TY - JOUR
T1 - 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
AU - Cubitt, Celia C.
AU - McClain, Ethan
AU - Becker-Hapak, Michelle
AU - Foltz, Jennifer A.
AU - Wong, Pamela
AU - Wagner, Julia A.
AU - Neal, Carly C.
AU - Marin, Nancy D.
AU - Marsala, Lynne
AU - Foster, Mark
AU - Schappe, Timothy
AU - Soon-Shiong, Patrick
AU - Lee, John
AU - Berrien-Elliott, Melissa M.
AU - Fehniger, Todd A.
N1 - Funding Information:
We acknowledge support from the National Institutes of Health : F30AI161318 (C.C.C.) T32HL00708843 (J.A.W. and P.W.), K12CA167540 (M.M.B.-E.), SPORE in Leukemia P50CA171063 (M.M.B.-E. and T.A.F.), R01CA205239 (T.A.F.), and NCI P30 CA091842 (Siteman Cancer Center), and the Children's Discovery Institute . We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis.
Funding Information:
We acknowledge support from the National Institutes of Health: F30AI161318 (C.C.C.) T32HL00708843 (J.A.W. and P.W.), K12CA167540 (M.M.B.-E.), SPORE in Leukemia P50CA171063 (M.M.B.-E. and T.A.F.), R01CA205239 (T.A.F.), and NCI P30 CA091842 (Siteman Cancer Center), and the Children's Discovery Institute. We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. C.C.C. and T.A.F. wrote the manuscript. T.A.F. M.B.-H. and M.M.B.-E. conceived and designed the study. C.C.C. M.B.-H. C.C.N. E.M. J.A.F. P.W. N.D.M. L.M. M.F. T.S. and J.A.W. collected, analyzed, and assembled the data. P.S.-S. and J.L. provided critical reagents. All authors reviewed the manuscript, edited, and provided approval of the final version of the manuscript. 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.
Funding Information:
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.
Publisher Copyright:
© 2022 The Authors
PY - 2022/3/17
Y1 - 2022/3/17
N2 - 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.
AB - 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.
KW - N-803
KW - NK cells
KW - cancer
KW - cytokines
KW - memory-like NK cell
KW - natural killer cells
UR - http://www.scopus.com/inward/record.url?scp=85125491378&partnerID=8YFLogxK
U2 - 10.1016/j.omto.2022.02.009
DO - 10.1016/j.omto.2022.02.009
M3 - Article
C2 - 35284622
AN - SCOPUS:85125491378
SN - 2372-7705
VL - 24
SP - 585
EP - 596
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
ER -