US-12618855-B2 - Serum protein biomarker panel for idiopathic pulmonary fibrosis

US12618855B2US 12618855 B2US12618855 B2US 12618855B2US-12618855-B2

Abstract

The instant disclosure relates to methods for assessing pulmonary fibrosis disorder disease status in an individual in need thereof. One aspect of the disclosed methods may comprise: detecting a level of one or more biomarkers in a biological sample obtained from an individual, comparing the level of the one or more biomarkers to that of a control value corresponding to the one or more biomarkers, characterizing the disease status in the individual based on the level of the one or more biomarkers as compared to that of a relevant control value; and administering a treatment to said individual based on the assessment of the one or more biomarker levels.

Inventors

William D. HARDIE
Assem Ziady
Bethany Moore

Assignees

CHILDREN'S HOSPITAL MEDICAL CENTER
UNIVERSITY OF MICHIGAN

Dates

Publication Date: 20260505
Application Date: 20201008

Claims (14)

1 . A method for assessing stable versus progressive pulmonary fibrosis disease status in an individual in need thereof, comprising a. detecting a level of one or more biomarkers in a biomarker panel comprising Ephrin B2, Epidermal Growth Factor, Ferritin-heavy chain, Apotransferrin, Phosphoinositide 3-kinase, Mdm2-binding protein isoform X3, Tubulin polyglutamylase TTLL13 isoform X7, Heparin sulfate glucosamine 3-O-sulfotransferase 2, in a biological sample obtained from the individual; b. comparing the level of the one or more biomarkers to that of a control value; c. based on a comparison of the one or more biomarker level to a control value, characterizing the disease status in said individual as either progressive or stable; and d. where the disease status is determined to be progressive, administering a treatment to the individual selected from one or more of a PI3K pathway inhibitor, an EGF pathway inhibitor, Pirfenidone, and Nintendanib.
2 . The method of claim 1 , the biomarker panel further comprising a biomarker selected from pregnancy zone protein, serotransferrin, alpha-2-macroglobulin, immunoglobulin lambda-like polypeptide 5, ceruloplasmin, alpha-1-antitrypsin precursor, complement C3 preproprotein, coiled-coil domain-containing protein 144A, cytochrome P450 3A43, myosin phosphatase Rho-interacting protein, collagen alpha-6 (IV) chain protein FAM110A, DNA polymerase epsilon catalytic subunit A, semaphorin-5B ephrin type-B receptor 1, zinc finger protein 532, tyrosine—tRNA ligase (cytoplasmic), mismatch repair endonuclease PMS2, cadherin EGF LAG seven-pass G-type receptor, cytoskeleton-associated protein 2, tyrosine—tRNA ligase (cytoplasmic), zinc finger protein 618, cytoskeleton-associated protein 2, alpha-2-macroglobulin, serine/threonine-protein kinase OSR1, collagen alpha-1 (XII) chain, zinc finger ZZ-type and EF-hand domain-containing protein 1, iporin, phospholipid-transporting ATPase IG, collagen alpha-6 (IV) chain, spatacsin, short stature homeobox protein 2, collagen alpha-1 (XII) chain, ubiquitin carboxyl-terminal hydrolase 28, phospholipid-transporting ATPase IG, cyclin-dependent kinase 13, A-kinase anchor protein 9, zinc finger protein 417, sorting nexin-13, hemoglobin subunit beta, hemoglobin subunit delta, hemoglobin subunit alpha, cytochrome P450 3A4 isoform, filamin-C, apolipoprotein A-IV, nebulin, SAA2-SAA2 protein precursor, plasminogen isoform 1 precursor, ATPase family AAA domain-containing protein 5, DNA damage-induced apoptosis suppressor protein, E3 ubiquitin-protein ligase Midline-1, mitogen-activated protein kinase kinase kinase kinase 1, mucin-16, probable E3 ubiquitin-protein ligase HECTD4, protein RRP5 homolog, retrotransposon Gag-like protein 9, serine/threonine-protein phosphatase 2A regulatory subunit B″ subunit gamma, and uncharacterized protein C12orf42.
3 . The method of claim 1 , further comprising identifying said individual as having improved disease, progressing disease, or a plateau in disease.
4 . The method of claim 1 , wherein an alteration in the biomarker level compared to the control level indicates the presence of disease or progression of disease.
5 . The method of claim 1 , wherein a second comparison step is carried out following administration of the treatment, wherein a return to the biomarker level to that of a control value indicates an improvement in disease.
6 . The method of claim 1 , wherein the pulmonary fibrosis disease is selected from progressive pulmonary fibrosis, interstitial lung disease (ILD), and idiopathic pulmonary fibrosis (IPF).
7 . The method of claim 1 , wherein the treatment is selected from erlotinib, cetuximab, panitumumab, lapatinib, and canertinib.
8 . The method of claim 1 , wherein the individual has one or more predispositions selected from a familial history of IPF, age of 60 years or greater, and a history of chronic smoking.
9 . A method of diagnosing and treating a pulmonary disease in an individual in need thereof, comprising a) establishing, using a computing system, a model for characterizing a disease state of an individual having or likely to have a pulmonary disease, by using expression level data of a biomarker panel comprising Ephrin B2, Epidermal Growth Factor, Ferritin-heavy chain, Apotransferrin, Phosphoinositide 3-kinase, Mdm2-binding protein isoform X3, Tubulin polyglutamylase TTLL13 isoform X7, and Heparin sulfate glucosamine 3-O-sulfotransferase 2; b) contacting a biological sample from said individual with at least one detection agent capable of specifically binding to one or more biomarkers of the biomarker panel; c) acquiring an expression level from the one or more biomarkers measured from said biological sample; d) characterizing the individual as one or more of likely to have a lung disease, having stable lung disease, having progressive lung disease, or having improving lung disease; and e) administering a therapy to said individual based on the characterization, wherein the therapy is selected from one or more of a PI3K pathway inhibitor, an EGF pathway inhibitor, Pirfenidone, and Nintendanib.
10 . The method of claim 9 , wherein said disease is idiopathic pulmonary fibrosis (IPF).
11 . The method of claim 1 , wherein the biological sample is a plasma sample.
12 . The method of claim 9 , wherein the biological sample is a plasma sample.
13 . The method of claim 1 , wherein each of the one or more biomarkers is a protein biomarker.
14 . The method of claim 9 , wherein each of the one or more biomarkers is a protein biomarker.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of International Application No. PCT/US20/54664, filed Oct. 8, 2020, entitled “Serum Protein Biomarker Panel for Idiopathic Pulmonary Fibrosis.” which claims priority to and benefit of U.S. 62/912,228, filed on Oct. 8, 2019, entitled “Serum Protein Biomarker Panel that Predicts the Development and Resolution of Idiopathic Pulmonary Fibrosis” and U.S. 63/024,139 filed May 13 2020, entitled “Serum Protein Biomarker Panel the Predicts the Development and Resolution of Idiopathic Pulmonary Fibrosis, the contents of each are incorporated in their entirety for all purposes. BACKGROUND Lung fibrosis complicates many interstitial lung diseases (ILD) including systemic connective tissue diseases, childhood interstitial lung disease syndrome, and in response to many types of lung injury1. The natural history is often inconsistent and unpredictable, and in some specific disorders, such as idiopathic pulmonary fibrosis (IPF), inexorably progressive. This variability in the rate and severity of disease progression makes prognostication for individual patients challenging and creates significant barriers to efficient drug development. Validation of sensitive, reproducible, and objective biomarkers that accurately tracks disease, the fibrotic burden, and response to therapy would be of enormous benefit to clinicians as well as clinical researchers. The current standard of care for diagnosing and monitoring pulmonary fibrosis includes pulmonary function testing (PFTs), imaging by high-resolution computed tomography (HRCT), and surgical lung biopsy. PFTs, specifically spirometry, plethysmography and diffusion, measure lung volumes, airflow and gas uptake and are the widely used for their relative ease in performance, high safety profile, low cost and rapid results. However, PFTs are nonspecific for identifying the underlying pathology. Further, longitudinal monitoring with PFTs is imprecise due to the high variability of endpoints. For instance. Forced vital capacity (FVC), which is often the primary endpoint in IPF clinical trials, varies up to 11% week to week in normal subjects and up to 20% in patients with emphysema2, 3. With this variability, PFTs must be obtained and followed over extended periods to confidently follow disease course. HRCT of the chest is routinely performed in patients with suspected fibrotic lung disease and the presence of typical clinical and radiographic features is sufficient to allow a confident diagnosis of fibrosis in more than 50% of suspected cases. While HRCT provides useful diagnostic information its prognostic value to track disease has several limitations including significant interobserver variability among radiologists in determining the extent of disease.4 Another restraint is defining small changes in the fibrotic burden when performing serial studies, especially among individual patients with extensive disease at the time of diagnosis. Further, HRCT has not been shown to reliably identify treatment failure early in trials of therapy.5 Surgical lung biopsy is the gold standard for diagnosis pulmonary fibrosis. However, the risk of performing a lung biopsy may be impracticable especially in patients with advanced disease or comorbidities. With an in-hospital mortality of 4.6%, surgical lung biopsies cannot be performed longitudinally to monitor fibrosis progression.6 Taken as a whole, currently there are no rapid predictors of disease progression for pulmonary fibrosis disorders. The discovery and development of pulmonary fibrosis-specific biomarkers for use as diagnostic adjuncts or measures of disease activity or treatment response remains a critical unmet need. Newly discovered biomarkers of human disease may reflect disease pathogenesis, change with intervention, and/or offer diagnostic or prognostic value beyond current measures.7 The foregoing disclosure addresses one or more of the aforementioned needs in the art. BRIEF SUMMARY The instant disclosure relates to methods for assessing pulmonary fibrosis disorder disease status in an individual in need thereof. One aspect of the disclosed methods may comprise: detecting a level of one or more biomarkers in a biological sample obtained from an individual, comparing the level of the one or more biomarkers to that of a control value corresponding to the one or more biomarkers, characterizing the disease status in the individual based on the level of the one or more biomarkers as compared to that of a relevant control value; and administering a treatment to said individual based on the assessment of the one or more biomarker levels. BRIEF DESCRIPTION OF THE DRAWINGS Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way. FIG. 1. ELISA confirmation of markers of IPF identified in model mouse plasma by MS p