Biomarkers and methods for assessing response to inflammatory disease therapy

Abstract

Provided herein are methods for assessing response to inflammatory disease therapy. The methods include performing immunoassays to generate scores based on quantitative data for expression of biomarkers relating to inflammatory biomarkers to assess disease activity in inflammatory diseases, e.g., rheumatoid arthritis. Also provided are uses of inflammatory biomarkers for guiding treatment decisions.

1 .- 20 . (canceled) 
     
     
         21 . A method predicting radiographic progression, flare, or joint damage in a subject with rheumatoid arthritis (RA), the method comprising:
 performing at least one immunoassay on a first blood sample from the first subject to generate a first dataset comprising protein level data for at least two protein markers, wherein the at least two protein markers comprise at least two markers selected from Serum Amyloid P-component (SAP), Cathepsin D (CPSD), Chemerin (TIG2), alpha-1-Microglobulin (A1M), Haptoglobin (Hp), Pigment Epithelium Derived Factor (PEDF), Clusterin (CLU), Tissue type Plasminogen activator (tPA), C-reactive protein (CRP), Monocyte Chemotactic Protein 4 (MCP-4), Alpha-1-acid glycoprotein 1 (AGP-1), Connecting Peptide (C-Peptide), Complement Factor H (CFH), Pulmonary and Activation-Regulated chemokine (PARC), growth-regulated alpha protein (GRO-alpha), Sex Hormone-Binding Globulin (SHBG), Matrix Metalloproteinase-7 (MMP-7), Growth/differentiation factor 15 (GDF-15), Fibroblast Growth Factor 21 (FGF-21), Angiopoietin-related protein 3 (ANGPTL3), Hemopexin (HPX), FASLG Receptor (FAS), Receptor for Advanced Glycosylation End products (RAGE), CD5 Antigen-like (CD5L), Endoglin (ENG), von Willebrand Factor (vWF), Apolipoprotein C-III (Apo C-III), Interleukin-1 receptor antagonist (IL-1ra), Ficolin-3 (FCN3), Peroxiredoxin-4 (Prx-IV), ST2 cardiac biomarker (ST2), Sortilin (SORT1), Tumor necrosis factor ligand superfamily member 12 (Tweak), Phosphoserine Aminotrasferase (PSAT), Heparin-Binding EGF-Like Growth Factor (HB-EGF), Interleukin-8 (IL-8), Beta-2-Microglobulin (B2M), Apolipoprotein E (Apo E), Urokinase-type Plasminogen Activator (uPA), Adrenomedullin (ADM), Urokinase-type plasminogen, activator receptor (uPAR), Tetranectin (TN), E-Selectin (ESEL), Monokine Induced by Gamma Interferon (MIG), Glucagon-like Peptide 1, total (GLP-1 total), Interleukin-12 Subunit p40 (IL-12p40), Cartilage Oligomeric Matric protein (COMP), Apolipoprotein H (Apo H), Factor VII (F7), Interferon-inducible T-cell alpha chemoattractant (ITAC), Antileukoproteinase (ALP), Thymus and activation-regulated chemokine (TARC), Plasminogen Activator Inhibitor 1 (PAI-1), Interleukin-15 (IL-15), Ceruloplasmin (CP), Complement Factor H—Related Protein 1 (CFHR1), Protein DJ-1 (DJ-1), Alpha-Fetoprotein (AFP), Chemokine CC-4 (HCC-4), Ferritin (FRTN), Interleukin-15 (IL-15), Immunoglobulin A (IgA), thrombin-Activatable Fibrinolysis (TAFI), Cystatin-B (CSTB), Alpha-1-Antichymotrypsin (AACT) Pancreatic Polypeptide (PPP), Heat-Shock Protein 70 (HSP-70), Transferrin Receptor Protein (TFR1), Tamm-Horsfall Urinary Glycoprotein (THP) Tenascin-C (TN-C), pepsinogen 1 (PG1), Hepatocyte Growth Factor (HGF), T-Cell-Specific Protein RANTES (RANTES), Tumor Necrosis Factor Receptor 2 (TNFR2), Macrophage Colony-Stimulating Factor 1 (M-CSF), Beta Amyloid 1-40 (AB-40), cystatin-C, Tissue Inhibitor of Metalloproteinases 3 (TIMP-3), Insulin-like Growth Factor binding Protein 4 (IGFBP4), Gastric Inhibitory Polypeptide (GIP), Midkine (MDK), Angiogenin (ANG), Stem Cell Factor (SCF), Myeloid Progenitor Inhibitory Factor 1 (MPIF-1), Osteoprotegerin (OPG), CD 40 antigen (CD40), Monocyte Chemotactic Protein 2 (MCP-2), Insulin-like Growth Factor-binding Protein 1 (IGFBP-1), Vitamin K-Dependent Protein S (VKDPS), Hepatocyte Growth Factor Receptor (HGFR), Brain-Derived Neurotrophic Factor (BDNF), Macrophage-Stimulating Protein (MSP), or Monocyte Chemotactic Protein 1 (MCP-1); and   determining a RA radiographic progression, flare, or joint damage score from the first dataset using an interpretation function, wherein said RA radiographic progression, flare, or joint damage score provides a quantitative measure of RA radiographic progression, flare, or joint damage in said first subject.   
     
     
         22 . The method of  claim 21 , wherein the at least two protein markers comprise at least two markers selected from CPSD, SAP, PEDF, C-Peptide, tPA, TIG2, or FAS. 
     
     
         23 . The method of  claim 21 , wherein the at least two protein markers comprise at least two markers selected from CPSD, A1M, TIG2, C-Peptide, tPA, SHBG, GDF-15, Hp, CD5L, AGP-1, CLU, FAS, CRP, CFH, RAGE, FGF-21, vWF, CRP, AACT, CSTB, ST2, TAFI, uPA, TN, Prx-IV, Tweak, PSAT, GLP-1 total, or IL-15. 
     
     
         24 . The method of  claim 21 , wherein the at least two protein markers comprise at least two markers selected from CPSD, PEDF, SAP, SHBG, A1M, tPA, AGP-1, TIG2, CD5L, FAS, C-Peptide, CRP, PSAT, uPA, GIP, Prx-IV, HGF, or IL-15. 
     
     
         25 . The method of  claim 21 , wherein the at least two protein markers comprise at least two markers selected from CPSD, SAP, PEDF, C-peptide, tPA, TIG2, or FAS. 
     
     
         26 . The method of  claim 21 , wherein performance of the at least one immunoassay comprises:
 obtaining the first blood sample, wherein the first blood sample comprises the protein markers;   contacting the first blood sample with a plurality of distinct reagents;   generating a plurality of distinct complexes between the reagents and markers; and   detecting the complexes to generate the data.   
     
     
         27 . The method of  claim 21 , wherein the at least one immunoassay comprises a multiplex assay. 
     
     
         28 . The method of  claim 21 , wherein the interpretation function is based on a predictive model. 
     
     
         29 . The method of  claim 21 , further comprising:
 receiving a second dataset associated with a second sample obtained from said first subject, wherein said first sample and said second sample are obtained from said first subject at different times;   determining a second RA radiographic progression, flare, or joint damage score from said second dataset using said interpretation function; and   comparing said first RA radiographic progression, flare, or joint damage score and said second RA radiographic progression, flare, or joint damage score to determine a change in said RA radiographic progression, flare, or joint damage scores, wherein said changes indicates a change in said RA radiographic progression, flare, or joint damage in said first subject.   
     
     
         30 . The method of  claim 29 , wherein said change in said RA radiographic progression, flare, or joint damage score indicates the presence, absence, or extent of the subject's response to a therapeutic regimen. 
     
     
         31 . A method for generating nucleic acid and/or protein level data for a first subject comprising:
 performing at least one immunoassay on a first blood sample from the first subject to generate a first dataset comprising protein level data for at least two protein markers, wherein the at least two protein markers comprise at least two markers selected from Serum Amyloid P-component (SAP), Cathepsin D (CPSD), Chemerin (TIG2), alpha-1-Microglobulin (A1M), Haptoglobin (Hp), Pigment Epithelium Derived Factor (PEDF), Clusterin (CLU), Tissue type Plasminogen activator (tPA), C-reactive protein (CRP), Monocyte Chemotactic Protein 4 (MCP-4), Alpha-1-acid glycoprotein 1 (AGP-1), Connecting Peptide (C-Peptide), Complement Factor H (CFH), Pulmonary and Activation-Regulated chemokine (PARC), growth-regulated alpha protein (GRO-alpha), Sex Hormone-Binding Globulin (SHBG), Matrix Metalloproteinase-7 (MMP-7), Growth/differentiation factor 15 (GDF-15), Fibroblast Growth Factor 21 (FGF-21), Angiopoietin-related protein 3 (ANGPTL3), Hemopexin (HPX), FASLG Receptor (FAS), Receptor for Advanced Glycosylation End products (RAGE), CD5 Antigen-like (CD5L), Endoglin (ENG), von Willebrand Factor (vWF), Apolipoprotein C-III (Apo C-III), Interleukin-1 receptor antagonist (IL-1ra), Ficolin-3 (FCN3), Peroxiredoxin-4 (Prx-IV), ST2 cardiac biomarker (ST2), Sortilin (SORT1), Tumor necrosis factor ligand superfamily member 12 (Tweak), Phosphoserine Aminotrasferase (PSAT), Heparin-Binding EGF-Like Growth Factor (HB-EGF), Interleukin-8 (IL-8), Beta-2-Microglobulin (B2M), Apolipoprotein E (Apo E), Urokinase-type Plasminogen Activator (uPA), Adrenomedullin (ADM), Urokinase-type plasminogen, activator receptor (uPAR), Tetranectin (TN), E-Selectin (ESEL), Monokine Induced by Gamma Interferon (MIG), Glucagon-like Peptide 1, total (GLP-1 total), Interleukin-12 Subunit p40 (IL-12p40), Cartilage Oligomeric Matric protein (COMP), Apolipoprotein H (Apo H), Factor VII (F7), Interferon-inducible T-cell alpha chemoattractant (ITAC), Antileukoproteinase (ALP), Thymus and activation-regulated chemokine (TARC), Plasminogen Activator Inhibitor 1 (PAI-1), Interleukin-15 (IL-15), Ceruloplasmin (CP), Complement Factor H—Related Protein 1 (CFHR1), Protein DJ-1 (DJ-1), Alpha-Fetoprotein (AFP), Chemokine CC-4 (HCC-4), Ferritin (FRTN), Interleukin-15 (IL-15), Immunoglobulin A (IgA), thrombin-Activatable Fibrinolysis (TAFI), Cystatin-B (CSTB), Alpha-1-Antichymotrypsin (AACT) Pancreatic Polypeptide (PPP), Heat-Shock Protein 70 (HSP-70), Transferrin Receptor Protein (TFR1), Tamm-Horsfall Urinary Glycoprotein (THP) Tenascin-C (TN-C), pepsinogen 1 (PG1), Hepatocyte Growth Factor (HGF), T-Cell-Specific Protein RANTES (RANTES), Tumor Necrosis Factor Receptor 2 (TNFR2), Macrophage Colony-Stimulating Factor 1 (M-CSF), Beta Amyloid 1-40 (AB-40), cystatin-C, Tissue Inhibitor of Metalloproteinases 3 (TIMP-3), Insulin-like Growth Factor binding Protein 4 (IGFBP4), Gastric Inhibitory Polypeptide (GIP), Midkine (MDK), Angiogenin (ANG), Stem Cell Factor (SCF), Myeloid Progenitor Inhibitory Factor 1 (MPIF-1), Osteoprotegerin (OPG), CD 40 antigen (CD40), Monocyte Chemotactic Protein 2 (MCP-2), Insulin-like Growth Factor-binding Protein 1 (IGFBP-1), Vitamin K-Dependent Protein S (VKDPS), Hepatocyte Growth Factor Receptor (HGFR), Brain-Derived Neurotrophic Factor (BDNF), Macrophage-Stimulating Protein (MSP), or Monocyte Chemotactic Protein 1 (MCP-1),   wherein the first subject has rheumatoid arthritis (RA) or is suspected of having RA.   
     
     
         32 . The method of  claim 31 , wherein the at least two protein markers comprise at least two markers selected from CPSD, SAP, PEDF, C-Peptide, tPA, TIG2, or FAS. 
     
     
         33 . The method of  claim 31 , wherein the at least two protein markers comprise at least two markers selected from CPSD, A1M, TIG2, C-Peptide, tPA, SHBG, GDF-15, Hp, CD5L, AGP-1, CLU, FAS, CRP, CFH, RAGE, FGF-21, vWF, CRP, AACT, CSTB, ST2, TAFI, uPA, TN, Prx-IV, Tweak, PSAT, GLP-1 total, or IL-15. 
     
     
         34 . The method of  claim 31 , wherein the at least two protein markers comprise at least two markers selected from CPSD, PEDF, SAP, SHBG, A1M, tPA, AGP-1, TIG2, CD5L, FAS, C-Peptide, CRP, PSAT, uPA, GIP, Prx-IV, HGF, or IL-15. 
     
     
         35 . The method of  claim 31 , wherein the at least two protein markers comprise at least two markers selected from CPSD, SAP, PEDF, C-peptide, tPA, TIG2, or FAS. 
     
     
         36 . The method of  claim 31 , wherein performance of the at least one immunoassay comprises:
 obtaining the first blood sample, wherein the first blood sample comprises the protein markers;   contacting the first blood sample with a plurality of distinct reagents;   generating a plurality of distinct complexes between the reagents and markers; and   detecting the complexes to generate the data.   
     
     
         37 . The method of  claim 31 , wherein the at least one immunoassay comprises a multiplex assay.