Evaluation of class C CpG ODN efficacy and safety profile in a squirrel monkey model of AD pathology

Background A drawback of current immunotherapeutic approaches is limited effectiveness against cerebral amyloid angiopathy (CAA) and CAA‐linked complications. The failures of many Alzheimer’s disease (AD) clinical trials have been related to poor translatability of promising rodent data to humans. Our initial study using a non‐human primate (NHP) model of AD amyloid pathology with a propensity for developing abundant CAA, squirrel monkey (SQM), indicates that chronic administration of TLR9 agonist, Class B CpG ODN, safely ameliorates CAA. Here, we advanced our work to evaluate the long‐term efficacy and safety of Class C CpG ODN, which has shown favorable safety profiles in a variety of human diseases. The present study was designed to assess CpG ODN immunostimulatory patterns and to monitor disease progression by a combination of behavioral measures and biomarker signatures of pathology development. Method Geriatric SQMs received either CpG ODN or saline every 4 weeks as part of an ongoing long‐term treatment study (currently in month 22). Changes in mRNA expression levels were periodically evaluated in isolated PBMCs prior to and 24hrs after representative injections using the Nanostring nCounter System. SIMOA and Luminex assays were used to measure AD related fluid biomarkers. Both treatment groups were subjected to locomotor activity testing prior to cognitive assessment. Result Longitudinal Nanostring analyses demonstrated significant up‐regulation of IFN‐inducible genes (e.g., IFIT2, Mx2/MxB, GBP1, MIG, IP10), specific cytokine‐chemokine genes, and TLR9 signaling genes (e.g., UNC93B1) following CpG ODN injections. Ongoing SIMOA examination of neurofilament light, a biomarker of neurodegeneration, showed higher plasma levels in the control group compared to CpG ODN group. Our preliminary measurements of a biomarker of glial injury, YKL‐40, indicated increased plasma levels in control animals compared to CpG ODN‐treated animals. Monitoring of additional AD pathology and cerebrovascular dysfunction biomarkers throughout the treatment period will further assess CpG ODN efficacy and safety. Importantly, no significant differences were observed between treatment groups in locomotor performance. Cognitive assessments are underway. Conclusion Overall, the present findings provide essential information prior to any clinical use of CpG ODN in AD. The use of this advantageous model is important to reach efficient translation for human benefit.