A Novel PEGylation Method for Improving the Pharmacokinetic Properties of Anti-Interleukin-17A RNA Aptamers

被引：41

作者：

Haruta, Kazuhiko ^{[1
]}

Otaki, Natsuki ^{[1
]}

Nagamine, Masakazu ^{[1
]}

Kayo, Tomoyoshi ^{[1
]}

Sasaki, Asako ^{[1
]}

Hiramoto, Shinsuke ^{[1
]}

Takahashi, Masayuki ^{[1
]}

Hota, Kuniyoshi ^{[1
]}

Sato, Hideaki ^{[2
]}

Yamazaki, Hiroaki ^{[3
]}

机构：

[1] Zenyaku Kogyo Co Ltd, R&D Ctr, 2-33-7 Oizumi, Tokyo 1780062, Japan

[2] Zenyaku Kogyo Co Ltd, Prescript Prod Dev, Tokyo, Japan

[3] GeneDesign Inc, Osaka, Japan

来源：

NUCLEIC ACID THERAPEUTICS | 2017年 / 27卷 / 01期

关键词：

aptamer; interleukin-17A; PEGylation; pharmacokinetics; IN-VITRO SELECTION; THERAPEUTICS; ARTHRITIS; INFLAMMATION; SECUKINUMAB; EVOLUTION; LIGANDS; PROTEIN; TRIALS; VEGF;

D O I：

10.1089/nat.2016.0627

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The obstacles to the development of therapeutic aptamers for systemic inflammatory diseases, such as nuclease degradation and renal clearance, have not been fully overcome. Here, we report a novel PEGylation method, sbC-PEGylation, which improves the pharmacokinetic properties of RNA aptamers that act against interleukin-17A (IL-17A) in mice and monkeys. sbC-PEGylated aptamers were synthesized by coupling the symmetrical branching molecule 2-cyanoethyl-N, N-diisopropyl phosphoroamidite to the 5' end of the aptamer, before conjugating two polyethylene glycol (PEG) molecules to the aptamer. Pharmacokinetic studies showed that compared with conventionally PEGylated aptamers, the sbC-PEGylated aptamer exhibited excellent stability in the blood circulation of mice and monkeys. In addition, one of the sbC-PEGylated aptamers, 17M-382, inhibited the interleukin-6 (IL-6) production induced by IL-17A in NIH3T3 cells in a concentration-dependent manner, and the half-maximal inhibitory concentration of sbC-PEGylated 17M-382 was two times lower than that of non-PEGylated 17M-382. Furthermore, the intraperitoneal administration of sbC-PEGylated 17M-382 significantly inhibited the IL-6 production induced by IL-17A in a mouse air pouch model. Our findings suggest that the novel PEGylation method described in this study, sbC-PEGylation, could be used to develop anti-IL-17A aptamers as a therapeutic option for systemic inflammatory disease.

引用

页码：36 / 44

页数：9

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