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A Next-Generation Tumor-Targeting IL-2 Preferentially Promotes Tumor-Infiltrating CD8

A Next-Generation Tumor-Targeting IL-2 Preferentially Promotes Tumor-Infiltrating CD8

Zhichen Sun, Zhenhua Ren, Kaiting Yang, Zhida Liu, Shuaishuai Cao, Sisi Deng, Lily Xu, Yong Liang, Jingya Guo, Yingjie Bian, Hairong Xu, Jiyun Shi, Fan Wang, Yang-Xin Fu, Hua Peng

Nat Commun. 2019 Aug 28;10(1):3874.

PMID: 31462678

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1217448662	IL-2Rα Antagonist - CAS 1217448-66-2		1217448-66-2	Price

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