A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

Eric J. Hsu, Xuezhi Cao (), Benjamin Moon, Joonbeom Bae, Zhichen Sun, Zhida Liu and Yang-Xin Fu ()
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Eric J. Hsu: UT Southwestern Medical Center
Xuezhi Cao: UT Southwestern Medical Center
Benjamin Moon: UT Southwestern Medical Center
Joonbeom Bae: UT Southwestern Medical Center
Zhichen Sun: UT Southwestern Medical Center
Zhida Liu: UT Southwestern Medical Center
Yang-Xin Fu: UT Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

Date: 2021
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DOI: 10.1038/s41467-021-22980-w

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