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

Kazuhiko Haruta | Zendy; Natsuki Otaki | Zendy; Masakazu Nagamine | Zendy; Tomoyoshi Kayo | Zendy; Asako Sasaki | Zendy; Shinsuke Hiramoto | Zendy; Masayuki Takahashi | Zendy; Kuniyoshi Hota | Zendy; Hideaki Sato | Zendy; Hiroyuki Yamazaki | Zendy

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

Author(s) -

Kazuhiko Haruta,

Natsuki Otaki,

Masakazu Nagamine,

Tomoyoshi Kayo,

Asako Sasaki,

Shinsuke Hiramoto,

Masayuki Takahashi,

Kuniyoshi Hota,

Hideaki Sato,

Hiroyuki Yamazaki

Publication year - 2016

Publication title -

nucleic acid therapeutics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.255

H-Index - 67

eISSN - 2159-3345

pISSN - 2159-3337

DOI - 10.1089/nat.2016.0627

Subject(s) - aptamer , pegylation , pharmacokinetics , computational biology , rna , chemistry , pharmacology , biology , biochemistry , microbiology and biotechnology , gene , polyethylene glycol

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.

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