A novel fusion protein scaffold 18/12/TxM activates the IL-12, IL-15, and IL-18 receptors to induce human memory-like natural killer cells.

Autor:	Cubitt CC; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., McClain E; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Becker-Hapak M; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Foltz JA; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Wong P; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Wagner JA; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Neal CC; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Marin ND; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Marsala L; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Foster M; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Schappe T; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Soon-Shiong P; ImmunityBio, Culver City, CA 90232, USA., Lee J; ImmunityBio, Culver City, CA 90232, USA., Berrien-Elliott MM; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA., Fehniger TA; Washington University School of Medicine, 425 South Euclid Avenue, Campus Box 8007, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy oncolytics [Mol Ther Oncolytics] 2022 Feb 15; Vol. 24, pp. 585-596. Date of Electronic Publication: 2022 Feb 15 (Print Publication: 2022).
DOI:	10.1016/j.omto.2022.02.009
Abstrakt:	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. Competing Interests: This study was funded in part by ImmunityBio. M.M.B.-E. and T.A.F. consult for Wugen (equity) and are inventors of technology that Washington University has licensed to Wugen. T.A.F. has received research support from ImmunityBio, Compass Therapeutics, HCW Biologics, Wugen and advises Kiadis, Nkarta, Indapta, and Orca Biosystems. (© 2022 The Authors.)
Databáze:	MEDLINE
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