CpG 1018® | ALZFORUM (2024)

Name: CpG 1018®
Synonyms: CpG oligodeoxynucleotides, CpG ODN
Therapy Type: Immunotherapy (active) (timeline), DNA/RNA-based
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Dynavax Technologies

CpG 1018 is a proprietary immune adjuvant made up of short, unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). Its components mimic bacterial DNA to activate innate immunity through binding to the toll-like receptor 9 (TLR9). CpG 1018 is added to vaccines to enhance immune responses to protein antigens. TLR9 is also an important regulator of microglia, and CpG 1018 is being tested on its own for its potential to stimulate clearance of amyloid pathology and treat Alzheimer’s disease. It is given by subcutaneous injection, and does not enter the brain.

In early studies, CpG ODNs stimulated the uptake of Aβ by mouse microglia (Iribarren et al., 2005). More recently, New York University researchers showed that CpG ODN treatment reduced Aβ and tau pathologies, and improved performance on cognitive tests, in the Tg2576 mouse amyloidosis model (Scholtzova et al., 2009; Scholtzova et al., 2014). CpG ODN stimulated clearance of vascular amyloid and improved cognition in Tg-SwDI mice, without causing microhemorrhages (Scholtzova et al., 2017). In old squirrel monkeys, a nonhuman primate model of sporadic Alzheimer’s disease, two years of subcutaneous CpG ODN injections reduced vascular amyloid and phosphorylated tau in brain, and improved behavior, without inducing microhemorrhages or inflammatory responses (Patel et al., 2021).

CpG 1018 is a component of several approved vaccines, including hepatitis B and COVID vaccines.

In March 2023, CpG 1018 began a Phase 1 safety trial in 39 people with amyloid PET-confirmed early Alzheimer’s disease. Participants in the ascending dose study will receive three subcutaneous injections, three weeks apart, of 0.1, 0.25, or 0.5 mg/kg, or placebo. Dosing cohorts will proceed sequentially, with higher doses commencing after safety confirmation of the preceding dose. Primary outcomes are adverse events, levels of various autoimmunity markers in blood, and ARIA-E or -H on MRI. Secondary outcomes include change in the ADAS-COG13, ADCS-ADL, CDR, and MoCA, as well as amyloid and tau CSF and plasma biomarkers. Funded by the Alzheimer’s Association, the trial is taking place at New York University, with completion anticipated in November 2024.

Dynavax is also evaluating CpG 1018-containing vaccines for pneumonic plaque, TDaP, and shingles.

For details on CpG 1018 trials, see clinicaltrials.gov

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Paper Citations

1. Iribarren P, Chen K, Hu J, Gong W, Cho EH, Lockett S, Uranchimeg B, Wang JM.CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1-42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2. FASEB J. 2005 Dec;19(14):2032-4. PubMed.
2. Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T.Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. J Neurosci. 2009 Feb 11;29(6):1846-54. PubMed.
3. Scholtzova H, Chianchiano P, Pan J, Sun Y, Goñi F, Mehta PD, Wisniewski T.Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun. 2014 Sep 2;2:101. PubMed.
4. Scholtzova H, Do E, Dhakal S, Sun Y, Liu S, Mehta PD, Wisniewski T.Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. J Neurosci. 2017 Jan 25;37(4):936-959. PubMed.
5. Patel AG, Nehete PN, Krivoshik SR, Pei X, Cho EL, Nehete BP, Ramani MD, Shao Y, Williams LE, Wisniewski T, Scholtzova H.Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer's disease pathology in aged squirrel monkeys. Brain. 2021 Aug 17;144(7):2146-2165. PubMed.

External Citations

1. clinicaltrials.gov

No Available Further Reading