Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703

Nucleic Acid Therapeutics

Volumn 25, Issue 3, 2015, Pages 130-140

  Schmidt, Manuel ^a   Hagner, Nicole ^b   Marco, Alberto ^c   König Merediz, Sven A ^d   Schroff, Matthias ^a   Wittig, Burghardt ^b  

^a MOLOGEN AG   (Germany)

^b FREIE UNIVERSITÄT BERLIN   (Germany)

^c UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^d Vivotecnia   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; B7 ANTIGEN; CD40 ANTIGEN; CPG OLIGODEOXYNUCLEOTIDE; DNA; GAMMA INTERFERON; HLA DR ANTIGEN; IMMUNOMODULATING AGENT; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 12; INTERLEUKIN 12P40; INTERLEUKIN 2; INTERLEUKIN 6; MGN 1703; ODN 1826; UNCLASSIFIED DRUG; IMMUNOLOGICAL ADJUVANT; LEFITOLIMOD; TLR9 PROTEIN, HUMAN; TOLL LIKE RECEPTOR 9;

ACUTE TOXICITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CELL ACTIVATION; CELL STIMULATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; ENZYME LINKED IMMUNOSORBENT ASSAY; EXTRAMEDULLARY HEMATOPOIESIS; FEMALE; FLOW CYTOMETRY; GEL ELECTROPHORESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFLAMMATION; LIVER INJURY; MOLECULAR WEIGHT; MOUSE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; AGONISTS; ANIMAL; CELL LINE; CHEMISTRY; DRUG DESIGN;

MUS; PRIMATES;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; CELL LINE; DNA; DRUG DESIGN; FEMALE; HUMANS; MICE; TOLL-LIKE RECEPTOR 9;

EID: 84926128648     PISSN: 21593337     EISSN: 21593345     Source Type: Journal    
DOI: 10.1089/nat.2015.0533     Document Type: Article

References (62)

1. Krieg AM. (2002). CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709-760.
2. Klinman DM. (2004). Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4:249-258.
3. Lotze MT, HJ Zeh, A Rubartelli, LJ Spavero, AA Amoscato, NR Washburn N, ME Devera, X Liang, M Tör and T Billar. (2007). The grateful dead: damage-associated molecule pattern molecules and reduction/ oxidation regulate immunity. Immunol Rev 220:60-81.
4. Haas T, J Metzger, F Schmitz, A Heit, T Müller, E Latz and H Wagner. (2008). The DNA sugar backbone 2′ deoxyribose determines toll-like receptor 9 activation. Immunity 28:315-323.
5. Kawai T and S Akira. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373-384.
6. Iwasaki A and R Medzhitov. (2003). Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987-995.
7. Hemmi H, O Takeuchi, T Kawai, T Kaisho, S Sato, H Sanjo, M Matsumoto, K Hoshino, H Wagner, K Takeda and S Akira. (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408:740-745.
8. Häcker H, RM Vabulas, O Takeuchi, K Hoshino, S Akira and H Wagner. (2000). Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med 192:595-600.
9. Latz E, A Schoenemeyer, A Visintin, KA Fitzgerald, BG Monks, CF Knetter, E Lien, NJ Nilsen, T Espevik and DT Golenbock. (2004). TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190-198.
10. Krieg AM, AK Yi, S Matson, TJ Waldschmidt, GA Bishop, R Teasdale, GA Koretzky and DM Klinman. (1995). CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546-549.
11. Klinman D, AK Yi, SL Beaucage, J Conover and AM Krieg. (1996). CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci (USA) 93:2879-2883.
12. Sparwasser T, ES Koch, RM Vabulas, K Heeg, GB Lipford, JW Ellwart and H Wagner. (1998). Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 28:2045-2054.
13. Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. (2006). Nat Rev Drug Discov 5:471-484.
14. Liu Y, X Luo, C Yang, S Yu and H Xu. (2011). Three CpG oligodeoxynucleotide classes differentially enhance antigen-specific humoral and cellular immune responses in mice. Vaccine 29:5778-5784.
15. McCluskie MJ and H.L Davis. (1998). CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J Immunol 161:4463-4466.
16. Brazolot Millan CL., R Weeratna, AM Krieg, CA Siegrist and HL Davis. (1998). CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc Natl Acad Sci (USA) 95:15553-15558.
17. Weeratna RD, MJ McCluskie, Y Xu and HL Davis. (2000). CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 18:1755-1762.
18. Verthelyi D, RT Kenney, RA Seder, AA Gam, B Friedag and DM Klinman. (2002). CpG oligodeoxynucleotides as vaccine adjuvants in primates. J Immunol 168:1659-1663.
19. Krieg AM, L Love-Homan, AK Yi and JT Harty. (1998). CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 161:2428-2434.
20. Ray NB and AM Krieg. (2003). Oral pretreatment of mice with CpG DNA reduces susceptibility to oral or intraperitoneal challenge with virulent Listeria monocytogenes. Infect Immun 71:4398-4404.
21. Carpentier AF, G Auf and JY Delattre. (2003). CpG-oligonucleotides for cancer immunotherapy: review of the literature and potential applications in malignant glioma. Front Biosci 8:115-127.
22. Jahrsdörfer B and GJ Weiner. (2003). CpG oligodeoxynucleotides for immune stimulation in cancer immunotherapy. Curr Opin Investig Drugs 4:686-690.
23. Krieg AM. (2004). Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6:88-95.
24. Krieg AM. (2012). CpG still rocks! Update on an accidental drug. Nucleic Acid Ther 22:77-89.
25. Hirsh V, L Paz-Ares, M Boyer, R Rosell, G Middleton and W Eberhardt. (2011). Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 29:2667-2674.
26. Manegold C, N van Zandwijk, A Szczesna, P Zatloukal, J Au and M Blasinska-Morawiec. (2012). A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol 23:72-77.
27. Zamecnik PC, J Goodchild, Y Taguchi and PS Sarin. (1986). Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc Natl Acad Sci (USA) 83:4143-4146.
28. Stein CA, C Subasinghe, K Shinozuka and JS Cohen. (1988). Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 16:3209-3221.
29. Shaw JP, K Kent, J Bird, J Fishback and B Froehler. (1991). Modified deoxyoligonucleotides stable to exonuclease degradation in serum. Nucleic Acids Res 19:747-750.
30. Krieg A.M, S Matson and E Fisher. (1996). Oligodeoxynucleotide modifications determine the magnitude of B cell stimulation by CpG motifs. Antisense Nucleic Acid Drug Dev 6:133-139.
31. Sheehan JP and HC Lan. (1998). Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. Blood 92:1617-1625.
32. Henry SP, W Novotny, J Leeds, C Auletta and DJ Kornbrust. (1997). Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev 7:503-510.
33. Shaw DR, PK Rustagi, ER Kandimalla, AN Manning, Z Jiang and S Agrawal. (1997). Effects of synthetic oligonucleotides on human complement and coagulation. Biochem Pharmacol 53:1123-1132.
34. Brown DA, SH Kang, S.M Gryaznov, L DeDionisio, O Heidenreich, S Sullivan, X Xu and MI Nerenberg. (1994). Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem 269: 26801-26805.
35. Levin AA. (1999). A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1489:69-84.
36. Henry SP, G Beattie, G Yeh, A Chappel, P Giclas, A Mortari, MA Jagels, DJ Kornbrust and AA Levin. (2002). Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int Immunopharmaco. 2:1657-1666.
37. Agrawal S, Q Zhao, Z Jiang, C Oliver, H Giles, J Heath and D Serota. (1997). Toxicologic effects of an oligodeoxynucleotide phosphorothioate and its analogs following intravenous administration in rats. Antisense Nucleic Acid Drug Dev 7:575-584.
38. Bjersing JL, K Eriksson, A Tarkowski and LV Collins. (2004). The arthritogenic and immunostimulatory properties of phosphorothioate oligodeoxynucleotides rely on synergy between the activities of the nuclease-resistant backbone and CpG motifs. Inflammation 28:39-51.
39. Heikenwalder M, M Polymenidou, T Junt, C Sigurdson, H Wagner, S Akira, R Zinkernagel and A Aguzzi. (2004). Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 10:187-192.
40. Erie D, N Sinha, W Olson, R Jones and K Breslauer. (1987). A dumbbell-shaped, double-hairpin structure of DNA: a thermodynamic investigation. Biochemistry 26:7150-7159.
41. Chu BC and LE Orgel. (1992). The stability of different forms of double-stranded decoy DNA in serum and nuclear extracts. Nucleic Acids Res 20:5857-5858.
42. Clusel D, E Ugarte, N Enjolras, M Vasseur and M. Blumenfeld. (1993). Ex vivo regulation of specific gene expression by nanomolar concentration of double-stranded dumbbell oligonucleotides. Nucleic Acids Res 21:3405-3411.
43. Köchling J, SA Konig-Merediz, R Stripecke, D Buchwald, A Korte, HG Von Einsiedel, F Sack, G Henze, K Seeger, B Wittig and M Schmidt. (2003). Protection of mice against Philadelphia chromosome-positive acute lymphoblastic leukemia by cell-based vaccination using nonviral, minimalistic expression vectors and immunomodulatory oligonucleotides. Clin Cancer Res 9:3142-3129.
44. Weihrauch MR, S Ansen, E Jurkiewicz, C Geisen, Z Xia, KS Anderson, E Gracien, M Schmidt, B Wittig, V Diehl, J Wolf, H Bohlen and LM Nadler. (2005). Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5-fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer. Clin Cancer Res 11:5993-6001.
45. Schmidt M, S Nagel, J Proba, C Thiede, M Ritter, JF Waring, F Rosenbauer, D Huhn, B Wittig, I Horak and A Neubauer. (1998). Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91:22-29.
46. Schmidt M, A Hochhaus, SA Konig-Merediz, C Brendel, J Proba, GJ Hoppe, B Wittig, G Ehninger, R Hehlmann and A Neubauer. (2000). Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy. J Clin Oncol 18:3331-3338.
47. Burchert A, D Cai, LC Hofbauer, MK Samuelsson, EP Slater, J Duyster, M Ritter, A Hochhaus, R Muller, M Eilers, M Schmidt and A Neubauer. (2004). Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 103:3480-3489.
48. Kandimalla ER, L Bhagat, YP Cong, RK Pandey, D Yu, Q Zhao and S Agrawal. (2003). Secondary structures in CpG oligonucleotides affect immunostimulatory activity. Biochem Biophys Res Commun 306:948-953.
49. Rutz M, J Metzger, T Gellert, P Luppa, GB Lipford, H Wagner and S Bauer. (2004). Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34:2541-2550.
50. Paul S. (2003). Technology evaluation: CpG-7909, Coley. Curr Opin Mol Ther 5:553-559.
51. Krieg AM. (2007). Development of TLR9 agonists for cancer therapy. J Clin Invest 117:1184-94.
52. Hartmann G, RD Weeratna, ZK Ballas, P Payette, S Blackwell, I Suparto, WL Rasmussen, M Waldschmidt, D Sajuthi, R.H Purcell, HL Davis and AM Krieg. (2000). Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617-1624.
53. Klinman DM and D Currie. (2003). Hierarchical recognition of CpG motifs expressed by immunostimulatory oligodeoxynucleotides. Clin Exp Immunol 133:227-232.
54. Roberts TL, MJ Sweet, DA Hume and KJ Stacey. (2005). Cutting edge: species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J Immunol 174:605-608.
55. Kandimalla ER, L Bhagat, FG Zhu, D Yu, YP Cong, D Wang, JX Tang, JY Tang, CF Knetter, E Lien and S Agrawal. (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.
56. Steinman RM, IS Mellman, WA Muller and ZA Cohn. (1983). Endocytosis and the recycling of plasma membrane. J Cell Biol 96:1-27.
57. Roberts TL, JA Dunn, TD Terry, MP Jennings, DA Hume, MJ Sweet and KJ Stacey. (2005). Differences in macrophage activation by bacterial DNA and CpG-containing oligonucleotides. J Immunol 175:3569-3576.
58. Latz E, A Verma, A Visintin, M Gong, CM Sirois, DC Klein, BG Monks, CJ McKnight, MS Lamphier, WP Duprex, T Espevik and DT Golenbock. 2007. Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772-779.
59. Bandholtz L, Y Guo, C Palmberg, K Mattsson, B Ohlsson, A High, J Shabanowitz, DF Hunt, H Jornvall, H Wigzell, B Agerberth and GH. Gudmundsson. (2003). Hsp90 binds CpG oligonucleotides directly: implications for hsp90 as a missing link in CpG signaling and recognition. Cell Mol Life Sci 60:422-429.
60. Okuya K, Y Tamura, K Saito, G Kutomi, T Torigoe, H Hirata and N Sato. (2010). Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type I IFN induction via targeting to static early endosome. J Immunol 184:7092-7099.
61. Weihrauch MR, H Richly, MS von Bergwelt-Baildon, HJ Becker, M Schmidt, UT Hacker, A Shimabukuro-Vornhagen, U Holtick, B Nokay, M Schroff, B Wittig and ME Scheulen. (2015). Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours. Eur J Cancer 51:146-156.
62. Schmoll HJ, B Wittig, D Arnold, J Riera-Knorrenschild, D Nitsche, H Kroening, F Mayer, J Andel, R Ziebermayr and W Scheithauer. (2014). Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. J Cancer Res Clin Oncol 140:1615-1624.