Mutated nucleophosmin 1 peptide–HLA-A*02:01 complex (ΔNPM1-HLA-A*02:01)

The mutated nucleophosmin 1 (ΔNPM1) peptide–HLA-A*02:01 complex is a tumor-specific neoantigen target primarily expressed on the surface of acute myeloid leukemia (AML) cells (Van der Lee et al., Cancer Cell, 2019). NPM1 mutations occur in approximately 30% of AML cases, characterized by a 4-base pair insertion in exon 12 that leads to a frameshift and a novel C-terminal protein sequence (NPM1c). This mutated protein is localized to the cytoplasm and undergoes proteasomal degradation, resulting in the presentation of unique peptides like CLAVEEVSL on the cell surface via HLA-A*02:01 (Greiner et al., Blood, 2012). As a neoantigen, this complex is absent from healthy tissues, providing a high degree of tumor specificity and reducing the risk of on-target, off-tumor toxicity. The target is particularly valuable because NPM1 mutations are considered founder mutations that are stable during disease progression and present in leukemic stem cells. Therapeutic approaches targeting this complex include T-cell receptor-engineered T-cell (TCR-T) therapies, such as MDG1021, and TCR-mimetic bispecific antibodies (Medigene AG, 2021). These agents are designed to recognize the specific peptide-MHC configuration and trigger a potent cytotoxic immune response against the leukemia.

Other names

NPM1c-HLA-A*02:01Mutated NPM1-HLA-A2 complexCLAVEEVSL-HLA-A*02:01 complexNPM1-mutant neoantigenNPM1c peptide-MHC complex

Recognition of the neoantigen peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to induce targeted T-cell mediated lysis of leukemic cells.