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

Autor: Gauthier L; Innate Pharma, Marseille, France. laurent.gauthier@innate-pharma.fr., Virone-Oddos A; Sanofi Immuno-Oncology Research, Vitry sur-Seine, France. Angela.Virone-Oddos@sanofi.com., Beninga J; Sanofi Large Molecules Research, Frankfurt, Germany., Rossi B; Innate Pharma, Marseille, France., Nicolazzi C; Sanofi Immuno-Oncology Research, Vitry sur-Seine, France., Amara C; Sanofi Drug Metabolism and Pharmacokinetics, Chilly Mazarin, France., Blanchard-Alvarez A; Innate Pharma, Marseille, France., Gourdin N; Innate Pharma, Marseille, France., Courta J; Sanofi TMED Biomarkers and Clinical Bioanalysis, Chilly Mazarin, France., Basset A; Sanofi Preclinical Safety, Chilly Mazarin, France., Agnel M; Sanofi Global Project Management, Vitry sur-Seine, France., Guillot F; Innate Pharma, Marseille, France., Grondin G; Innate Pharma, Marseille, France., Bonnevaux H; Sanofi Immuno-Oncology Research, Vitry sur-Seine, France., Bauchet AL; Sanofi Global Project Management, Vitry sur-Seine, France., Morel A; Innate Pharma, Marseille, France., Morel Y; Innate Pharma, Marseille, France., Chiron M; Sanofi Immuno-Oncology Research, Vitry sur-Seine, France., Vivier E; Innate Pharma, Marseille, France. eric.vivier@innate-pharma.fr.; Aix-Marseille University, Centre of National Scientific Research (CNRS), National Insititute of Health and Medical Research (INSERM), Centre of Immunology at Marseille-Luminy (CIML), Marseille, France. eric.vivier@innate-pharma.fr.; APHM, Marseille-Immunopole, University Hospital of Timone, Marseille, France. eric.vivier@innate-pharma.fr.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2023 Sep; Vol. 41 (9), pp. 1296-1306. Date of Electronic Publication: 2023 Jan 12.
DOI: 10.1038/s41587-022-01626-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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