Biomarkers for assessing risk of transitioning to systemic lupus erythematosus classification and disease pathogenesis
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-12140592-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The present invention includes methods, systems, and kits, for identifying and modifying the treatment of a systemic lupus erythematosus (SLE) patient prior to the presence of autoantibodies, comprising: (a) obtaining a dataset representing protein expression level values for cytokines and molecules; (b) assessing the dataset for protein expression levels of at least one innate serum mediator; (c) assessing the dataset for protein expression levels of at least one adaptive serum mediator; and (d) determining the likelihood that the patient will develop SLE prior to the onset of autoantibodies when compared to a control.
Core Innovation
The invention discloses a pre-classification soluble mediator scoring method that assesses a blood, serum, plasma, or urine sample for amounts of protein expression of defined soluble mediator biomarkers and SLE-associated autoantibody specificities, log-transforms and standardizes assessed expression levels, weights each marker by a Spearman r correlation with the total number of positive autoantibody specificities, and sums the weighted values to yield a global score relative to a healthy control baseline. The score indicates increased risk to transition to clinical systemic lupus erythematosus. Computational processing is described [procedural detail omitted for safety].
The score distinguishes future systemic lupus erythematosus cases up to four or more years before clinical classification and identifies increased stem cell factor (SCF) and decreased transforming growth factor-β (TGF-β) as independent predictors of transition, with BLyS, MCP-1, MCP-3 and IL-10 correlating with disease but not independently predictive. Combining soluble mediator data with SLE-CSQ or ACR scores yields high diagnostic performance (test-set AUC approximately 0.92–0.93; validation AUC approximately 0.80–0.89), and multi-marker models outperform ANA alone with reported accuracies up to approximately 92%. The method contemplates applying the assessment to relatives and administering treatments upon determining increased risk; numerical cutoffs and assay platforms are described [procedural detail omitted for safety].
Claims Coverage
The independent claims (claims 1, 10, 14, and 15) cover methods that measure a specified multiplex panel of soluble mediator biomarkers and SLE-associated autoantibody specificities in bodily fluids, mathematically process assessed expression levels to derive a pre-classification risk score [procedural detail omitted for safety], and administer or initiate treatment prior to clinical SLE classification, with use of biomarker-based determination to define clinical classification. Six main inventive features are identified below.
Specified biomarker panel measurement
Assessing a blood, serum, plasma, or urine sample for amounts of protein expression of a defined panel comprising innate mediators (IL-1α, IL-1β, IL-1RA, IL-12p70, IL-6, IL-23p19), adaptive mediators (IL-2, IFN-γ, IL-4, IL-5, IL-1β, IL-17A, IL-21, TGF-β), chemokines (IL-8/CXCL8, IP-10/CXCL10, MIG/CXCL9, MIP-1α/CCL3, MCP-3/CCL7), TNF-superfamily members (TNFRI, TNFRII, Fas, CD40L/CD154, BLyS, APRIL), inflammatory mediators (SCF, PAI-1, Resistin), and SLE-associated autoantibody specificities (dsDNA, chromatin, RiboP, Ro/SSA, La/SSB, Sm, SmRNP, RNP) (claims 1, 10, 14, 15).
Log transforming and standardizing assessed expression levels
Log transforming assessed expression levels for each claimed mediator and SLE-associated autoantibody specificity and standardizing those assessed expression levels prior to further processing (claims 1, 10, 14, 15).
Weighting by Spearman correlation with autoantibody count
Weighting the assessed expression levels for each biomarker by a Spearman r correlation between a total number of positive autoantibody specificities and each biomarker (claims 1, 10, 14, 15).
Summation to yield a global score indicative of risk
Summing the (weighted) assessed expression levels for the claimed biomarkers to yield a score, wherein a higher score relative to a healthy control score indicates that the subject is at increased risk to transition to clinical disease classification of SLE (explicit in claim 1; summation present in claims 10, 14, 15).
Administration or initiation of treatment prior to clinical disease classification
Administering or initiating treatment to a subject who has not reached clinical disease classification after determining that the subject is at an increased risk to transition to clinical disease classification of SLE, wherein the treatment comprises at least one of hydroxychloroquine, belimumab, a nonsteroidal anti-inflammatory drug, a steroid, and a disease-modifying anti-rheumatic drug (claims 1, 10, 14, 15).
Use of biomarker-based determination to define clinical classification
Determining clinical disease classification of SLE by assessing the defined biomarker panels with computational processing [procedural detail omitted for safety] to support classification decisions that precede or inform treatment (claims 14, 15).
The independent claims define a biomarker-based workflow that measures a comprehensive panel of soluble mediators and autoantibody specificities, log-transforms and standardizes measurements, weights markers by Spearman correlation with total positive autoantibody specificities, and sums weighted values to produce a score used to identify subjects at increased risk and to administer or initiate treatments prior to clinical classification, with biomarker-based determination informing clinical classification.
Stated Advantages
Enables distinction of future SLE cases up to four or more years before clinical classification.
Identifies SCF (positive association) and TGF-β (negative association) as independent predictors of transition to clinical SLE even when adjusted for demographics, ANA, SLE-CSQ or ACR scores.
Combining soluble mediator data with SLE-CSQ or ACR scores yields high diagnostic performance (test-set AUC approximately 0.92–0.93; validation AUC approximately 0.80–0.89).
Multi-marker predictive models that outperform ANA alone with reported predictive accuracies up to approximately 92%.
Provides numeric cutoffs for key predictors (SCF [procedural detail omitted for safety]; TGF-β [procedural detail omitted for safety]) to stratify risk as described in the patent.
Enables initiation or administration of treatments prior to a subject reaching clinical disease classification of SLE.
Application to at-risk relatives and incorporation into clinical screening workflows and kit-based screening as described use cases.
Documented Applications
Determining a score indicative of whether a subject who has not reached clinical disease classification of SLE is at increased risk to transition to clinical disease classification of SLE.
Identifying at-risk relatives and applying the scoring method to relatives to indicate that relative's risk of transitioning to clinical SLE.
Using the biomarker-derived score in combination with SLE-CSQ or ACR scores to improve diagnostic performance for predicting progression to clinical SLE and for clinical screening and progression assessment.
Administering treatments (hydroxychloroquine, belimumab, a nonsteroidal anti-inflammatory drug, a steroid, or a disease-modifying anti-rheumatic drug) to subjects prior to reaching clinical disease classification when increased risk is determined.
Implementing the method in kit and clinical screening use-cases as described in the document.
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