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Evaluating the utility of proteomics for the identification of circulating pharmacodynamic biomarkers of IFNβ-1 biologics

ABSTRACT: In this study, we evaluated the utility of proteomics to identify plasma proteins in healthy participants from a phase I clinical trial with IFNβ-1a and pegIFNβ-1a biologics to identify potential pharmacodynamic (PD) biomarkers. Using a linear mixed-effects model with repeated measurement for product-time interaction, we found that 248 and 528 analytes detected by the SOMAscan® assay were differentially expressed (p-value < 6.86E-06) between therapeutic doses of IFNβ-1a or pegIFNβ-1a, and placebo, respectively. We further prioritized signals based on peak change, area under the effect curve over the study duration, and overlap in signals from the two products. Analysis of prioritized datasets indicated activation of IFNB1 signaling and an IFNB signaling node with IL-6 as upstream regulators of the plasma protein patterns from both products. Increased TNF, IL-1B, IFNG, and IFNA signaling also occurred early in response to each product suggesting a direct link between each product and these upstream regulators. In summary, we identified longitudinal global PD changes in a large array of new and previously reported circulating proteins in healthy participants treated with IFNβ-1a and pegIFNβ-1a that may help identify novel single proteomic PD biomarkers and/or composite PD biomarker signatures as well as provide insight into the mechanism of action of these products. Independent replication is needed to confirm present proteomic results and to support further investigation of the identified candidate PD biomarkers for biosimilar product development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207945 | GEO | 2023/10/31

REPOSITORIES: GEO

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Project description:IFNβ, an effective therapy against relapsing-remitting (RR) multiple sclerosis (MS) is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFNβ targeting innate immune response and their effects on DC-mediated regulation of T-cell differentiation. We found that IFNβ−1a in-vitro treatment of human monocyte-derived dendritic cells (DCs) induced the expression of TLR7 and the members of its downstream signaling pathway, including myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK)4, and TNF receptor-associated factor (TRAF)6, while it inhibited the expression of IL-1R. Using siRNA TLR7 gene silencing, we confirmed that IFNβ-1a-induced changes in MyD88, IRAK4 and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFNβ-1a-induced inhibition of IL-1β and IL-23, and the induction of IL-27 secretion by DCs. Supernatant (SN) transfer experiments confirmed that IFNβ-1a-induced changes in DCs’ cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C (RORC) and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFNβ−1a, that selectively targets the autoimmune response in MS. Overall design: Gene expression changes induced by IFNβ−1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized αCD3 (1 μg/ml) and αCD28 (5 μg/ml) mAb (BD Biosciences) in the absence or presence of IFNβ-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChip® Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning and basic analysis.

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Evaluating the utility of proteomics for the identification of circulating pharmacodynamic biomarkers of IFNβ-1 biologics

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