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

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

PROVIDER: PRJNA857727 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2023-10-31 | GSE207945 | GEO

Evaluating MiRomics and Integrative Proteomics for Identification of Plasma miRNAs as Potential Pharmacodynamic Biomarkers of IFNβ-1a Biologics

Project description:We used miRNA-sequencing to identify candidate plasma pharmacodynamic (PD) biomarkers of interferon beta-1a (IFNβ-1a) biologics and to explore miRNA-mRNA targeted protein relationships and networks to support identified miRNA candidates. Plasma samples from 36 healthy subjects from a placebo-controlled randomized single dose clinical study with IFNβ-1a and pegIFNβ-1a were used. Mature miRNAs were measured using an in-house miRNA-seq workflow at baseline, at 9 timepoints over 6 days in IFNβ-1a group (n=11[30µg]), and at 11 timepoints over 13 days in pegIFNβ-1a group (n=11[125µg]) and placebo-specific groups (n=6 each). A miRNA was only considered expressed if it had a read count ≥10 in more than 50% of the samples across all treatment groups. Linear mixed-effects models (lmer) regressing miRNA changes with treatment, time and their interaction were used to identify differentially expressed miRNAs, which were further prioritized based on magnitude of response and biological relevance using in silico predicted miRNA-protein targets and regulatory network analyses. Ten and 13 miRNAs were impacted by IFNβ-1a and pegIFNβ-1a, respectively (lmer FDR-corrected p- value <0.1), compared to placebo, of which miR.223.3p and miR.21.5p were prioritized as candidate PD biomarkers for both products. Systems level analysis of integrated proteomics data highlighted miRNA protein targets for both miR.223.3p and miR.21.5p that were linked to previously reported top proteomic response proteins and predicted regulatory networks including IFN beta. Using miRNA-sequencing and linking candidates to predicted target proteins and regulatory networks, results suggest miR.223.3p and miR.21.5p as potential novel PD biomarkers of IFNβ-1a biologics for further investigation.

2026-02-09 | GSE308162 | GEO

Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [inter]

Project description:The current project is designed to evaluate the utility of proteomics in identifying pharmacodynamic (PD) biomarkers for biosimilarity assessment. This is an extension of the data submitted in GSE207945 which profiled longitudinal plasma samples from healthy subjects treated with single therapeutic doses/high doses of IFNβ-1a (30 μg) or Pegylated IFNβ-1a (125 μg) or placebo, to identify candidate PD biomarkers for the two biologics (n=248 for IFNβ-1a and N=528 for pegIFNβ-1a). The current project is a continuation study profiling longitudinal plasma samples from healthy subjects treated with an intermediate/lower dose of IFNβ-1a (15 μg) and pegIFNβ-1a (62.5 μg). Here, we reproduced the previous PD biomarker candidate responses at a lower dose, and further characterized their PD response using characteristics such as significant area under the effect curve, dose-response, temporal profile and return to baseline, variability and sensitivity of the biomarker with sensitive doses on the steep portion of the dose-response curve and mechanism of action using all three tested dose groups (high, intermediate and low).

2026-06-23 | GSE300488 | GEO

Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [low]

Project description:The current project is designed to evaluate the utility of proteomics in identifying pharmacodynamic (PD) biomarkers for biosimilarity assessment. This is an extension of the data submitted in GSE207945 which profiled longitudinal plasma samples from healthy subjects treated with single therapeutic doses/high doses of IFNβ-1a (30 μg) or Pegylated IFNβ-1a (125 μg) or placebo, to identify candidate PD biomarkers for the two biologics (n=248 for IFNβ-1a and N=528 for pegIFNβ-1a). The current project is a continuation study profiling longitudinal plasma samples from healthy subjects treated with a low dose of IFNβ-1a (7.5 μg) and pegIFNβ-1a (31.25 μg). In the current study, we reproduced the previous PD biomarker candidate responses at an intermediate/lower dose IFNβ-1a (15 μg) and pegIFNβ-1a (62.5 μg), and further characterized their PD response using characteristics such as significant area under the effect curve, dose-response, temporal profile and return to baseline, variability and sensitivity of the biomarker with sensitive doses on the steep portion of the dose-response curve and mechanism of action using the three tested dose-groups (high, intermediate and low) in the study.

2026-06-23 | GSE300489 | GEO

Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [low]

Project description:Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [low]

| PRJNA1281052 | ENA

Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [inter]

Project description:Characterizing circulating pharmacodynamic biomarkers of IFNβ-1a biologics [inter]

| PRJNA1281053 | ENA

Evaluating MiRomics and Integrative Proteomics for Identification of Plasma miRNAs as Potential Pharmacodynamic Biomarkers of IFNβ-1a Biologics

Project description:Evaluating MiRomics and Integrative Proteomics for Identification of Plasma miRNAs as Potential Pharmacodynamic Biomarkers of IFNβ-1a Biologics

| PRJNA1329123 | ENA

Evaluating miRNA Sequencing and Integrative Proteomics for Identifying Plasma miRNAs as Potential Pharmacodynamic Biomarkers of IFNβ-1a Biologics.

Project description: Not available

| S-EPMC12717852 | biostudies-literature

Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis

Project description:Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis

| PRJNA491863 | ENA

Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis

Project description:A major unmet need in rheumatoid arthritis (RA) is the choice of treatment options for patients with an inadequate response to anti-TNF agents (anti-TNF–IR). In order to identify pharmacodynamic biomarkers and assess differential effects of TNF- and non–TNF-targeting agents on RA patients with an inadequate response to anti-TNF–IR in comparison with biologic-naïve patients, peripheral protein markers and gene expression levels in association with clinical response posttreatment in two disease strata were assessed in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including IL-6, CRP, IL2RA, and MMP1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF–IR patients, whereas mavrilimumab-induced changes were maintained through Day 169. RNA sequencing demonstrated gene expression changes at Day 169 after administration of mavrilimumab but not golimumab in anti-TNF–IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients. Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF–IR and DMARD-IR patients respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.

2019-06-13 | GSE120178 | GEO

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