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Cubitt, Celia C.; McClain, Ethan; Becker-Hapak, Michelle; Foltz, Jennifer A.; Wong, Pamela; Wagner, Julia A.; Neal, Carly C.; Marin, Nancy D.; Marsala, Lynne; Foster, Mark; Schappe, Timothy; Soon-Shiong, Patrick; Lee, John; Berrien-Elliott, Melissa M.; Fehniger, Todd A.
Molecular therapy. Oncolytics, 03/2022, Letnik: 24Journal Article
Natural killer (NK) cells are cytotoxic innate lymphoid cells that are emerging as a cellular immunotherapy for various malignancies. NK cells are particularly dependent on interleukin (IL)-15 for their survival, proliferation, and cytotoxic function. NK cells differentiate into memory-like cells with enhanced effector function after a brief activation with IL-12, IL-15, and IL-18. N-803 is an IL-15 superagonist composed of an IL-15 mutant (IL-15N72D) bound to the sushi domain of IL-15Rα fused to the Fc region of IgG1, which results in physiological trans-presentation of IL-15. Here, we describe the creation of a novel triple-cytokine fusion molecule, 18/12/TxM, using the N-803 scaffold fused to IL-18 via the IL-15N72D domain and linked to a heteromeric single-chain IL-12 p70 by the sushi domain of the IL-15Rα. This molecule displays trispecific cytokine activity through its binding and signaling through the individual cytokine receptors. Compared with activation with the individual cytokines, 18/12/TxM induces similar short-term activation and memory-like differentiation of NK cells on both the transcriptional and protein level and identical in vitro and in vivo anti-tumor activity. Thus, N-803 can be modified as a functional scaffold for the creation of cytokine immunotherapies with multiple receptor specificities to activate NK cells for adoptive cellular therapy. Display omitted Fehniger and colleagues describe the creation of a novel triple-cytokine fusion molecule, 18/12/TxM, containing an interleukin (IL)-15 superagonist backbone (N-803) fused to IL-18 and IL-12. This trimeric molecule retained specific and unique IL-12, IL-15, and IL-18 activities and generated potent human memory-like natural killer cells in vitro and in vivo.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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