Targeting mutant NPM1-expressing AML with T-cell receptor-like antibodies

Abstract
Mutant NPM1 protein accumulation is a hallmark of acute myeloid leukemia (AML). Although intracellular proteins are generally inaccessible to antibody-based therapies, proteasomal degradation of mutant NPM1 results in the generation of peptides on the tumor cell surface via major histocompatibility complex (MHC) class I molecules. Enhanced presentation of NPM1 mutant A-derived peptides (NPM1mutA283-291-CLAVEEVSL) on HLA-A*02:01-positive tumor cells distinguishes malignant cells from healthy cells. Here, we report the development of an antibody, 2E2, that specifically targets the NPM1 mutant A peptide bound to HLA-A*02:01. We modified 2E2, including chimeric antibodies and bispecific antibodies. Modified antibodies selectively recognize mutant NPM1-expressing cells and mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro. Moreover, bispecific antibodies derived from 2E2 redirect CD3+ T cells and NK cells to mutant NPM1-expressing cells, suppressing tumor growth both in vitro and in vivo. These findings underscore the potential of NPM1 peptide‒MHC complexes as novel immunotherapeutic targets in AML.

Keywords: TCR-like antibody, Acute myeloid leukemia, Tumor immunotherapy, NPM1, HLA