Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance

Xuezhi Cao, Yong Liang, Zhenxiang Hu, Huiyu Li, Jiaming Yang, Eric J. Hsu, Jiankun Zhu, Jin Zhou and Yang-Xin Fu ()
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Xuezhi Cao: UT Southwestern Medical Center
Yong Liang: UT Southwestern Medical Center
Zhenxiang Hu: LivzonBio, Inc.
Huiyu Li: UT Southwestern Medical Center
Jiaming Yang: LivzonBio, Inc.
Eric J. Hsu: UT Southwestern Medical Center
Jiankun Zhu: UT Southwestern Medical Center
Jin Zhou: LivzonBio, Inc.
Yang-Xin Fu: UT Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.

Date: 2021
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DOI: 10.1038/s41467-021-26112-2

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