Mutant Nucleophosmin 1 peptide-HLA complex (Mutant NPM1-HLA)

The Mutant Nucleophosmin 1 (NPM1) peptide-HLA complex is a highly specific neoantigen target found in approximately 30% of adult Acute Myeloid Leukemia (AML) cases (van der Lee et al., 2019, Cancer Cell). Mutations in the NPM1 gene, primarily a 4-base pair insertion in exon 12, cause a frameshift that generates a unique C-terminal sequence and leads to the cytoplasmic localization of the protein (NPM1c). This mutant sequence is processed by the proteasome into neoantigenic peptides, such as the 9-mer CLAVEEVSL, which are then presented on the cell surface by Human Leukocyte Antigen (HLA) molecules, specifically HLA-A*02:01 (Hagedoorn et al., 2021, Blood). Because this peptide-HLA complex is exclusively expressed by leukemic cells and not by healthy tissues, it represents an ideal target for T-cell receptor (TCR)-based therapies, including TCR-engineered T cells (TCR-T) and TCR-like bispecific antibodies (Medigene AG, 2024). These therapies are designed to recognize the specific peptide-MHC configuration, triggering a potent and selective immune response against the leukemia. Current clinical strategies involve screening patients for both the NPM1 mutation and the compatible HLA allele to ensure therapeutic efficacy and minimize off-target risks. This target offers a promising avenue for personalized immunotherapy in patients with refractory or relapsed AML.

Other names

NPM1c-HLA complexMutant NPM1 neoantigenNPM1-mutant peptide-MHC complexCLAVEEVSL-HLA-A*02:01 complexNPM1-mutant neoepitope

Targeted T-cell mediated cytotoxicity via T-cell receptor (TCR) recognition of the mutant peptide-HLA complex on the surface of leukemic cells.