Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy

Scientific Reports
Qiyue HuWeikang Tao

Abstract

Interleukin-15 (IL-15) can promote both innate and adaptive immune reactions by stimulating CD8+/CD4+ T cells and natural killer cells (NK) while showing no effect in activating T-regulatory (Treg) cells or inducing activation-associated death among effector T cells and NK cells. Thus, IL-15 is considered as one of the most promising molecules for antitumor immune therapy. To improve the drug-like properties of natural IL-15, we create an IL-15-based molecule, named P22339, with the following characteristics: 1) building a complex of IL-15 and the Sushi domain of IL-15 receptor α chain to enhance the agonist activity of IL-15 via transpresentation; 2) through a rational structure-based design, creating a disulfide bond linking the IL-15/Sushi domain complex with an IgG1 Fc to augment its half-life. P22339 demonstrates excellent developability, pharmacokinetic and pharmacodynamic properties as well as antitumor efficacy in both in vitro assessments and in vivo studies. It significantly suppresses tumor growth and metastasis in rodent models, and activates T effector cells and NK cells in cynomolgus monkey. Overall, these data suggest that P22339 has a great potential for cancer immunotherapy.

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Citations

Aug 20, 2019·Immunotherapy·Faezeh GhaemdoustNima Rezaei
Dec 21, 2018·Frontiers in Immunology·Cordelia ManickamR Keith Reeves
Apr 26, 2019·International Journal of Molecular Sciences·Joana R LériasMarkus Maeurer
Mar 30, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sarah A WeissMario Sznol
Jan 1, 2021·International Immunopharmacology·Shuling ZhangFengping Shan
May 20, 2021·Nature Reviews. Clinical Oncology·Ignacio MeleroAurelien Marabelle

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Methods Mentioned

BETA
flow cytometry
FACS
ELISA
transfection

Software Mentioned

Phoenix WinNonlin
Discovery Studio
MOE Operating Environment
Disulfide
CHARMm
Disulfide Scan

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