CPG 10101 (ACTILON™) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV.
Objectives and Methods
In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks.
Results
A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2’,5’-oligoadenylate synthetase were sustained for several days.
Conclusion
This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
References
1.
KriegA.M.Therapeutic potential of Toll-like receptor 9 activation.Nat Rev Drug Discov2006; 5: 471–484.
2.
VidalD.Topical imiquimod: mechanism of action and clinical applications.Mini Rev Med Chem2006; 6: 499–503.
3.
SchetterC., VollmerJ.Toll-like receptors involved in the response to microbial pathogens: development of agonists for Toll-like receptor 9.Curr Opin Drug Discov Devel2004; 7: 204–210.
4.
WagnerH.Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity.Curr Opin Microbiol2002; 5: 62–69.
5.
VollmerJ., WeeratnaR., PayetteP.Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities.Eur J Immunol2004; 34: 251–262.
6.
HartmannG., BattianyJ., PoeckH.Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells.Eur J Immunol2003; 33: 1633–1641.
7.
MarshallJ.D., FearonK., AbbateC.Identification of a novel CpG DNA class and motif that optimally stimulate B-cell and plasmacytoid dendritic cell functions.J Leukoc Biol2003; 73: 781–792.
8.
PawlotskyJ.M.Current and future concepts in hepatitis C therapy.Semin Liver Dis2005; 25: 72–83.
9.
BowenD.G., WalkerC.M.Adaptive immune responses in acute and chronic hepatitis C virus infection.Nature2005; 436: 946–952.
10.
SugimotoK., IkedaF., StadanlickJ.Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection.Hepatology2003; 38: 1437–1448.
11.
HoffmannR.M., DiepolderH.M., ZachovalR.Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection.Hepatology1995; 21: 632–638.
12.
HempelG., GalleP.R., LohrH.F.Quantitative analysis of specific Th1/Th2 helper cell responses and IgG subtype antibodies in interferon-alpha-treated patients with chronic hepatitis C.J Med Virol2001; 64: 340–349.
13.
LohrH.F., SchmitzD., ArenzM.The viral clearance in interferon-treated chronic hepatitis C is associated with increased cytotoxic T-cell frequencies.J Hepatol1999; 31: 407–415.
14.
KamalS.M., FehrJ., RoeslerB., PetersT., RasenackJ.W.Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C.Gastroenterology2002; 123: 1070–1083.
15.
VollmerJ., JurkM., VolpK.Combined immunostimulatory activities of the C-class TLR9 agonist, CPG 10101, IFN-α, and ribavirin on IFN-dependent and regulatory gene expression in human immune cells.Hepatology2006; 44Suppl 1: 617A.
16.
VicariA.P., TrinchieriG.Interleukin-10 in viral diseases and cancer: exiting the labyrinth?Immunol Rev2004; 202: 223–236.
17.
National Cancer Institute [homepage on the internet].Bethesda, MA: National Cancer Institute [updated 1999 April 30; cited 2007 March 27]. Common Toxicity Criteria version 2.0 (CTC). Available from http://ctep.cancer.gov/forms/CTCv20_4-30–992.pdf.
18.
EflerS.M., ZhangL., NollB.O., UhlmannE., DavisH.L.Quantification of oligodeoxynucleotides in human plasma with a novel hybridization assay offers greatly enhanced sensitivity over capillary gel electrophoresis.Oligonucleotides2005; 15: 119–131.
19.
MarnellL., MoldC., Du ClosT.W.C-reactive protein: ligands, receptors and role in inflammation.Clin Immunol2005; 117: 104–111.
20.
GlueP., FangJ.W., Rouzier-PanisR.Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group.Clin Pharmacol Ther2000; 68: 556–567.
21.
AulitzkyW.E., TilgH., VogelW.Acute hematologic effects of interferon alpha, interferon gamma, tumor necrosis factor alpha and interleukin 2.Ann Hematol1991; 62: 25–31.
22.
GunzerM., RiemannH., BasogluY.Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion.Blood2005; 106: 2424–2432.
23.
KriegA.M., EflerS.M., WittpothM., Al AdhamiM.J., DavisH.L.Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist.J Immunother2004; 27: 460–471.
24.
NollB.O., McCluskieM.J., SniatalaT.Biodistribution and metabolism of immunostimulatory oligodeoxynucleotide CPG 7909 in mouse and rat tissues following subcutaneous administration.Biochem Pharmacol2005; 69: 981–991.
25.
CocciaE.M., SeveraM., GiacominiE.Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells.Eur J Immunol2004; 34: 796–805.
26.
BrassardD.L., GraceM.J., BordensR.W.Interferon-alpha as an immunotherapeutic protein.J Leukoc Biol2002; 71: 565–581.
27.
DurandV., WongS.Y., ToughD.F., Le BonA.Shaping of adaptive immune responses to soluble proteins by TLR agonists: a role for IFN-alpha/beta.Immunol Cell Biol2004; 82: 596–602.
28.
SporriR., Reis e SousaC.Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function.Nat Immunol2005; 6: 163–170.
29.
GautierG., HumbertM., DeauvieauF.A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.J Exp Med2005; 201: 1435–1446.
30.
IoannouY., IsenbergD.A.Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy.Arthritis Rheum2000; 43: 1431–1442.
31.
KlinmanD.M.Immunotherapeutic uses of CpG oligodeoxynucleotides.Nat Rev Immunol2004; 4: 249–259.
32.
LeadbetterE.A., RifkinI.R., HohlbaumA.M.Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.Nature2002; 416: 603–607.
33.
VigliantiG.A., LauC.M., HanleyT.M.Activation of autoreactive B cells by CpG dsDNA.Immunity2003; 19: 837–847.
