Biomarkers for systemic lupus erythematosus disease activity, and intensity and flare

• US 10,393,739 B2
• Filed: 08/11/2016
• Issued: 08/27/2019
• Est. Priority Date: 10/03/2013
• Status: Active Grant

• Current Assignee: Oklahoma Medical Research Foundation
• Original Assignee: Oklahoma Medical Research Foundation
• Inventors: James, Judith A., Munroe, Melissa E.
• Primary Examiner(s): Gangle, Brian
• Assistant Examiner(s): McCollum, Andrea K
• Application Number:
  US15/234,754
• Publication Number:
  US 20160349256A1
• Time in Patent Office: 1,111 Days
• Field of Search: None
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/104 Lupus erythematosus [SLE]
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/564 for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors

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.

Claims

1. A method for assessing protein expression levels in a systemic lupus erythematosus (SLE) patient comprising:

(a) obtaining a blood, serum or plasma sample from the SLE patient;

(b) assessing protein expression levels of at least one cytokine from each of (i), (ii), (iii), and (iv), wherein (i) is an innate-type cytokine selected from an interleukin-1 alpha (IL-1α

), an interleukin-1 beta (IL-1β

), an interferon-alpha (IFN-α

), interferon-beta (IFN-β

), a granulocyte-colony stimulating factor 3 (G-CSF), interleukin-7 (IL-7), and an interleukin-15 (IL-15), (ii) is a T-helper type-1 (Th1) cytokine selected from an interleukin-2 (IL-2), an interleukin-12 (IL-12), and an interferon-gamma (IFN-γ

), (iii) is a T-helper type-2 (Th2) cytokine selected from an interleukin-4 (IL-4), an interleukin-5 (IL-5), and an interleukin-13 (IL-13), and (iv) is a T-helper type-17 (Th17) cytokine selected from an interleukin-6 (IL-6), an interleukin-17A (IL-17A), an interleukin-21 (IL-21), and an interleukin-23 (IL-23); and

(c) assessing protein expression levels of each molecule from each of (v), (vi), (vii), and (viii), wherein (v) comprises the following chemokine(s) or adhesion molecules;

a C—

X—

C motif chemokine ligand 8 (CXCL8)/interleukin-8 (IL-8), a C—

X—

C motif chemokine ligand 10 (CXCL10)/IFN-gamma-inducible protein 10 (IP-10), one or both of a C—

C motif chemokine ligand 5 (CCL5) and regulated on activation normal T cell expressed and secreted (RANTES), a C—

C motif chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1), a C—

C motif chemokine ligand 7 (CCL7)/monocyte chemoattractant protein-3 (MCP-3), a C—

C motif chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1 alpha (MIP-1α

), a C—

C motif chemokine ligand 4 (CCL4)/macrophage inflammatory protein-1 beta (MIP-1β

), a C—

X—

C motif chemokine ligand 1 (CXCL1)/growth-regulated oncogene-alpha (GRO-α

), a C—

X—

C motif chemokine ligand 9 (CXCL9)/monokine induced by interferon-gamma (MIG), an eotaxin, an Intercellular Adhesion Molecule 1 (ICAM-1), and an E-selectin, (vi) comprises the following tumor necrosis factor receptor (TNFR) superfamily member molecules;

a tumor necrosis factor alpha (TNF-α

), a tumor necrosis factor receptor I (TNFRI), a tumor necrosis factor receptor II (TNFRII), a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a first apoptosis signal (Fas), a first apoptosis signal ligand (FasL), a B-lymphocyte stimulator (BLyS), a proliferation-inducing ligand (APRIL), and a nerve growth factor-beta (NGFβ

), (vii) comprises the following regulatory mediator molecules;

an interleukin-10 (IL-10), a transforming growth factor beta (TGF-β

), a C—

X—

C motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1), and an interleukin-1 receptor antagonist (IL-1RA), and (viii) comprises the following systemic lupus erythematosus (SLE) mediator molecules;

a leukemia inhibitor factor (LIF), a plasminogen activator inhibitor-1 (PAI-1), a platelet-derived growth factor subunit beta homodimer (PDGF-BB), a leptin, a stem cell factor (SCF), and an interleukin-2 receptor alpha chain (IL-2RA).

2. The method of claim 1, wherein each cytokine from each of (i), (ii), (iii), and (iv) is assessed.

3. The method of claim 1, wherein assessing comprises immunologic detection.

4. The method of claim 3, wherein the immunologic detection comprises flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or Western blot.

5. The method of claim 3, wherein the immunologic detection comprises a multiplexed bead-based assay.

6. The method of claim 1, wherein the eotaxin is eotaxin-1.

7. The method of claim 4, wherein the immunologic detection comprises ELISA.