Biomarkers for systemic lupus erythematosus disease activity, and intensity and flare
Inventors
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-10393739-B2
Publication Date
2019-08-27
Expiration Date
Abstract
The present invention involves the identification of biomarkers that are predictive of impeding systemic lupus erythematosus (SLE) disease flare. Methods for treating patients so identified are also provided.
Core Innovation
The invention provides a diagnostic method for predicting impending systemic lupus erythematosus (SLE) flares by obtaining a blood, serum, or plasma sample and assessing a defined panel of soluble mediators. The panel comprises at least one cytokine from each of four cytokine classes—innate-type, Th1, Th2, and Th17—and at least two mediators from each of four mediator groups including chemokines/adhesion molecules, TNFR superfamily members, regulatory mediators, and SLE mediator molecules, with exemplary analytes enumerated.
The method implements a normalized, weighted soluble inflammatory mediator score derived from multiplex measurement of the panel to discriminate pre-flare versus non-flare. The score shows high statistical significance in longitudinal analyses and validates across multiple cohorts, including clinical validation in an SLE Influenza Vaccination Cohort. The approach addresses assessment of protein expression levels in SLE patients to detect impending flare and to provide prognostic and clinical utility.
Reported data show pro-inflammatory and TNF receptor-family mediators are elevated prior to flare, including IL‑1α/β, TNF‑α, TNFRI/TNFRII, Fas/FasL, CD40L, and chemokines/adhesion molecules such as IP‑10, MCP‑3, MIG, MCP‑1, and ICAM‑1, while regulatory mediators TGF‑β and IL‑10 are reduced. A mechanistic interpretation includes ADAM-mediated TNFR shedding. The disclosure also describes immunologic and nucleic-acid detection modalities [procedural detail omitted for safety] and a bead-based kit.
Claims Coverage
Independent claim 1 recites six main inventive features.
Obtaining a blood, serum or plasma sample
Obtaining a blood, serum or plasma sample from the SLE patient.
Assessing cytokines from four cytokine classes
Assessing protein expression levels of at least one cytokine from each of (i) innate-type cytokines (selected from IL-1α, IL-1β, IFN-α, IFN-β, G-CSF, IL-7, IL-15), (ii) Th1 cytokines (selected from IL-2, IL-12, IFN-γ), (iii) Th2 cytokines (selected from IL-4, IL-5, IL-13), and (iv) Th17 cytokines (selected from IL-6, IL-17A, IL-21, IL-23).
Assessing chemokines and adhesion molecules
Assessing protein expression levels of molecules in group (v): CXCL8/IL-8, CXCL10/IP-10, one or both of CCL5 and RANTES, CCL2/MCP-1, CCL7/MCP-3, CCL3/MIP-1α, CCL4/MIP-1β, CXCL1/GRO-α, CXCL9/MIG, an eotaxin, ICAM-1, and E-selectin.
Assessing TNF receptor superfamily member molecules
Assessing protein expression levels of molecules in group (vi): TNF-α, TNFRI, TNFRII, TRAIL, Fas, FasL, BLyS, APRIL, and NGFβ.
Assessing regulatory mediator molecules
Assessing protein expression levels of molecules in group (vii): IL-10, TGF-β, CXCL12/SDF-1, and IL-1RA.
Assessing SLE mediator molecules
Assessing protein expression levels of molecules in group (viii): LIF, PAI-1, PDGF-BB, leptin, SCF, and IL-2RA.
Claim 1 covers obtaining a blood/serum/plasma sample and assessing specified panels of cytokines, chemokines/adhesion molecules, TNFR-family members, regulatory mediators, and SLE mediator molecules as listed in groups (i) through (viii).
Stated Advantages
Predicts impending systemic lupus erythematosus (SLE) flares by identification and validation of a panel of soluble inflammatory and regulatory mediators.
Discriminates flare versus non-flare in SLE patients using a normalized, weighted soluble inflammatory mediator score with high statistical significance.
Provides potential prognostic and clinical utility for identifying impending SLE flare.
Documented Applications
Diagnosis of a pre-flare state in SLE patients by measuring defined panels of soluble mediators in blood, serum, or plasma samples.
Use in methods, kits, and assays for assessment of soluble mediators, including a bead-based kit.
Use of a soluble inflammatory mediator score to discriminate impending flare versus non-flare and for potential prognostic/clinical utility in SLE.
Clinical application demonstrated via validation in an SLE Influenza Vaccination Cohort (European-American patients) with longitudinal sampling and statistical analyses.
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