A Novel PEGylation Method for Improving the Pharmacokinetic Properties of Anti-Interleukin-17A RNA Aptamers.
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.
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Kazuhiko
K
Haruta
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Natsuki
N
Otaki
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Masakazu
M
Nagamine
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Tomoyoshi
T
Kayo
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Asako
A
Sasaki
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Shinsuke
S
Hiramoto
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Masayuki
M
Takahashi
1 R&D Center, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Kuniyoshi
K
Hota
2 GeneDesign, Inc. , Osaka, Japan .
Hideaki
H
Sato
3 Prescription Products Development, Zenyaku Kogyo Co., Ltd. , Tokyo, Japan .
Hiroaki
H
Yamazaki
D000818:Animals; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011092:Polyethylene Glycols / Q000737:chemistry*; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
D052157:Aptamers, Nucleotide; D020381:Interleukin-17; D011092:Polyethylene Glycols; D000093242:Interleukin-6 Inhibitors; C508717:IL17A protein, human; C577686:interleukin-6, mouse; D015850:Interleukin-6
PEGylation; aptamer; interleukin-17A; pharmacokinetics