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

Abstract

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.

Polymer Micropatches as Natural Killer Cell Engagers for Tumor Therapy

“…However, maintaining their in vivo activation and persistence is challenging. , Various strategies have been recently reported to augment the antitumor efficacy of NK cells . Some of these strategies, such as NK engagers, facilitate the interaction of endogenous NK cells with tumor cells by simultaneously targeting an NK activating receptor and a tumor antigen target. ,,− Genetic engineering approaches for adoptive NK therapy, namely, the CAR-NK cells, are also being explored for certain tumors. , However, identifying antigen targets for NK engagers and CAR-NK cells poses a challenge due to tumor heterogeneity. − Among nontargeted approaches for improving adoptive NK transfer, preactivation and expansion of NK cells with cytokines is widely adopted. However, activated NK cells need constant cytokine infusions to maintain their activity in vivo , which may lead to off-target adverse effects. ,, …”

The Function of NK Cells in Tumor Metastasis and NK Cell-Based Immunotherapy

“…In recent years, a variety of combined approaches have been tested, including NKIR and immune checkpoint blockers, CAR-NK producing Bi-specific scFv and immune checkpoint blocker, CAR-NK with NKIR blocker, CAR-NK with targeted inhibitor, or multifunctional BiKEs and TriKEs ( Figure 7 ) [ 274 , 275 , 276 ]. The fusion molecules containing one or two NK activating receptors binding scFv or IgG (CD16-binding scFv and NKG2D binding IgG VHH or NKp46 binding Fc) and one or more tumor-specific antigens binding regions have been engineered as the trifunctional or tetrafunctional NK cell engager that targets tumor-specific antigens and activates NK cells for eliminating the tumors significantly with minimized side effects [ 38 , 277 , 278 , 279 ]. This approach combined the different strategies for activating NK cells to kill tumors specifically and efficiently, which is particularly innovative.…”

Addressing Natural Killer Cell Dysfunction and Plasticity in Cell-Based Cancer Therapeutics

“…These NK cell engagers link a monoclonal antibody targeting the activating NK cell receptor NKp46 (or NKp30), an Fc fragment to promote ADCC via CD16, and an antibody targeting a tumor associated antigen, to enable the tumor-localized activation of host NK cells [ 76 ]. Work with these engagers has shown promise in targeting various cancer cell lines [ 76 , 77 , 78 ]. Recently, Demaria and colleagues reported a tetraspecific CD20-ANKET, which engages NKp46, CD16a, the beta chain of the IL-2 receptor, and a tumor associated antigen to induce preferential NK cell activation and target cell killing [ 79 ].…”