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

Celia C. Cubitt, Ethan McClain, Michelle Becker-Hapak, Jennifer A. Foltz, Pamela Wong, Julia A. Wagner, Carly C. Neal, Nancy D. Marin, Lynne Marsala, Mark Foster, Timothy Schappe, Patrick Soon-Shiong, John Lee, Melissa M. Berrien-Elliott, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)585-596
Number of pages12
JournalMolecular Therapy - Oncolytics
Volume24
DOIs
StatePublished - Mar 17 2022

Keywords

  • N-803
  • NK cells
  • cancer
  • cytokines
  • memory-like NK cell
  • natural killer cells

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