Faculty, Staff and Student Publications
Publication Date
4-1-2025
Journal
Leukemia
Abstract
Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2+ AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report on the engineering, preclinical efficacy, and safety evaluation of a novel CG1/HLA-A2-targeting, T cell-engager, bispecific antibody (CG1/A2xCD3). CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and to AML and T cells, with potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo. This correlated with both tumor- and CG1/A2xCD3-dependent T cell activation and cytokine secretion. Lastly, CG1/A2xCD3 had no activity against normal bone marrow. Together, these results support the targeting of LS-derived peptides and the continued clinical development of CG1/A2xCD3 in the setting of AML.
Keywords
Humans, Animals, Leukemia, Myeloid, Acute, Immunotherapy, Mice, Cathepsin G, HLA-A2 Antigen, Peptides, Antibodies, Bispecific, Protein Sorting Signals, T-Lymphocytes, Cell Line, Tumor, Xenograft Model Antitumor Assays
DOI
10.1038/s41375-025-02520-x
PMID
39939820
PMCID
PMC11976275
PubMedCentral® Posted Date
2-12-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Hematology Commons, Medical Genetics Commons, Oncology Commons