Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.

UNLABELLED: 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.

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.

Subcutaneous injection of normal human volunteers with a B-class CpG oligodeoxynucleotide (ODN) TLR9 agonist, CPG 7909, induced a TH1-like pattern of systemic innate immune activation manifested by expression of IL-6, IL-12p40, IFN-alpha, and IFN-inducible chemokines. Serum IP-10 was found to be the most sensitive assay for subcutaneous CPG 7909 stimulation; its level was significantly increased in all subjects at all dose levels, including the lowest tested dose of just 0.0025 mg/kg. This pattern of chemokine and cytokine induction was markedly different from that previously reported to be induced by TLR9 stimulation in rodents, most likely reflecting species-specific differences in the cell types expressing TLR9. Subcutaneous CPG 7909 injection induced transient shifts in blood neutrophils, lymphocytes, and monocytes, consistent with the increased chemokine expression. Levels of acute phase reactants such as C-reactive protein were also increased. A second subcutaneous CPG 7909 injection administered 2 weeks after the first elicited similar immune responses, showing little or no tolerance to the effects of repeated in vivo TLR9 stimulation. Subjects developed dose-dependent transient injection site reactions and flu-like symptoms but otherwise tolerated injection well, with no evidence of organ toxicity or systemic autoimmunity. The activation of innate immunity was dependent on the route of ODN administration, since intravenous injection caused no such effects. These studies indicate that in vivo activation of TLR9 by subcutaneous administration of CPG 7909 could be a well-tolerated immunotherapeutic approach for induction of TH1 innate immune activation.