-derived peptide presented by HLA-A*02:01 (TdT/HLA-A*02:01)

The Terminal deoxynucleotidyl transferase (TdT)-derived peptide presented by HLA-A*02:01 is a specialized immunotherapy target used primarily in the treatment of hematologic malignancies. TdT (encoded by the DNTT gene) is an intracellular enzyme responsible for adding non-templated nucleotides during V(D)J recombination, and it is highly expressed in over 80-90% of acute lymphoblastic leukemias (ALL) but absent in mature lymphocytes and other healthy tissues (Ali et al., Nature Medicine, 2017; UniProt P04053). Because TdT is an intracellular protein, it cannot be targeted by conventional monoclonal antibodies; however, its degradation products are presented as peptides on the cell surface by the Major Histocompatibility Complex (MHC) class I molecule HLA-A*02:01 (IMGT/HLA Database). This peptide-MHC (pMHC) complex serves as a specific epitope for engineered T-cell receptors (TCRs), allowing T-cells to identify and eliminate leukemic cells while sparing most healthy cells. Therapeutic strategies, such as KITE-439, utilize TCR-engineered T-cells (TCR-T) to bind this complex, triggering a potent cytotoxic immune response (Gilead Sciences Pipeline, 2023). This target is particularly valuable for treating relapsed or refractory B-cell and T-cell ALL, offering a high degree of tumor specificity due to the restricted expression profile of the TdT enzyme.

Other names

TdT-pMHCDNTT-derived peptide/HLA-A*02:01TdT peptide-HLA-A2 complexTerminal transferase-derived peptide/HLA-A*02:01

Engineered T-cell receptors (TCRs) specifically recognize the TdT peptide fragment displayed by the HLA-A*02:01 molecule on the surface of leukemic cells, triggering T-cell activation, cytokine release, and direct cytotoxic killing of the target cell (Ali et al., Nature Medicine, 2017).