Human leukocyte antigen A*02:01-restricted mutated nucleophosmin 1 peptide complex (HLA-A*02:01/dNPM1)

The HLA-A*02:01/dNPM1 peptide complex is a highly specific tumor-associated neoantigen found on the surface of leukemic blasts in patients with Acute Myeloid Leukemia (AML). It consists of a neoantigenic peptide (typically CLAVEEVSL) derived from the mutated C-terminus of the Nucleophosmin 1 (NPM1) protein, which is presented by the Human Leukocyte Antigen (HLA) allele A*02:01 (van der Lee et al., 2019, Blood). NPM1 mutations, particularly the Type A frameshift, occur in approximately 30% of AML cases and result in a novel protein sequence that is entirely absent in healthy tissues, making it an ideal target for precision immunotherapy (Falini et al., 2005, NEJM). This complex is recognized by the T-cell receptor (TCR) of cytotoxic T lymphocytes, which triggers a targeted immune response against the malignant cells. Therapeutic strategies currently under investigation include TCR-engineered T-cell therapies (TCR-T), such as MDG1011, and TCR-like antibodies that mimic the specificity of the immune system (Medigene AG, 2023). Because the NPM1 mutation is a founder mutation and is relatively stable during disease progression, this complex serves as a 'public neoantigen' with a low risk of immune escape compared to other tumor antigens.

Other names

HLA-A*02:01/NPM1mut complexNPM1-mutated neoantigen-MHC complexHLA-A2/NPM1c+ complexpMHC complex (NPM1mut)CLAVEEVSL/HLA-A*02:01 complex

Targeting of the specific peptide-MHC complex by engineered T-cell receptors (TCR-T) or TCR-like antibodies to induce directed T-cell mediated cytotoxicity against leukemic cells.