Modulation of endosomal toll-like receptor-mediated immune responses by synthetic oligonucleotides

Advances in Polymer Science

Volumn 249, Issue , 2012, Pages 61-93

  Kandimalla, Ekambar R ^a   Agrawal, Sudhir ^a  

^a HYBRIDON INC   (United States)

Author keywords

Agonist; Antagonist; Immune stimulation; Immune modulatory oligonucleotides; Oligodeoxynucleotides; Oligonucleotides; Oligoribonucleotides; Toll like receptor 7; Toll like receptor 8; Toll like receptor 9

Indexed keywords

EID: 84865430097     PISSN: 00653195     EISSN: None     Source Type: Book Series    
DOI: 10.1007/12_2011_138     Document Type: Article

References (150)

1. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20: 197-216
2. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291-295
3. Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24-32
4. Lasker MV, Nair SK (2006) Intracellular TLR signaling: A structural perspective on human disease. J Immunol 177:11-16
5. Kenny EF, O'Neill LA (2008) Signalling adaptors used by Toll-like receptors: An update. Cytokine 43:342-349
6. Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19:3-10
7. Alexopoulou L, Holt AC, Medzhitov R (2001) Recognition of double-stranded RNA and activation of NF-kB by Toll-like receptor 3. Nature 413:732-738
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
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
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
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
12. Hemmi H, Takeuchi O, Kawai T et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740-745
13. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987-995
14. Diebold SS (2008) Recognition of viral single-stranded RNA by Toll-like receptors. Adv Drug Deliv Rev 60:813-823
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
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
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
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
19. Karlsson A, Jagervall 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
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
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
22. Marques JT, Williams BR (2005) Activation of the mammalian immune system by siRNAs. Nat Biotechnol 23:1399-1405
23. Sioud M (2005) Induction of inflammatory cytokines and interferon responses by doublestranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 348:1079-1090
24. Kariko K, Bhuyan P, Capodici J et al (2004) Small interfering RNAs mediate sequenceindependent gene suppression and induce immune activation by signaling through Toll-like receptor 3. J Immunol 172:6545-6549
25. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence-and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591-597
26. Dow S (2008) Liposome-nucleic acid immunotherapeutics. Expert Opin Drug Deliv 5:11-24
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
28. Agrawal S, Kandimalla ER (2007) Synthetic agonists of Toll-like receptors 7, 8, and 9. Biochem Soc Trans 35:1461-1467
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
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
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
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
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
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
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
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
37. Messina JP, Gilkeson GS, Pisetsky DS (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol 147:1759-1764
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
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
40. Krieg AM, Yi AK, Matson S et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546-549
41. Agrawal S, Kandimalla ER (2004) Roll of Toll-like receptors in antisense and siRNA. Nat Biotechnol 22:1533-1537
42. Agrawal S, Kandimalla ER (2000) Antisensense therapeutics: is it as simple as complementary base recognition? Mol Med Today 6:72-81
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
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
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
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
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
48. Agrawal S, Martin RR (2003) Was induction of HIV-1 through TLR9? J Immunol 171:1621
49. Klinman DM (2004) Immunotherapeutic uses of CpG oligdeoxynucleotides. Nat Rev Immunol 4:249-258
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
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
52. Krug A, Rothenfusser S, Hornung V et al (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-a/b in plasmacytoid dendritic cells. Eur J Immunol 31:2154-2163
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
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
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
56. Sato Y, Roman M, Tighe H et al (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273:352-354
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
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
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
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
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
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
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
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
65. Agrawal S, Kandimalla ER (2001) Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr Cancer Drug Target 1:197-209
66. Zhao Q, Temsamani J, Iadarola PL et al (1996) Effect of different chemically modified oligodeoxynucleotides on immune stimulation. Biochem Pharmacol 51:173-182
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
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
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
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
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
72. Yu D, Kandimalla ER, Zhao Q et al (2002) Immunostimulatory properties of phosphorothioate CpG DNA containing both 30-50-and 20-50-internucleotide linkages. Nucleic Acids Res 30:1613-1619
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
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
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
76. Kandimalla ER, Bhagat L, Yu D et al (2002) Conjugation of ligands at the 50-end of CpG DNA affects immunostimulatory activity. Bioconjug Chem 13:966-974
77. Yu D, Zhao Q, Kandimalla ER et al (2000) Accessible 50-end of CpG-containing phosphorothioate oligodeoxynucleotides is essential for immunostimulatory activity. Bioorg Med Chem Lett 10:2585-2588
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
79. Kandimalla ER, Bhagat L, Li Y et al (2005) Immunomodulatory oligonucleotides containing a cytosine-phosphate-20-deoxy-7-deazaguanosine motif as potent Toll-like receptor 9 agonists. Proc Natl Acad Sci USA 102:6925-6930
80. Yu D, Kandimalla ER, Bhagat L et al (2002) 'Immunomers'-novel 30-30-linked CpG oligodeoxynucleotides as potent immunomodulatory agents. Nucleic Acids Res 30:4460-4469
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
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
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
84. Putta MR, Zhu FG, Wang D et al (2010) Peptide conjugation at the 50-end of oligodeoxynucleotides abrogates Toll-like receptor 9-mediated immune stimulatory activity. Bioconjug Chem 21:39-45
85. Creticos PS, Schroeder JT, Hamilton RG et al (2006) Immunotherapy with a ragweedtoll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445-1455
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
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
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: structureimmunostimulatory activity relationships. Bioorg Med Chem 9:807-813
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
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
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
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
93. Yu D, Putta MR, Bhagat L et al (2008) Impact of secondary structure of Toll-like receptor 9 agonists on interferon-a induction. Antimicrob Agents Chemother 52:4320-4325
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
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
96. Mbow ML, Sarisky RT (2005) Modulating Toll-like receptor signaling as a novel antiinfective approach. Drug News Perspect 18:179-184
97. Daubenberger CA (2007) TLR9 agonists as adjuvants for prophylactic and therapeutic vaccines. Curr Opin Mol Ther 9:45-52
98. Li Y, Kandimalla ER, Yu D et al (2005) Immunomodulatory oligonucleotides containing synthetic CpR and R0pG motifs augment long-term immune responses to HBsAg in mice. Int Immunopharmacol 5:981-991
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
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
101. Conforti A, Cipriani B, Peruzzi D et al (2010) A TLR9 agonist enhances therapeutic effects of telomerase genetic vaccine. Vaccine 28:3522-3530
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
103. Murad YM, Clay TM (2009) CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs 23:361-375
104. Wang D, Li Y, Yu D et al (2004) Immunopharmacological and antitumor effects of secondgeneration immunomodulatory oligonucleotides containing synthetic CpR motifs. Int J Oncol 24:901-908
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
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
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
108. Duez C, Gosset P, Tonnel AB (2006) Dendritic cells and Toll-like receptors in allergy and asthma. Eur J Dermatol 16:12-16
109. Horner AA (2006) Update on Toll-like receptor ligands and allergy: implications for immunotherapy. Curr Allergy Asthma Rep 6:395-401
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
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
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
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
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
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)
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
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)
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
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
120. Kuzel T, Dutcher J, Ebbinghaus S et al (2009) A phase 2 multi-center, randomized, openlabel 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
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)
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
123. Muir A, Ghalib R, Lawitz E et al (2010) A phase 1, multi-center, randomized, placebocontrolled, 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
124. Marshak-Rothstein A, Rifkin IR (2007) Immunologically active autoantigens: the role of tolllike receptors in the development of chronic inflammatory disease. Annu Rev Immunol 25: 419-441
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
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
127. Lande R, Gregorio J, Facchinetti V et al (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449:564-569
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
129. Ronnblom L, Pascual V (2008) The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17:394-399
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
131. Ashman RF, Goeken JA, Drahos J et al (2005) Sequence requirements for oligodeoxyribonucleotide inhibitory activity. Int Immunol 17:411-420
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
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
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
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
136. Lenert P (2005) Inhibitory oligodeoxynucleotides-therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol 140:1-10
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
138. Shirota H, Gursel M, Klinman DM (2004) Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-g-and IL-12-mediated signaling. J Immunol 173:5002-5007
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
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
141. Guan Y, Reddy KR, Zhu Q et al (2010) G-rich oligonucleotides inhibit HIF-1a and HIF-2a and block tumor growth. Mol Ther 18:188-197
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
143. Patole PS, Zecher D, Pawar RD et al (2005) G-rich DNA suppresses systemic lupus. J Am Soc Nephrol 16:3273-3280
144. Yamada H, Gursel I, Takeshita F et al (2002) Effect of suppressive DNA on CpG-induced immune activation. J Immunol 169:5590-5594
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
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
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
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
149. Wang D, Bhagat L, Yu D et al (2009) Oligodeoxyribonucleotide-based antagonists for Tolllike receptors 7 and 9. J Med Chem 52:551-558
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