Abstract
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.
Highlights
Aptamers are artificial oligonucleotides that bind to target molecules with a high affinity
Phosphoramidite PEGylation, and we evaluated the effects of sbC-PEGylation on the PK properties of RNA aptamers that inhibit interleukin-17A (IL-17A), which were originally reported by Ishiguro et al [17]
To evaluate the effects of sbC-PEGylation on the renal clearance and nuclease degradation of aptamers in vivo, we first used 17M-200-S1, which was degraded in mouse serum (Supplementary Fig. S1; Supplementary Data are available online at www.liebertpub.com/nat). sbCPEGylated 17M-200-S1 had the longest plasma half-life (t1/2, 22.5 h) of the aptamers that were conjugated with 80-kDa polyethylene glycol (PEG)
Summary
Aptamers are artificial oligonucleotides that bind to target molecules with a high affinity. They can inhibit the binding of a protein to its receptor, similar to therapeutic neutralizing antibodies. Aptamers are considered to have some clinical advantages over therapeutic antibodies, for example, they exhibit low immunogenicity [1,2,3]. Recent developments in this area have focused on treatments for ophthalmic disease [7]. These points indicate that the obstacles to the development of therapeutic aptamers for other diseases, especially systemic diseases, such as nuclease degradation and renal clearance, have not been fully overcome
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