Early-Stage Identification and Avoidance of Antisense Oligonucleotides Causing Species-Specific Inflammatory Responses in Human Volunteers Peripheral Blood Mononuclear Cells

Author:

Burel Sebastien A.,Machemer Todd,Baker Brenda F.,Kwoh T. Jesse,Paz Suzanne,Younis Husam,Henry Scott P.

Abstract

AbstractA human peripheral blood mononuclear cell (PBMC)-based assay was developed to identify antisense oligonucleotide (ASO) with the potential to activate a cellular innate immune response outside of an acceptable level. The development of this assay was initiated when ISIS 353512 targeting the mRNA for human C-reactive protein was tested in a phase I clinical trial in which healthy human volunteers unexpectedly experienced increases in interleukin-6 (IL-6) and C-reactive protein. This level of immune stimulation was not anticipated following rodent and non-human primate safety studies in which no evidence of exaggerated proinflammatory effects were observed. The IL-6 increase induced by ISIS 353512 was caused by activation of B-cells. The IL-6 induction was inhibited by chloroquine pretreatment of the PBMC and the nature of the ASOs suggested that the response is mediated by a toll like receptor, in all likelihood TLR9. While assessing the inter PBMC donor variability, two class of responders to ISIS 353512 were identified (discriminator and non-discriminators). The discriminator source of PBMC was shown to produce low level of IL-6 after 24 hours in culture in absence of ASO treatment. The PBMC assay using discriminator donors was shown to be reproducible allowing to assess reliably the immune potential of ASOs via comparison to known benchmark ASO controls that were previously shown to be either safe or inflammatory in clinical trials.

Publisher

Cold Spring Harbor Laboratory

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