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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.

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References

Bruno

. (2015). Predicting the uncertain future of aptamer-based diagnostics and therapeutics. Molecules, 20:6866–6887.

Sun

and Zu

. (2015). A highlight of recent advances in aptamer technology and its application. Molecules, 20:11959–11980.

Keefe

, Pai

and Ellington

. (2010). Aptamers as therapeutics. Nat Rev Drug Discov, 9:537–550.

Tuerk

and Gold

. (1990). Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science, 249:505–510.

Ellington

and Szostak

. (1990). In vitro selection of RNA molecules that bind specific ligands. Nature, 346:818–822.

EWM

, Shima

, Calias

, Cunningham

Jr , Guyer

and Adamis

. (2006). Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov, 5:123–132.

Burke

. (2015). The ups and downs of clinical translation of new technologies: Déjà vu all over again. Mol Ther, 23:791–792.

Roberts

, Bentley

and Harris

. (2002). Chemistry for peptide and protein PEGylation. Adv Drug Delivery Rev, 54:459–476.

Harris

and Chess

. (2003). Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov, 2:214–221.

10.

Fishburn

. (2008). The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci, 97:4167–4183.

11.

, Lei

, Su

and Ma

. (2007). Comparison of bioactivities of monopegylated rhG-CSF with branched and linear mPEG. Process Biochem, 42:1625–1631.

12.

Schmidt

, Borkowski

, Kurreck

, Stephens

, Bald

, Hecht

, Friebe

, Dinkelborg

and Erdmann

. (2004). Application of locked nucleic acids to improve aptamer in vivo stability and targeting function. Nucleic Acids Res, 32:5757–5765.

13.

Ozer

, Pagano

and Lis

. (2014). New technologies provide quantum changes in the scale, speed, and success of SELEX methods and aptamer characterization. Mol Ther Nucleic Acids, 3:e183.

14.

Burmeister

, Lewis

, Silva

, Preiss

, Horwitz

, Pendergrast

, McCauley

, Kurz

, Epstein

, Wilson

and Keefe

. (2005). Direct in vitro selection of a 2′-O-methyl aptamer to VEGF. Chem Biol, 12:25–33.

15.

Gupta

, Hirota

, Waugh

, Murakami

, Suzuki

, Muraguchi

, Shibamori

, Ishikawa

, Jarvis

, et al. (2014). Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem, 289:8706–8719.

16.

Vater

and Klussmann

. (2015). Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer^® therapeutics. Drug Discov Today, 20:147–155.

17.

Ishiguro

, Akiyama

, Adachi

, Inoue

and Nakamura

. (2011). Therapeutic potential of anti-interleukin-17A aptamer: suppression of interleukin-17A signaling and attenuation of autoimmunity in two mouse models. Arthritis Rheum, 63:455–466.

18.

Healy

, Lewis

, Kurz

, Boomer

, Thompson

, Wilson

and McCauley

. (2004). Pharmacokinetics and biodistribution of novel aptamer compositions. Pharm Res, 21:2234–2246.

19.

Maione

, Pashalidis

, Mascolo

, Dufton

, Perretti

and D'Acquisto

(2009). Interleukin 17 sustains rather than induces inflammation. Biochem Pharmacol, 77:878–887.

20.

Kang

, Park

, Seu

and Hahn

. (2007). A novel branch-type PEGylation of aptamer therapeutics. Key Eng Mater. 342–343:529–532.

21.

Yamaoka

, Tabata

and Ikeda

. (1994). Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci, 83:601–606.

22.

Lee

, Stovall

and Ellington

. (2006). Aptamer therapeutics advance. Curr Opin Chem Biol, 10:282–289.

23.

Palframan

, Airey

, Moore

, Vugler

and Nesbitt

. (2009). Use of biofluorescence imaging to compare the distribution of certolizumab pegol, adalimumab, and infliximab in the inflamed paws of mice with collagen-induced arthritis. J Immunol Methods, 348:36–41.

24.

Mcginness

, Diener

, Schaub

and Thompson

. (2010). Patent US2010/023599; PCT/WO/10/091396.

25.

Siller-Matula

, Merhi

, Tanguay

, Duerschmied

, Wagner

, McGinness

, Pendergrast

, Chung

, Tian

, Schaub

and Jilma

. (2012). ARC15105 is a potent antagonist of von Willebrand Factor mediated platelet activation and adhesion. Arterioscler Thromb Vasc Biol, 32:902–909.

26.

Miossec

and Kolls

. (2012). Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov, 11:763–776.

27.

Chen

, Li

, Zhong

, Wu

, Chen

, Peng

and Liu

. (2011). IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis. Osteoarthritis Cartilage, 19:711–718.

28.

Otaki

, Sasaki

, Hiramoto

, Nagamine

, Mori

, Kayo

, Hota

, Takahashi

, Haruta

and Nakamura

. (2014) Improvement of the stability of RNA aptamers against Interleukin-17A. Arthritis Rheum, 66 (Suppl. 10):S332.

29.

Uyttenhove

and Van Snick

. (2006). Development of an anti-IL-17A auto-vaccine that prevents experimental auto-immune encephalomyelitis. Eur J Immunol, 36:2868–2874.

30.

Iwanami

, Matsumoto

, Tanaka-Watanabe

, Inoue

, Mihara

, Ohsugi

, Mamura

, Goto

, Ito

, et al. (2008). Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum, 58:754–763.

31.

Rizzo

, Kagami

, Phillips

, Kurtz

, Jacques

and Blauvelt

. (2011). IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol, 186:1495–1502.

32.

Langley

, Elewski

, Lebwohl

, Reich

, Griffiths

CEM

, Papp

, Puig

, Nakagawa

, Spelman

, et al. (2014). Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med, 371:326–338.

33.

Griffiths

CEM

, Reich

, Lebwohl

, van de Kerkhof

, Paul

, Menter

, Cameron

, Erickson

, Zhang

, et al. (2015). Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet, 386:541–551.

34.

Baeten

, Sieper

, Braun

, Baraliakos

, Dougados

, Emery

, Deodhar

, Porter

, Martin

, et al. (2015). Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med, 373:2534–2548.

35.

Osborn

, Olsen

, Nardelli

, Murray

, Zhou

JXH

, Garcia

, Moody

, Zaritskaya

and Sung

. (2002). Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-α fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther, 303:540–548.

36.

Takeuchi

, Miyasaka

, Kawai

, Sugiyama

, Yuasa

, Yamashita

, Sugiyama

, Wagerle

, Vlahos

and Wajdula

. (2015). Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials. Mod Rheumatol, 25:173–186.

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

Abstract

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