Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

• Published in: Nature biotechnology Vol. 41; no. 9; pp. 1296 - 1306
• Main Authors: Gauthier, Laurent, Virone-Oddos, Angela, Beninga, Jochen, Rossi, Benjamin, Nicolazzi, Céline, Amara, Céline, Blanchard-Alvarez, Audrey, Gourdin, Nicolas, Courta, Jacqueline, Basset, Alexandra, Agnel, Magali, Guillot, Franceline, Grondin, Gwendoline, Bonnevaux, Hélène, Bauchet, Anne-Laure, Morel, Ariane, Morel, Yannis, Chiron, Marielle, Vivier, Eric
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2023; Nature Publishing Group
• Subjects: 631/154/51/1568; 631/250/251; 631/61/24; 631/67/1059/2325; Acute myeloid leukemia; Agriculture; Animals; Antibodies; Antibody-Dependent Cell Cytotoxicity; Anticancer properties; Antitumor activity; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cancer; CD123 antigen; Cell activation; Clinical trials; Cytokines; Cytokines - metabolism; Cytotoxicity; Hematology; Human health and pathology; Humans; Immunoglobulin G; Immunology; Immunotherapy; Inflammation; Interleukin-3 Receptor alpha Subunit; Killer Cells, Natural; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Life Sciences; Lymphocytes; Lymphocytes T; Mice; Natural killer cells; Pharmacodynamics; Receptors; T-Lymphocytes; Toxicity
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-022-01626-2

CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123 + tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123 + cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE. Leukemia cells resistant to CD123-targeted therapies are susceptible to a trifunctional NK cell engager.