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Sun, Zhichen; Ren, Zhenhua; Yang, Kaiting; Liu, Zhida; Cao, Shuaishuai; Deng, Sisi; Xu, Lily; Liang, Yong; Guo, Jingya; Bian, Yingjie; Xu, Hairong; Shi, Jiyun; Wang, Fan; Fu, Yang-Xin; Peng, Hua
Nature communications, 08/2019, Volume: 10, Issue: 1Journal Article
While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
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