Skip to main content
SpringerLink
Log in

Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

  • Chapter
  • First Online:
Nucleic Acid Drugs

Part of the book series: Advances in Polymer Science ((POLYMER,volume 249))

Abstract

Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

AE:

Adverse event

CMI:

Cell-mediated immunity

CpG:

Cytidine-phosphate-guanosine

DC:

Dendritic cell

ds:

Double-stranded

EGFR:

Endothelial growth factor receptor

HEK:

Human embryonic kidney

HIV:

Human immunodeficiency virus

IFN:

Interferon

IL:

Interleukin

IMO:

Immune-modulatory oligonucleotide

IP-10:

IFN-γ-inducible protein 10

IRAK:

IL-1-associated kinase

LPS:

Lipopolysaccharide

LTR:

Long terminal repeat

mDCs:

Myeloid dendritic cells

MyD8:

Myeloid differentiation factor 88

NF-κB:

Nuclear factor-kappa B

NK:

Natural killer

NSCLC:

Nonsmall cell lung carcinoma

ODN:

Oligodeoxynucleoide

OME:

Otitis-mediated effusion

ORN:

Oligoribonucleotide

OVA:

Ovalbumin

PAMP:

Pathogen-associated molecular pattern

PBMC:

Peripheral blood mononuclear cell

pDC:

Plasmacytoid dendritic cell

PFS:

Progression-free survival

PO:

Phosphodiester

PRR:

Pattern-recognition receptor

PS:

Phosphorothioate

RA:

Rheumatoid arthritis

s.c.:

Subcutaneous

SIMRA:

Stabilized immune modulatory RNA

ss:

Single-stranded

TERT:

Telomerase reverse transcriptase

Th1:

T helper type 1

TIR:

Toll/interleukin-1 receptor

TLR:

Toll-like receptor

TRAF6:

TNF receptor-associated factor 6

TRIF:

TIR domain-containing adaptor-inducing interferon-β

VEGF:

Vascular endothelial growth factor

References

  1. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    CAS  Google Scholar 

  2. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291–295

    CAS  Google Scholar 

  3. Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32

    CAS  Google Scholar 

  4. Lasker MV, Nair SK (2006) Intracellular TLR signaling: A structural perspective on human disease. J Immunol 177:11–16

    CAS  Google Scholar 

  5. Kenny EF, O’Neill LA (2008) Signalling adaptors used by Toll-like receptors: An update. Cytokine 43:342–349

    CAS  Google Scholar 

  6. Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19:3–10

    CAS  Google Scholar 

  7. Alexopoulou L, Holt AC, Medzhitov R (2001) Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–738

    CAS  Google Scholar 

  8. Heil F, Hemmi H, Hochrein H et al (2004) Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303:1526–1529

    CAS  Google Scholar 

  9. Diebold SS, Kaisho T, Hemmi H et al (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531

    CAS  Google Scholar 

  10. Hemmi H, Kaisho T, Takeuchi O et al (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200

    CAS  Google Scholar 

  11. Lee J, Chuang TH, Redecke V et al (2003) Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 100:6646–6651

    CAS  Google Scholar 

  12. Hemmi H, Takeuchi O, Kawai T et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    CAS  Google Scholar 

  13. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    CAS  Google Scholar 

  14. Diebold SS (2008) Recognition of viral single-stranded RNA by Toll-like receptors. Adv Drug Deliv Rev 60:813–823

    CAS  Google Scholar 

  15. Lund JM, Alexopoulou L, Sato A et al (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603

    CAS  Google Scholar 

  16. Schon MP, Schon M, Klotz KN (2006) The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. J Invest Dermatol 126:1338–1347

    Google Scholar 

  17. Zagon IS, Donahue RN, Rogosnitzky M et al (2008) Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function. Exp Biol Med 233:968–979

    CAS  Google Scholar 

  18. Gilliet M, Conrad C, Geiges M et al (2004) Psoriasis triggered by Toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol 140:1490–1495

    CAS  Google Scholar 

  19. Karlsson A, Jägervall K, Utkovic H et al (2008) Intra-colonic administration of the TLR7 agonist R-848 induces an acute local and systemic inflammation in mice. Biochem Biophys Res Commun 367:242–248

    CAS  Google Scholar 

  20. Savage P, Horton V, Moore J et al (1996) A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. Br J Cancer 74:1482–1486

    CAS  Google Scholar 

  21. Judge AD, Sood V, Shaw JR et al (2005) Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 23:457–462

    CAS  Google Scholar 

  22. Marques JT, Williams BR (2005) Activation of the mammalian immune system by siRNAs. Nat Biotechnol 23:1399–1405

    CAS  Google Scholar 

  23. Sioud M (2005) Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 348:1079–1090

    CAS  Google Scholar 

  24. Kariko K, Bhuyan P, Capodici J et al (2004) Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through Toll-like receptor 3. J Immunol 172:6545–6549

    CAS  Google Scholar 

  25. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597

    CAS  Google Scholar 

  26. Dow S (2008) Liposome-nucleic acid immunotherapeutics. Expert Opin Drug Deliv 5:11–24

    CAS  Google Scholar 

  27. Lan T, Kandimalla ER, Yu D et al (2007) Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. Proc Natl Acad Sci USA 104:13750–13755

    CAS  Google Scholar 

  28. Agrawal S, Kandimalla ER (2007) Synthetic agonists of Toll-like receptors 7, 8, and 9. Biochem Soc Trans 35:1461–1467

    CAS  Google Scholar 

  29. Lan T, Dai M, Wang D et al (2009) Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure–activity relationship studies. J Med Chem 52:6871–6879

    CAS  Google Scholar 

  30. Lan T, Bhagat L, Wang D et al (2009) Synthetic oligoribonucleotides containing arabinonucleotides act as agonists of TLR7 and 8. Bioorg Med Chem Lett 19:2044–2047

    CAS  Google Scholar 

  31. Lan T, Putta MR, Wang D et al (2009) Synthetic oligoribonucleotides-containing secondary structures act as agonists of Toll-like receptors 7 and 8. Biochem Biophys Res Commun 386:443–448

    CAS  Google Scholar 

  32. Colonna M, Krug A, Cella M (2002) Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol 14:373–379

    CAS  Google Scholar 

  33. Shimada S, Yano O, Inoue H et al (1985) Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors. J Natl Cancer Inst 74:681–688

    CAS  Google Scholar 

  34. Tokunaga T, Yamamoto H, Shimada S et al (1984) Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst 72:955–962

    CAS  Google Scholar 

  35. Shimada S, Yano O, Tokunaga T (1986) In vivo augmentation of natural killer cell activity with a deoxyribonucleic acid fraction of BCG. Jpn J Cancer Res 77:808–816

    CAS  Google Scholar 

  36. Yamamoto S, Kuramoto E, Shimada S et al (1988) In vitro augmentation of natural killer cell activity and production of interferon-alpha/beta and -gamma with deoxyribonucleic acid fraction from Mycobacterium bovis BCG. Jpn J Cancer Res 79:866–873

    CAS  Google Scholar 

  37. Messina JP, Gilkeson GS, Pisetsky DS (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol 147:1759–1764

    CAS  Google Scholar 

  38. Tokunaga T, Yano O, Kuramoto E et al (1992) Synthetic oligonucleotides with particular base sequences from the cDNA encoding proteins of Mycobacterium bovis BCG induce interferons and activate natural killer cells. Microbiol Immunol 36:55–66

    CAS  Google Scholar 

  39. Yamamoto S, Yamamoto T, Kataoka T et al (1992) Unique palindromic sequences in synthetic oligonucleotides are required to induce INF and augment INF-mediated natural killer activity. J Immunol 148:4072–4076

    CAS  Google Scholar 

  40. Krieg AM, Yi AK, Matson S et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549

    CAS  Google Scholar 

  41. Agrawal S, Kandimalla ER (2004) Roll of Toll-like receptors in antisense and siRNA. Nat Biotechnol 22:1533–1537

    CAS  Google Scholar 

  42. Agrawal S, Kandimalla ER (2000) Antisensense therapeutics: is it as simple as complementary base recognition? Mol Med Today 6:72–81

    CAS  Google Scholar 

  43. Branda RF, Moore AL, Mathews L et al (1993) Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1. Biochem Pharmacol 45:2037–2043

    CAS  Google Scholar 

  44. McIntyre KW, Lombard-Gillooly K, Perez JR et al (1993) A sense phosphorothioate oligonucleotide directed to the initiation codon of transcription factor NF-kappa B p65 causes sequence-specific immune stimulation. Antisense Res Dev 3:309–322

    CAS  Google Scholar 

  45. Mojcik CF, Gourley MF, Klinman DM et al (1993) Administration of a phosphorothioate oligonucleotide antisense to murine endogenous retroviral MCF env causes immune effects in vivo in a sequence-specific manner. Clin Immunol Immunopathol 67:130–136

    CAS  Google Scholar 

  46. Tanaka T, Chu CC, Paul WE et al (1992) An antisense oligonucleotide complementary to a sequence in I gamma 2b increases gamma 2b germline transcripts, stimulates B cell DNA synthesis, and inhibits immunoglobulin secretion. J Exp Med 175:597–607

    CAS  Google Scholar 

  47. Equils O, Schito ML, Karahashi H et al (2003) Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat Trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: Implications of simultaneous activation of TLRs on HIV replication. J Immunol 170:5159–5164

    CAS  Google Scholar 

  48. Agrawal S, Martin RR (2003) Was induction of HIV-1 through TLR9? J Immunol 171:1621

    CAS  Google Scholar 

  49. Klinman DM (2004) Immunotherapeutic uses of CpG oligdeoxynucleotides. Nat Rev Immunol 4:249–258

    CAS  Google Scholar 

  50. Kumagai Y, Takeuchi O, Akira S (2008) TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev 60:795–804

    CAS  Google Scholar 

  51. Verthelyi D, Ishii KJ, Gursel M et al (2001) Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J Immunol 166:2372–2377

    CAS  Google Scholar 

  52. Krug A, Rothenfusser S, Hornung V et al (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur J Immunol 31:2154–2163

    CAS  Google Scholar 

  53. Lang R, Hultner L, Lipford GB, Wagner H, Heeg K (1999) Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of mucrine baone marrow cells. Eur J Immunol 29:3496–3506

    CAS  Google Scholar 

  54. Hartmann G, Weeratna RD, Balla ZK et al (2000) Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617–1624

    CAS  Google Scholar 

  55. Bauer S, Kirschning CJ, Hacker H et al (2001) Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA 98:9237–9242

    CAS  Google Scholar 

  56. Sato Y, Roman M, Tighe H et al (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273:352–354

    CAS  Google Scholar 

  57. Hartmann G, Battiany J, Poeck H et al (2003) Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. Eur J Immunol 33:1633–1641

    CAS  Google Scholar 

  58. Marshall JD, Fearon K, Abbate C et al (2003) Identification of novel CpG DNA class and motif that optimally stimulate B cells and plasmacytoid dendritic cell function. J Leukoc Biol 73:781–792

    CAS  Google Scholar 

  59. Vollmer J, Weeratna R, Payette P et al (2004) Characterization of three CpG oligodeoxynucleotide classes with distinct immunestimulatory activities. Eur J Immunol 34:251–262

    CAS  Google Scholar 

  60. Kandimalla ER, Agrawal S (2005) Synthetic agonists of Toll-like receptor 9. In: Rich T (ed) Toll and Toll receptors an immunologic perspective. Kluwer Academic/Plenum, New York, NY, pp 181–212

    Google Scholar 

  61. Dalpke AH, Zimmermann S, Albrecht I, Heeg K (2002) Phosphodiester CpG oligonucleotides as adjuvants: polyguanosine runs enhance cellular uptake and improve immunostimulative activity of phosphodiester CpG oligonucleotides in vitro and in vivo. Immunology 106:102–112

    CAS  Google Scholar 

  62. Yu D, Zhu FG, Bhagat L et al (2002) Potent CpG oligonucleotides containing phosphodiester linkages: in vitro and in vivo immunostimulatory properties. Biochem Biophys Res Commun 297:83–90

    CAS  Google Scholar 

  63. Agrawal S, Temsamani J, Tang JY (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci USA 88:7595–7599

    CAS  Google Scholar 

  64. Yu D, Kandimalla ER, Roskey A et al (2000) Stereo-enriched phosphorothioate oligodeoxynucleotides: synthesis, biophysical and biological properties. Bioorg Med Chem 8:275–284

    CAS  Google Scholar 

  65. Agrawal S, Kandimalla ER (2001) Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr Cancer Drug Target 1:197–209

    CAS  Google Scholar 

  66. Zhao Q, Temsamani J, Iadarola PL et al (1996) Effect of different chemically modified oligodeoxynucleotides on immune stimulation. Biochem Pharmacol 51:173–182

    CAS  Google Scholar 

  67. Agrawal S, Kandimalla ER (2003) Modulation of Toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA. Ann N Y Acad Sci 1002:30–42

    CAS  Google Scholar 

  68. Kandimalla ER, Zhu FG, Bhagat L et al (2003) Toll-like receptor 9: modulation of recognition and cytokine induction by novel synthetic CpG DNAs. Biochem Soc Trans 31:654–658

    CAS  Google Scholar 

  69. Yu D, Kandimalla ER, Zhao Q et al (2001) Immunostimulatory activity of CpG oligonucleotides containing non-ionic methylphosphonate linkages. Bioorg Med Chem 9:2803–2808

    CAS  Google Scholar 

  70. Zhao Q, Yu D, Agrawal S (1999) Site of chemical modification in CpG containing phosphorothioate oligodeoxynucleotide modulates its immunostimulatory activity. Bioorg Med Chem Lett 9:3453–3458

    CAS  Google Scholar 

  71. Zhao Q, Yu D, Agrawal S (2000) Immunostimulatory activity of CpG containing phosphorothioate oligodeoxynucleotide is modulated by modification of a single deoxynucleoside. Bioorg Med Chem Lett 10:1051–1054

    CAS  Google Scholar 

  72. Yu D, Kandimalla ER, Zhao Q et al (2002) Immunostimulatory properties of phosphorothioate CpG DNA containing both 3′-5′- and 2′-5′-internucleotide linkages. Nucleic Acids Res 30:1613–1619

    CAS  Google Scholar 

  73. Yu D, Kandimalla ER, Cong YP et al (2002) Design, synthesis, and immunostimulatory properties of CpG DNAs containing alkyl-linker substitutions: role of nucleosides in the flanking sequences. J Med Chem 45:4540–4548

    CAS  Google Scholar 

  74. Yu D, Kandimalla ER, Zhao Q et al (2001) Modulation of immunostimulatory activity of CpG oligonucleotides by site-specific deletion of nucleobases. Bioorg Med Chem Lett 11:2263–2267

    CAS  Google Scholar 

  75. Yu D, Kandimalla ER, Zhao Q et al (2003) Requirement of nucleobase proximal to CpG dinucleotide for immunostimulatory activity of synthetic CpG DNA. Bioorg Med Chem 11:459–464

    CAS  Google Scholar 

  76. Kandimalla ER, Bhagat L, Yu D et al (2002) Conjugation of ligands at the 5′-end of CpG DNA affects immunostimulatory activity. Bioconjug Chem 13:966–974

    CAS  Google Scholar 

  77. Yu D, Zhao Q, Kandimalla ER et al (2000) Accessible 5′-end of CpG-containing phosphorothioate oligodeoxynucleotides is essential for immunostimulatory activity. Bioorg Med Chem Lett 10:2585–2588

    CAS  Google Scholar 

  78. Kandimalla ER, Bhagat L, Wang D et al (2003) Divergent synthetic nucleotide motif recognition pattern: design and development of potent immunomodulatory oligodeoxyribonucleotide agents with distinct cytokine induction profiles. Nucleic Acids Res 31:2393–2400

    CAS  Google Scholar 

  79. Kandimalla ER, Bhagat L, Li Y et al (2005) Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent Toll-like receptor 9 agonists. Proc Natl Acad Sci USA 102:6925–6930

    CAS  Google Scholar 

  80. Yu D, Kandimalla ER, Bhagat L et al (2002) ‘Immunomers’ – novel 3′-3′-linked CpG oligodeoxynucleotides as potent immunomodulatory agents. Nucleic Acids Res 30:4460–4469

    CAS  Google Scholar 

  81. Bhagat L, Zhu FG, Yu D et al (2003) CpG penta- and hexadeoxyribonucleotides as potent immunomodulatory agents. Biochem Biophys Res Commun 300:853–861

    CAS  Google Scholar 

  82. Wang D, Kandimalla ER, Yu D et al (2005) Oral administration of second-generation immunomodulatory oligonucleotides induce mucosal Th1immune responses and adjuvant activity. Vaccine 23:2614–2622

    CAS  Google Scholar 

  83. Zhu FG, Kandimalla ER, Yu D et al (2007) Oral administration of a synthetic agonist of TLR9 potently modulates peanut-induced allergy in mice. J Allergy Clin Immunol 120:631–637

    CAS  Google Scholar 

  84. Putta MR, Zhu FG, Wang D et al (2010) Peptide conjugation at the 5′-end of oligodeoxynucleotides abrogates Toll-like receptor 9-mediated immune stimulatory activity. Bioconjug Chem 21:39–45

    CAS  Google Scholar 

  85. Creticos PS, Schroeder JT, Hamilton RG et al (2006) Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445–1455

    CAS  Google Scholar 

  86. Latz E, Verma A, Visintin A et al (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772–779

    CAS  Google Scholar 

  87. Putta MR, Zhu F, Li Y et al (2006) Novel oligodeoxynucotide agonists of TLR9 containing N3-Me-dC or N1-Me-dG modifications. Nucleic Acids Res 34:3231–3238

    Google Scholar 

  88. Kandimalla ER, Yu D, Zhao Q et al (2001) Effect of chemical modifications of cytosine and guanine in a CpG-motif of oligonucleotides on immunostimulatory activity: structure-immunostimulatory activity relationships. Bioorg Med Chem 9:807–813

    CAS  Google Scholar 

  89. Kandimalla ER, Bhagat L, Zhu F-G et al (2003) A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species specific recognition observed with CpG motif. Proc Natl Acad Sci USA 100:14303–14308

    CAS  Google Scholar 

  90. Yu D, Putta MR, Bhagat L et al (2007) Agonists of Toll-like receptor 9 containing synthetic dinucleotide motifs. J Med Chem 50:6411–6418

    CAS  Google Scholar 

  91. Cong YP, Song SS, Bhagat L et al (2003) Self-stabilized CpG DNAs optimally activate human B cells and plasmacytoid dendritic cells. Biochem Biophys Res Commun 310:1133–1139

    CAS  Google Scholar 

  92. Kandimalla ER, Bhagat L, Cong YP et al (2003) Secondary structures in CpG oligonucleotides affect immunostimulatory activity. Biochem Biophys Res Commun 306:948–953

    CAS  Google Scholar 

  93. Yu D, Putta MR, Bhagat L et al (2008) Impact of secondary structure of Toll-like receptor 9 agonists on interferon-α induction. Antimicrob Agents Chemother 52:4320–4325

    CAS  Google Scholar 

  94. Vicari AP, Schmalbach T, Lekstrom-Himes J et al (2007) Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILONTM), an investigational synthetic Toll-like receptor 9 agonist. Antiviral Ther 12:741–751

    CAS  Google Scholar 

  95. Putta MR, Zhu FG, Wang D et al (2010) Impact of nature and length of linker incorporated in agonists on Toll-like receptor 9-mediated immune responses. J med chem 53:3730–3738

    Google Scholar 

  96. Mbow ML, Sarisky RT (2005) Modulating Toll-like receptor signaling as a novel antiinfective approach. Drug News Perspect 18:179–184

    CAS  Google Scholar 

  97. Daubenberger CA (2007) TLR9 agonists as adjuvants for prophylactic and therapeutic vaccines. Curr Opin Mol Ther 9:45–52

    CAS  Google Scholar 

  98. Li Y, Kandimalla ER, Yu D et al (2005) Immunomodulatory oligonucleotides containing synthetic CpR and R′pG motifs augment long-term immune responses to HBsAg in mice. Int Immunopharmacol 5:981–991

    CAS  Google Scholar 

  99. Trabattoni D, Clivio A, Bray DH et al (2006) Immunization with gp120-depleted whole killed HIV immunogen and a second-generation CpG DNA elicits strong HIV-specific responses in mice. Vaccine 24:1470–1477

    CAS  Google Scholar 

  100. Aurisicchio L, Peruzzi D, Conforti A et al (2009) Treatment of mammary carcinomas in Her-2 transgenic mice through combination of genetic vaccine and an agonist of Toll-like receptor 9. Clin Cancer Res 15:1575–1584

    CAS  Google Scholar 

  101. Conforti A, Cipriani B, Peruzzi D et al (2010) A TLR9 agonist enhances therapeutic effects of telomerase genetic vaccine. Vaccine 28:3522–3530

    CAS  Google Scholar 

  102. Dharmapuri S, Peruzzi D, Mennuni C et al (2009) Immunologic characterization of co-administration of telomerase genetic vaccine and a novel TLR9 agonist in non-human primates. Mol Ther 17:1804–1813

    CAS  Google Scholar 

  103. Murad YM, Clay TM (2009) CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs 23:361–375

    CAS  Google Scholar 

  104. Wang D, Li Y, Yu D et al (2004) Immunopharmacological and antitumor effects of second-generation immunomodulatory oligonucleotides containing synthetic CpR motifs. Int J Oncol 24:901–908

    CAS  Google Scholar 

  105. Damiano V, Caputo R, Bianco R et al (2006) Novel Toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12:577–583

    CAS  Google Scholar 

  106. Damiano V, Caputo R, Garofalo S et al (2007) Novel TLR9 agonist synergizes by different mechanisms with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci USA 104:12468–12473

    CAS  Google Scholar 

  107. Damiano V, Garofalo S, Rosa R et al (2009) A novel Toll-like receptor 9 agonist cooperates with trastuzumab in trastuzumab-resistant breast tumors via multiple mechanisms of action. Clin Cancer Res 15:6921–6930

    CAS  Google Scholar 

  108. Duez C, Gosset P, Tonnel AB (2006) Dendritic cells and Toll-like receptors in allergy and asthma. Eur J Dermatol 16:12–16

    CAS  Google Scholar 

  109. Horner AA (2006) Update on Toll-like receptor ligands and allergy: implications for immunotherapy. Curr Allergy Asthma Rep 6:395–401

    CAS  Google Scholar 

  110. Agrawal DK, Edwan J, Kandimalla ER et al (2004) Novel Immunomodulatory oligonucleotides (IMOs) prevent development of allergic airway inflammation and airway hyperresponsiveness in asthma. Int Immunopharmacol 4:127–138

    CAS  Google Scholar 

  111. Zhu FG, Kandimalla ER, Yu D et al (2004) Modulation of ovalbumin induced Th2 responses by second generation immunomodulatory oligonucleotides in mice. Int Immunopharmacol 4:851–862

    CAS  Google Scholar 

  112. Ebert CS Jr, Rose AS, Patel MR et al (2006) The role of immunomodulatory oligonucleotides in prevention of OVA-induced Eustachian tube dysfunction. Int J Pediatr Otorhinolaryngol 70:2019–2026

    Google Scholar 

  113. Ebert CS Jr, Rose AS, Blanks DA et al (2007) Immunomodulatory oligonucleotides in prevention of nasal allergen-induced Eustachian tube dysfunction in rats. Otolaryngol Head Neck Surg 137:250–255

    Google Scholar 

  114. Blanks DA, Ebert CS Jr, Eapen RP et al (2007) The Immunomodulatory oligonucleotides in the prevention and treatment of OVA-induced Eustachian tube dysfunction in rats. Otolaryngol Head Neck Surg 137:321–326

    Google Scholar 

  115. Hwang J, Fox-Sinclair E, Bahrani A et al (2003) A phase I study of a second-generation immunomodulatory oligonucleotide (HYB2055) in patients with advanced solid malignancies. Presented at the AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics, 17–21 Nov, Boston, MA (abstract # C111)

    Google Scholar 

  116. Hwang J, Malik S, Park S et al (2004) Clinical safety and pharmacodynamics of IMOxineTM, a second-generation immunomodulatory oligonucleotide, in refractory cancer patients. Presented at TOLL 2004, 8–11 May, Taormina, Sicily, Italy

    Google Scholar 

  117. Martin R, Sullivan T, Bhagat L et al (2003) A phase 1 placebo-controlled study in volunteers of escalating doses of HYB2055, a second-generation immunomodulatory agent based on CpG DNA. Presented at the AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics, 17–21 Nov 2003, Boston, MA (abstract # C100)

    Google Scholar 

  118. Sullivan T, Bhagat L, Kandimalla E et al (2004) Immunological activity of HYB2055, a TLR-9 agonist, in healthy volunteers. Presented at the 2004 AACR annual meeting, 26–30 March, Orlando, Florida (abstract # 4707) Proc Am Assoc Cancer Res 45:1087

    Google Scholar 

  119. Malik S, Hwang J, Cotarla I, Sullivan T, Karr R, Marshall J (2007) Initial phase 1 results of gemcitabine, carboplatin and IMO-2055, a Toll-like Receptor 9 (TLR9) agonist, in patients with advanced solid tumors. Presented at the 12th World conference on lung cancer, 2–6 Sept, Seoul, Korea

    Google Scholar 

  120. Kuzel T, Dutcher J, Ebbinghaus S et al (2009) A phase 2 multi-center, randomized, open-label study of two dose levels of IMO-2055 in patients (pts) with metastatic or recurrent renal cell carcinoma (RCC). Presented at the eighth international kidney cancer symposium, 25 and 26 September, Chicago, IL

    Google Scholar 

  121. Smith DA, Conkling P, Richards D et al (2009) Phase 1b clinical trial of IMO-2055 in combination with Tarceva and Avastin in non-small cell lung cancer. Presented at Joint 15th Congress of the European Cancer Organization (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO), Berlin, Germany, 23 September (abstract # 9148, Eur J Cancer 7, 549–550)

    Google Scholar 

  122. Dubois G, Simmons J, Martin E et al (2008) Effects of a novel synthetic TLR9 agonist on repeated allergen challenge in allergic monkeys. Presented at Toll 2008: recent advances in pattern recognition, Lisbon, Portugal, 24–27 September

    Google Scholar 

  123. Muir A, Ghalib R, Lawitz E et al (2010) A phase 1, multi-center, randomized, placebo-controlled, dose-escalation study of IMO-2125, a TLR9 agonist, in Hepatitis C-nonresponders. Presented at the International Liver Congress 2010 by EASL, 14–18 April, Vienna, Austria

    Google Scholar 

  124. Marshak-Rothstein A, Rifkin IR (2007) Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol 25:419–441

    CAS  Google Scholar 

  125. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR et al (2010) Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 6:146–156

    CAS  Google Scholar 

  126. Uccellini MB, Avalos AM, Marshak-Rothstein A et al (2009) Toll-like receptor-dependent immune complex activation of B cells and dendritic cells. Methods Mol Biol 517:363–380

    CAS  Google Scholar 

  127. Lande R, Gregorio J, Facchinetti V et al (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449:564–569

    CAS  Google Scholar 

  128. Niessner A, Sato K, Chaikof EL et al (2006) Pathogen-sensing plasmacytoid dendritic cells stimulated cytotoxic T-cell function in the atherosclerotic plaque through intereferon-alpha. Circulation 114:2482–2489

    CAS  Google Scholar 

  129. Ronnblom L, Pascual V (2008) The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17:394–399

    CAS  Google Scholar 

  130. Kyburz D (2006) Mode of action of hydroxychloroquine in RA – evidence of an inhibitory effect on Toll-like receptor signaling. Nat Clin Pract Rheumatol 2:458–459

    Google Scholar 

  131. Ashman RF, Goeken JA, Drahos J et al (2005) Sequence requirements for oligodeoxyribonucleotide inhibitory activity. Int Immunol 17:411–420

    CAS  Google Scholar 

  132. Barrat FJ, Meeker T, Gregorio J et al (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythemaosus. J Exp Med 202:1131–1139

    CAS  Google Scholar 

  133. Duramad O, Fearon KL, Chang B et al (2005) Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J Immunol 174:5193–5200

    CAS  Google Scholar 

  134. Gursel I, Gursel M, Yamada H et al (2003) Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol 171:1393–1400

    CAS  Google Scholar 

  135. Krieg AM, Wu T, Weeratna R et al (1998) Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 95:12631–12636

    CAS  Google Scholar 

  136. Lenert P (2005) Inhibitory oligodeoxynucleotides – therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol 140:1–10

    CAS  Google Scholar 

  137. Lenert P, Stunz L, Yi AK et al (2001) CpG stimulation of primary mouse B cells is blocked by inhibitory oligodeoxyribonucleotides at a site proximal to NF-kappaB activation. Antisense Nucleic Acid Drug Dev 11:247–256

    CAS  Google Scholar 

  138. Shirota H, Gursel M, Klinman DM (2004) Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-γ- and IL-12-mediated signaling. J Immunol 173:5002–5007

    CAS  Google Scholar 

  139. Ballas ZK, Krieg AM, Warren T et al (2001) Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs. J Immunol 167:4878–4886

    CAS  Google Scholar 

  140. Bates PJ, Laber DA, Miller DM et al (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151–164

    CAS  Google Scholar 

  141. Guan Y, Reddy KR, Zhu Q et al (2010) G-rich oligonucleotides inhibit HIF-1α and HIF-2α and block tumor growth. Mol Ther 18:188–197

    CAS  Google Scholar 

  142. Verthelyi DJ, Gursel M, Kenney RT et al (2003) CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection. J Immunol 170:4717–4723

    CAS  Google Scholar 

  143. Patole PS, Zecher D, Pawar RD et al (2005) G-rich DNA suppresses systemic lupus. J Am Soc Nephrol 16:3273–3280

    CAS  Google Scholar 

  144. Yamada H, Gursel I, Takeshita F et al (2002) Effect of suppressive DNA on CpG-induced immune activation. J Immunol 169:5590–5594

    CAS  Google Scholar 

  145. Stunz LL, Lenert P, Peckham D et al (2002) Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells. Eur J Immunol 32:1212–1222

    CAS  Google Scholar 

  146. Dong L, Ito S, Ishii KJ et al (2005) Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice. Arthritis Rheum 52:651–658

    CAS  Google Scholar 

  147. Agrawal S, Iadorola PL, Temsamani J et al (1996) Effect of G-rich sequences on the synthesis, purification, hybridization, cell uptake, and hemolytic activity of oligonucleotides. Bioorg Med Chem Lett 6:2219–2214

    CAS  Google Scholar 

  148. Agrawal S, Tan W, Cai Q et al (1997) In vivo pharmacokinetics of phosphorothioate oligonucleotides containing contiguous guanosines. Antisense Nucleic Acid Drug Dev 7:245–249

    CAS  Google Scholar 

  149. Wang D, Bhagat L, Yu D et al (2009) Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9. J Med Chem 52:551–558

    CAS  Google Scholar 

  150. Yu D, Wang D, Zhu FG et al (2009) Modifications incorporated in CpG motifs of oligodeoxynucleotides lead to antagonist activity of Toll-like receptors 7 and 9. J Med Chem 52:5108–5114

    CAS  Google Scholar 

Download references

Acknowledgments

The authors thank their colleagues, Lakshmi Bhagat, Weiwen Jiang, Tao Lan, Victoria Philbin, Melissa Precopio, Mallik Putta, Tim Sullivan, Jimmy Tang, Daqing Wang, Dong Yu, and Fu-Gang Zhu for their contributions, as cited by publications.

Author information

Authors and Affiliations

  1. Idera Pharmaceuticals, 167 Sidney Street, Cambridge, MA, 02139, USA

    Ekambar R. Kandimalla & Sudhir Agrawal

Authors
  1. Ekambar R. Kandimalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sudhir Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sudhir Agrawal .

Editor information

Editors and Affiliations

  1. Dept. Biomolecular Engineering, Kyoto Institute of Technology, Matsugasaki, Kyoto, 606-8585, Japan

    Akira Murakami

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kandimalla, E.R., Agrawal, S. (2011). Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides. In: Murakami, A. (eds) Nucleic Acid Drugs. Advances in Polymer Science, vol 249. Springer, Berlin, Heidelberg. https://doi.org/10.1007/12_2011_138

Download citation

Publish with us

Policies and ethics

Search

Navigation