The field of oligonucleotide (OGN)–based therapeutics has been growing dramatically in the past decade, providing innovative platforms to develop agents for the treatment of a wide variety of clinical conditions. OGN agents have unique physicochemical properties and pharmacokinetic/pharmacodynamic characteristics. This review considers findings from the literature and information on new molecular entities submitted to the US Food and Drug Administration as OGN-based therapeutics. In addition, the article discusses several challenging issues from the perspective of clinical pharmacology, emphasizing the potential of immunogenicity, the effect of renal impairment on OGN exposure, drug-drug interactions, and the utility of pharmacokinetic/pharmacodynamic modeling. The field of OGN-based therapeutics is in evolution and will benefit from further studies as well as clinical experience to formulate guidelines and promote the development of this class of agents.
TalbotDCRansonMDaviesJ. Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. Clin Cancer Res. 2010;16(24):6150–6158.
WangJ. Drug-drug interactions for nucleic acid-based derivatives. In: MeibohmHZAB, ed. Drug-Drug Interactions for Therapeutic Biologics. Indianapolis, IN: Wiley; 2013:257–274.
10.
GearyRSBradleyJDWatanabeT. Lack of pharmacokinetic interaction for ISIS 113715, a 2′-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone. Clin Pharmacokinet. 2006;45(8):789–801.
11.
YuRZGearyRSFlaimJD. Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2′-O-methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet. 2009;48(1):39–50.
12.
LiZHardMLGrundyJS. Lack of clinical pharmacodynamic and pharmacokinetic drug-drug interactions between warfarin and the antisense oligonucleotide mipomersen. J Cardiovasc Pharmacol. 2014;64(2):164–171.
13.
ChiKNGleaveMEKlasaR. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clinical Cancer Res. 2001;7(12):3920–3927.
14.
ShibataSIDoroshowJHFrankelP. Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study. Cancer Chemother Pharmacol. 2009;64(6):1149–1155.
15.
DornAKippenbergerS. Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators. Curr Opin Mol Ther. 2008;10(1):10–20.
16.
KlinmanDMKlaschikSTomaruK. Immunostimulatory CpG oligonucleotides: effect on gene expression and utility as vaccine adjuvants. Vaccine. 2010;28(8):1919–1923.
17.
YuRZGrundyJSGearyRS. Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin Drug Metab Toxicol. 2013;9(2):169–182.
18.
ChiKNEisenhauerEFazliL. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2′-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst. 2005;97(17):1287–1296.
19.
HongDSKurzrockROhY. A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer. Clin Cancer Res. 2011;17(20):6582–6591.
20.
TaniokaMNokiharaHYamamotoN. Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;68(2):505–511.
21.
TalbotDCDaviesJOlsenA. Pharmacodynamic (PD) evaluation of LY2181308 in patients with metastatic malignancies. J Clin Oncol. 2009;27:3507.
22.
CrookeST. Antisense Drug Technology: Principles, Strategies, and Applications. 2nd ed. London, UK: CRC Press; 2008.
23.
GearyRSWancewiczEMatsonJ. Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2’-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN. Biochem Pharmacol. 2009;78(3):284–291.
24.
YuRZZhangHGearyRS. Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice. J Pharmacol Exp Ther. 2001;296(2):388–395.
25.
MarshallJLEisenbergSGJohnsonMD. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2004;4(4):268–274.
26.
StevensonJPYaoKSGallagherM. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A). J Clin Oncol. 1999;17(7):2227–2236.
27.
FDA. Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins. Washington, DC: US Department of Health and Human Services; 2009.
28.
PisetskyDS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol. 2012;144(1):32–40.
KarbachJNeumannAWahleC. Therapeutic administration of a synthetic CpG oligodeoxynucleotide triggers formation of anti-CpG antibodies. Cancer Res. 2012;72(17):4304–4310.
31.
KimDRheeJWKwonS. Immunostimulation and anti-DNA antibody production by backbone modified CpG-DNA. Biochem Biophys Res Commun. 2009;379(2):362–367.
32.
PisetskyDSReichCF3rd. The binding of anti-DNA antibodies to phosphorothioate oligonucleotides in a solid phase immunoassay. Molecular Immunol. 1998;35(18):1161–1170.
33.
PisetskyDSUllalAJ. The blood nucleome in the pathogenesis of SLE. Autoimmun Rev. 2010;10(1):35–37.
34.
SchwarzenbachHHoonDSPantelK. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–437.
KlinmanDShirotaHTrossDSatoTKlaschikS. Synthetic oligonucleotides as modulators of inflammation. J Leukoc Biol. 2008;84(4):958–964.
37.
ChamilosGGregorioJMellerS. Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37. Blood. 2012;120(18):3699–3707.
38.
Di DomizioJDorta-EstremeraSGageaM. Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc Nat Acad Sci U S A. 2012;109(36):14550–14555.
39.
AtianandMKFitzgeraldKA. Molecular basis of DNA recognition in the immune system. J Immunol. 2013;190(5):1911–1918.
40.
BhatNFitzgeraldKA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur J Immunol. 2014;44(3):634–640.
HahnBH. Antibodies to DNA. N Engl J Med. 1998;338(19):1359–1368.
43.
JangYJStollarBD. Anti-DNA antibodies: aspects of structure and pathogenicity. Cell Mol Life Sci. 2003;60(2):309–320.
44.
KofflerDAgnelloVThoburnRKunkelHG. Systemic lupus erythematosus: prototype of immune complex nephritis in man. J Exp Med. 1971;134(3, pt 2):169s-179s.
45.
VallinHPerersAAlmGVRonnblomL. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol. 1999;163(11):6306–6313.
46.
PapalianMLaferEWongRStollarBD. Reaction of systemic lupus erythematosus antinative DNA antibodies with native DNA fragments from 20 to 1,200 base pairs. J Clin Invest. 1980;65(2):469–477.
47.
PisetskyDSReichCF. The influence of DNA size on the binding of anti-DNA antibodies in the solid and fluid phase. Clin Immunol Immunopathol. 1994;72(3):350–356.
48.
BrownDAKangSHGryaznovSM. Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem. 1994;269(43):26801–26805.
49.
PisetskyDS. Standardization of anti-DNA antibody assays. Immunol Res. 2013;56(2-3):420–424.
50.
RobertsonCRPisetskyDS. Specificity analysis of antibodies to single-stranded micrococcal DNA in the sera of normal human subjects and patients with systemic lupus erythematosus. Clin Exp Rheumatol. 1992;10(6):589–594.
51.
JudgeAMcClintockKPhelpsJRMaclachlanI. Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol Ther. 2006;13(2):328–337.
52.
McGowanMPTardifJCCeskaR. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006.
53.
OzaAMElitLSwenertonK. Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116). Gynecol Oncol. 2003;89(1):129–133.
54.
NemunaitisJHolmlundJTKraynakM. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol. 1999;17(11):3586–3595.
55.
RaoSWatkinsDCunninghamD. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin’s lymphoma. Ann Oncol. 2004;15(9):1413–1418.
56.
YuenARHalseyJFisherGA. Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. Clin Cancer Res. 1999;5(11):3357–3363.
57.
SridharSSCanilCMChiKN. A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2011;67(4):927–933.
58.
DesaiAASchilskyRLYoungA. A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors. Ann Oncol. 2005;16(6):958–965.
59.
AlbertsSRSchroederMErlichmanC. Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J Clin Oncol. 2004;22(24):4944–4950.
60.
AdjeiAADyGKErlichmanC. A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res. 2003;9(1):115–123.
61.
AdvaniPPPaulusAMasoodASherTChanan-KhanA. Pharmacokinetic evaluation of oblimersen sodium for the treatment of chronic lymphocytic leukemia. Expert Opin Drug Metab Toxicol. 2011;7(6):765–774.
62.
HauPJachimczakPBogdahnU. Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides. Expert Rev Anticancer Ther. 2009;9(11):1663–1674.
63.
ChiaSDentSEllardS. Phase II trial of OGX-011 in combination with docetaxel in metastatic breast cancer. Clin Cancer Res. 2009;15(2):708–713.
64.
ShiotaMBishopJLNipKM. Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Res. 2013;73(10):3109–3119.
65.
HiganoCS. Potential use of custirsen to treat prostate cancer. Onco Targets Ther. 2013;6:785–797.
66.
AkdimFTribbleDLFlaimJD. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J. 2011;32(21):2650–2659.
