iPSC-derived natural killer cells expressing the FcγR fusion CD64/16A can be armed with antibodies for multitumor antigen targeting.

Autor:	Snyder KM; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, USA., Dixon KJ; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, USA., Davis Z; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Hosking M; Fate Therapeutics Inc, San Diego, California, USA., Hart G; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Khaw M; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Matson A; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, USA., Bjordahl R; Fate Therapeutics Inc, San Diego, California, USA., Hancock B; Fate Therapeutics Inc, San Diego, California, USA., Shirinbak S; Fate Therapeutics Inc, San Diego, California, USA., Miller JS; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Valamehr B; Fate Therapeutics Inc, San Diego, California, USA., Wu J; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, USA., Walcheck B; Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, USA walch003@umn.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Dec 06; Vol. 11 (12). Date of Electronic Publication: 2023 Dec 06.
DOI:	10.1136/jitc-2023-007280
Abstrakt:	Background: Antibody therapies can direct natural killer (NK) cells to tumor cells, tumor-associated cells, and suppressive immune cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This antigen-specific effector function of human NK cells is mediated by the IgG Fc receptor CD16A (FcγRIIIA). Preclinical and clinical studies indicate that increasing the binding affinity and avidity of CD16A for antibodies improves the therapeutic potential of ADCC. CD64 (FcγRI), expressed by myeloid cells but not NK cells, is the only high affinity IgG Fc receptor and is uniquely capable of stably binding to free monomeric IgG as a physiological function. We have reported on the generation of the FcγR fusion CD64/16A, consisting of the extracellular region of CD64 and the transmembrane and cytoplasmic regions from CD16A, retaining its signaling and cellular activity. Here, we generated induced pluripotent stem cell (iPSC)-derived NK (iNK) cells expressing CD64/16A as a potential adoptive NK cell therapy for increased ADCC potency. Methods: iPSCs were engineered to express CD64/16A as well as an interleukin (IL)-15/IL-15Rα fusion (IL-15RF) protein and differentiated into iNK cells. iNK cells and peripheral blood NK cells were expanded using irradiated K562-mbIL21-41BBL feeder cells and examined. NK cells, ovarian tumor cell lines, and therapeutic monoclonal antibodies were used to assess ADCC in vitro, performed by a DELFIA EuTDA assay or in real-time by IncuCyte assays, and in vivo. For the latter, we developed a xenograft mouse model with high circulating levels of human IgG for more physiological relevance. Results: We demonstrate that (1) iNK-CD64/16A cells after expansion or thaw from cryopreservation can be coupled to therapeutic antibodies, creating armed iNK cells; (2) antibody-armed iNK-CD64/16A cells can be redirected by added antibodies to target new tumor antigens, highlighting additional potential of these cells; (3) cytokine-autonomous activity by iNK-CD64/16A cells engineered to express IL-15RF; and that (4) antibody-armed iNK-CD64/16A cells thawed from cryopreservation are capable of sustained and robust ADCC in vitro and in vivo, as determined by using a modified tumor xenograft model with high levels of competing human IgG. Conclusions: iNK cells expressing CD64/16A provide an off-the-shelf multiantigen targeting platform to address tumor heterogeneity and mitigate antigen escape. Competing Interests: Competing interests: JW and BW are inventors on the patent application WO2019084388A1 (Recombinant immune cells, methods of making, and methods of use). Human CD64/16A described in the patent application has been exclusively licensed to Fate Therapeutics. JSM is a paid consultant for Fate Therapeutics and JW, BW and JSM receive research funds from Fate Therapeutics. Fate Therapeutics owns patent No. 10626372 (Methods and compositions for inducing hematopoietic cell differentiation) covering the iPSC derived NK cells. MH, RB, BH, SS, and BV are employees of Fate Therapeutics. All other authors declare no conflicts. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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