A trifunctional natural killer cell engager (NKCE) kills CD123+ acute myeloid leukemia (AML) blasts.

  • Major Finding: A trifunctional natural killer cell engager (NKCE) kills CD123+ acute myeloid leukemia (AML) blasts.

  • Concept: The NKCE targets CD123 on AML blasts and engages two NK-cell activating receptors, NKp46 and CD16a.

  • Impact: This study supports the clinical development of CD123-NKCE for the treatment of AML.

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Acute myeloid leukemias (AML) often overexpress CD123, the alpha chain of the IL3 receptor, but efforts to target CD123 via monoclonal antibody– or T cell–based therapies have been limited by lack of clinical efficacy and toxicity, respectively. To understand the basis of resistance to CD123-targeted therapies, Gauthier, Virone-Oddos, and colleagues evaluated the extent of killing induced by an anti-CD123 antibody in a panel of primary blasts from patients with AML, revealing that killing through antibody-dependent cell cytotoxicity (ADCC) was hindered when cancer cells highly expressed the Fc-gamma receptor CD64, likely due to CD64-mediated antibody sequestration. Given the observed limitation of ADCC in this context, the focus shifted to the development of a natural killer cell engager (NKCE), which simultaneously targets CD123 on AML cells and engages two activating NK-cell receptors, NKp46 and CD16a. This trifunctional CD123-NKCE induced potent and specific killing of CD123+ AML cells by NK cells in vitro, demonstrating superior cytotoxicity when compared with an anti-CD123 antibody or a CD123-targeted NKCE that engaged only one NK-cell receptor. In a xenograft in vivo model of disseminated AML, treatment with a surrogate CD123-NKCE, modified to recognize murine NK cells, significantly prolonged survival to a greater extent than an anti-CD123 antibody. Moreover, CD123-NKCE efficacy was not affected by CD64 expression. Importantly, whereas a CD123-targeted T-cell engager induced the production of proinflammatory cytokines by human peripheral blood mononuclear cells, cytokine release following exposure to CD123-NKCE was minimal, even at higher doses. These results were further supported by the pharmacokinetic, pharmacodynamic, and safety profiles of CD123-NKCE in nonhuman primates. Overall, this study provides preclinical rationale to pursue the clinical development of CD123-NKCE for the treatment of AML.

Gauthier L, Virone-Oddos A, Beninga J, Rossi B, Nicolazzi C, Amara C, et al. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nat Biotechnol 2023 Jan 12 [Epub ahead of print].

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