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WO2018094221A1 - Évaluation et traitement d'une glomérulonéphrite fibrillaire - Google Patents

Évaluation et traitement d'une glomérulonéphrite fibrillaire Download PDF

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Publication number
WO2018094221A1
WO2018094221A1 PCT/US2017/062318 US2017062318W WO2018094221A1 WO 2018094221 A1 WO2018094221 A1 WO 2018094221A1 US 2017062318 W US2017062318 W US 2017062318W WO 2018094221 A1 WO2018094221 A1 WO 2018094221A1
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Prior art keywords
dnajb9
fgn
mammal
polypeptides
elevated level
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Inventor
Mariam P. ALEXANDER
Paul J. KURTIN
Surendra Dasari
Samih H. NASR
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy

Definitions

  • This document relates to materials and methods for identifying and/or treating fibrillary glomerulonephritis (e.g. , non-amyloid fibrillary glomerulonephritis).
  • fibrillary glomerulonephritis e.g. , non-amyloid fibrillary glomerulonephritis.
  • this document provides materials and methods for using one or more inhibitors of DnaJ homolog subfamily B member 9 (DNAJB9) polypeptide expression or activity to treat a mammal having fibrillary glomerulonephritis.
  • DNAJB9 DnaJ homolog subfamily B member 9
  • Fibrillary glomerulonephritis affects the ability of the filtering units (e.g. , glomeruli) of the kidney, and is characterized by fibrillary deposits in the glomeruli and inflammation of the glomeruli.
  • the pathogenesis of FGN is unknown.
  • This document provides materials and methods for identifying and/or treating
  • FGN e.g. , non-amyloid FGN.
  • FGN e.g. , non-amyloid FGN.
  • This document also provides methods and materials for treating one or more complications associated with FGN (e.g., high blood pressure, phosphorus imbalance, and/or anemia).
  • FGN e.g., high blood pressure, phosphorus imbalance, and/or anemia.
  • this document provides materials and methods for detecting the presence of an elevated level of DNAJB9 polypeptides
  • a mammal e.g., a human identified as a mammal as having FGN can be administered one or more inhibitors of DNAJB9 expression or activity.
  • the administered inhibitor(s) can reduce the severity of one or more symptoms of FGN within the mammal. In some cases, the administered inhibitor(s) can reduce the severity of one or more complications associated with FGN (e.g. , high blood pressure, phosphorus imbalance, and/or anemia).
  • one aspect of this document features a method for identifying a mammal having FGN.
  • the method includes, or consists essentially of, detecting the presence of an elevated level of DNAJB9 polypeptides in a biological sample from the mammal, and classifying the mammal as having FGN based at least in part on the presence of an elevated level of DNAJB9 polypeptides in the biological sample.
  • the level of DNAJB9 polypeptides in the biological sample can be determined using immunohistochemistry.
  • the level of DNAJB9 polypeptides in the biological sample can be determined using mass spectrometry.
  • the mass spectrometry can include proteomics- based mass spectrometry assay or targeted quantification-based mass spectrometry assay.
  • the biological sample can include serum or urine, and the detecting the presence of an elevated level of DNAJB9 polypeptides can include detecting the presence of anti-DNAJB9 autoantibodies in the sample.
  • this document features a method for treating FGN in a mammal.
  • he method includes, or consists essentially of, identifying a mammal as having an elevated level of DNAJB9 polypeptides within a biological sample from the mammal, and administering an inhibitor of DNAJB9 polypeptide expression or activity to the mammal under conditions wherein the severity of a symptom of FGN is reduced.
  • he method includes, or consists essentially of, identifying a mammal as having an elevated level of DNAJB9 polypeptides within a biological sample from the mammal, and administering an inhibitor of DNAJB9 polypeptide expression or activity to the mammal under conditions where progression of FGN to kidney failure in the mammal is reduced.
  • the mammal can be a human.
  • the biological sample can be a kidney tissue sample.
  • the biological sample can be a fluid sample (e.g., serum or urine).
  • Figure 1 includes mass spectrometry data (A) and immunohistochemistry images (B) of DNAJB9 expression.
  • A DNAJB9 is absent from the renal glomerular amyloid proteome and is present only in FGN proteome.
  • DNAJB9 is absent in the glomeruli of normal individual (left panel) and is present in the glomeruli of a patient with (right panel).
  • Figure 2 is a graph of DNAJB9 abundance in FGN and other renal diseases.
  • CR+ stands for Congo red (CR) positivity.
  • CR- stands for CR negativity.
  • Amyloid represents renal amyloidosis subtypes listed in the methods.
  • NFGNGD represents non-FGN glomerular diseases.
  • Norm-Gloms represent healthy glomerulus samples. **** stands for a Mann-Whitney rank sum test p-value of ⁇ 0.0001.
  • Figure 3 shows a use for serum DNAJB9 in identifying FGN patients.
  • DNAJB9 concentrations are elevated in serum of FGN patients relative to proteinuric controls.
  • B A receiver operating characteristic (ROC) curve for DNAJB9 as a serum marker for FGN.
  • DNAJB9 polypeptides e.g. , elevated levels of DNAJB9 polypeptides in fibrillary glomerular deposits
  • DNAJB9 polypeptides can be properly folded DNAJB9 polypeptides or misfolded DNAJB9 polypeptides.
  • FGN non-amyloid FGN
  • a complication associated with FGN e.g. , high blood pressure, phosphorus imbalance, and/or anemia
  • one or more inhibitors of DNAJB9 polypeptide expression or activity can be administered to a mammal identified as having FGN (e.g. , a mammal identified as having FGN as described herein) to reduce the severity of FGN and/or to reduce a symptom of FGN.
  • one or more inhibitors of DNAJB9 polypeptide expression or activity can be used to reduce and/or resolve fibrillary glomerular deposits within a mammal (e.g., a human).
  • one or more inhibitors of DNAJB9 polypeptide expression or activity can be used to slow or prevent the progression of FGN (e.g., to kidney failure) within a mammal (e.g., a human).
  • the term "elevated level” as used herein with respect to a level of DNAJB9 polypeptides refers to any level that is greater than a reference level of DNAJB9 polypeptides.
  • the term "reference level” as used herein with respect to DNAJB9 polypeptides refers to the level of DNAJB9 polypeptides typically observed in a sample (e.g., a control sample) from one or more mammals (e.g. , humans) without FGN.
  • Control samples can include, without limitation, samples from normal (e.g., healthy) mammals, mammals with renal amyloidosis, mammals with other forms of glomerulonephritis, diabetes, monoclonal immunoglobulin disease, and thrombotic microangiopathy.
  • an elevated level of DNAJB9 polypeptides can be a level that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater relative to a reference level of DNAJB9 polypeptides.
  • an elevated level can be a detectable level of DNAJB9 polypeptides. It will be appreciated that levels from comparable samples are used when determining whether or not a particular level is an elevated level.
  • any appropriate sample can be assessed to determine if a mammal (e.g. , a human) has an elevated level of DNAJB9 polypeptides.
  • biological samples such as tissue samples (e.g., kidney), and fluids (e.g., blood, serum, plasma, urine) can be obtained from a mammal and assessed for the presence of an elevated level of DNAJB9 polypeptides.
  • tissue samples e.g., kidney
  • fluids e.g., blood, serum, plasma, urine
  • a kidney tissue sample can be obtained and assessed to determine whether or not the mammal has an elevated level of DNAJB9 polypeptides.
  • serum and/or urine can be used as a biological sample to determine whether or not a mammal has an elevated level of DNAJB9 polypeptides.
  • any appropriate method can be used to detect the presence, absence, or level of DNAJB9 polypeptides within a sample (e.g. , within glomerular fibrillary deposits).
  • immunohistochemistry (IHC) techniques immunofluorescence, mass spectrometry techniques (e.g. , proteomics-based mass spectrometry assays or targeted quantification-based mass spectrometry assays), western blotting techniques, quantitative RT-PCR techniques, and/or ELISA can be used to determine whether or not a sample contains an elevated level of DNAJB9 polypeptides.
  • the presence, absence, or level of DNAJB9 can be detected using an anti-DNAJB9 antibody (e.g. , Sigma HPA040967).
  • IHC and/or MS can be used to determine whether or not a particular sample contains an elevated level of DNAJB9 polypeptides.
  • an elevated level of DNAJB9 polypeptides can be determined by detecting the presence of anti-DNAJB9 autoantibodies in a sample (a serum and/or urine sample) from the mammal.
  • a mammal can be administered or instructed to self-administer one or more inhibitors of DNAJB9 polypeptide expression or activity (e.g., one, two, three, four, five, or more DNAJB9 inhibitors).
  • Administration of an inhibitor of DNAJB9 polypeptide expression or activity to a mammal (e.g. , human) having an elevated level of DNAJB9 polypeptides can be effective to treat FGN.
  • the materials and methods provided herein can be used to reduce the symptoms of FGN.
  • Symptoms of FGN can include, without limitation, blood in the urine (hematuria), protein in the urine (proteinuria), swelling of legs and/or feet, anemia, and elevated blood pressure.
  • the materials and methods provided herein can be used to reduce a complication associated with FGN (e.g., inflammation in the glomeruli).
  • the materials and methods provided herein can be used to slow or prevent the progression of FGN.
  • one or more inhibitors of DNAJB9 polypeptide expression or activity can be used to slow or prevent the progression of FGN to kidney failure.
  • the FGN can be any FGN.
  • the FGN can be non-proliferative or proliferative.
  • FGN can be a primary FGN (e.g. , occurring spontaneously) or a secondary FGN (e.g. , caused by another disease, hepatitis C, solid malignancy, hematologic malignancy, monoclonal gammopathy, or autoimmune disease).
  • FGN can be non-amyloid (e.g. , Congo red-negative) or amyloid (e.g. , Congo red- positive).
  • Examples of FGN that can be treated as described herein include, without limitation, non-amyloid FGN, amyloid FGN, and immunotactoid glomerulopathy. In some cases, FGN treated as described herein can be non-amyloid FGN.
  • any type of mammal FGN or a complication of FGN can be treated as described herein.
  • humans and other primates such as monkeys having FGN or a complication of FGN and an elevated level of DNAJB9 polypeptides (e.g. , in glomerular fibrillary deposits) can be treated with one or more inhibitors of DNAJB9 polypeptide expression or activity as described herein.
  • dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats can be treated with one or more inhibitors of DNAJB9 polypeptide expression or activity as described herein.
  • Example of inhibitors of DNAJB9 polypeptide expression or activity include, without limitation, nucleic acid molecules designed to induce RNA interference (e.g., a siRNA molecule or a shRNA molecule), antisense molecules, miRNAs, and antibodies (e.g., antibodies (e.g. , monoclonal antibodies) that can neutralize DNAJB9 (e.g. , circulating DNAJB) and/or clear DNAJB9 from glomerular deposits).
  • RNA interference e.g., a siRNA molecule or a shRNA molecule
  • antisense molecules e.g., antisense molecules
  • miRNAs e.g., antisense molecules
  • miRNAs e.g., antisense molecules
  • antibodies e.g., antibodies (e.g. , monoclonal antibodies) that can neutralize DNAJB9 (e.g. , circulating DNAJB) and/or clear DNAJB9 from glomerular deposits).
  • an inhibitor of DNAJB9 polypeptide expression or activity can be readily designed based upon the nucleic acid and/or polypeptide sequences of DNAJB9.
  • DNAJB 9 nucleic acids include, without limitation, the human DNAJB9 sequences set forth in GenBank ® Accession Nos. NM_012328 (Version NM_012328.2; GI: 313482783), CR533475 (Version CR533475.1 ; GI: 49065375), and KJ891596 (Version KJ891596.1 ; GI: 649101389).
  • DNAJB9 polypeptides include, without limitation, the human DNAJB9 polypeptides having the amino acid sequence set forth in National Center for Biotechnology Information (NCBI) GenBank ® Accession Nos: CAG38506 (Version CAG38506.1), EAL24382 (Version EAL24382.1), and AAH28912 (Version AAH28912.1).
  • a human DNAJB9 polypeptide can have a sequence that deviates from a wild type DNAJB9 polypeptide sequence, sometimes referred to as a variant sequence.
  • a DNAJB9 polypeptide can have at least 80 (e.g., at least 85, at least 90, at least 95, at least 98, or at least 99) percent sequence identity to a wild type DNAJB9 polypeptide sequence.
  • a DNAJB9 polypeptide can have one or more (e.g. , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid modifications (e.g., substitutions) relative to a wild type DNAJB9 polypeptide sequence.
  • a DNAJB9 polypeptide can have a substitution of the arginine residue at position 68 (Arg68).
  • a DNAJB9 polypeptide can have an Arg68His (R68H) substitution.
  • one or more inhibitors of DNAJB9 polypeptide expression or activity can be formulated into a pharmaceutically acceptable composition for administration to a mammal having an elevated level of DNAJB9 polypeptides.
  • a therapeutically effective amount of an inhibitor of DNAJB9 polypeptide expression or activity can be formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • a pharmaceutical composition can be formulated for administration in solid or liquid form including, without limitation, sterile solutions, suspensions, sustained-release formulations, tablets, capsules, pills, powders, and granules.
  • a pharmaceutically acceptable composition including one or more inhibitors of DNAJB9 polypeptide expression or activity can be administered locally or systemically.
  • a composition containing an inhibitor of DNAJB9 polypeptide expression or activity can be administered systemically by an oral administration to or inhalation by a mammal (e.g., a human).
  • a pharmaceutical composition containing one or more inhibitors of DNAJB9 polypeptide expression or activity can be designed for oral, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal), or inhaled administration.
  • a pharmaceutical composition containing one or more DNAJB9 inhibitors can be in the form of a pill, tablet, or capsule.
  • Example 1 DNAJB9 is present in FGN renal biopsies
  • Mass spectrometry and immunohistochemistry were utilized for detecting FGN in renal tissues.
  • H&E stained FFPE tissue sections of each case were mounted on a special Director slide (OncoplexDX, Rockville, MD) and examined for presence of amyloid in renal glomeruli. Stained slides were loaded on a LMD apparatus (Lieca, Wetzlar, Germany) and renal glomeruli were visualized under florescent light for dissection.
  • LMD apparatus Lieca, Wetzlar, Germany
  • renal glomeruli were visualized under florescent light for dissection.
  • H&E hematoxylin and eosin
  • Extracted proteins were digested with trypsin and resulting peptides were analyzed on either a QExactive mass spectrometer (Thermo- Fisher Scientific, Waltham, MA) or LTQ-Velos mass spectrometer (Thermo-Fisher Scientific, Waltham, MA) or LTQ-Orbitrap mass spectrometer (Thermo-Fisher Scientific, Waltham, MA) using liquid chromatography-assisted tandem mass spectrometry (LC- MS/MS).
  • QExactive mass spectrometer Thermo- Fisher Scientific, Waltham, MA
  • LTQ-Velos mass spectrometer Thermo-Fisher Scientific, Waltham, MA
  • LTQ-Orbitrap mass spectrometer Thermo-Fisher Scientific, Waltham, MA
  • LC-MS/MS data from each patient sample was analyzed using multiple database search engines configured to match MS/MS against a composite protein sequence database containing SwissProt human proteome (downloaded 08/2012) and common contaminants (e.g. cotton, etc.). Reversed protein sequences were utilized to estimate false discovery rates.
  • the search engines were configured to derive tryptic peptides from the sequence database and look for the following variable modifications: oxidation of methionine (+15.994 Da) and formation of n-terminal pyroglutamic acid (-17.023 Da). Scaffold software processed the results and assembled protein identifications with at least two confident (identification probability > 0.9) and unique peptide matches.
  • Protein DNAJB9 was identified by mass spectrometry in the glomerular deposits of patients with FGN. This protein was not detected by mass spectrometry in normal glomeruli, in glomeruli of patients with renal amyloidosis, or in patients with other forms of glomerulonephritis ( Figure 1A). The presence of abundant DNAJB9 in the glomeruli of FGN was confirmed by immunohistochemistry ( Figure IB).
  • DNAJB9 levels were measured in serum of FGN patients and proteinuric controls using an immuno-MRM assay.
  • concentration of DNAJB9 in serum from FGN patients was significantly higher than the concentration of DNAJB9 in serum from healthy controls ( Figure 3A).
  • a biological sample (e.g. , serum or urine) is obtained from a human suspected of having a renal condition.
  • the obtained sample is examined for the presence of an elevated level of DNAJB9 polypeptide expression or the presence of anti-DNAJB9 autoantibodies.
  • an IHC assay is performed to detect the presence of an elevated level of DNAJB9 polypeptide expression the presence of anti-DNAJB9 autoantibodies.
  • a MS assay is performed to detect the presence of an elevated level of DNAJB9 polypeptide expression. If an elevated level of DNAJB9 polypeptide expression is detected in the sample, as compared to a control level, then the human is administered one or more inhibitors of DNAJB9 polypeptide expression or activity. The administered inhibitor(s) can reduce the severity of one or more symptoms of FGN.
  • a human identified as having FGN is administered one or more DNAJB9 inhibitors of DNAJB9 polypeptide expression or activity (e.g. , a DNAJB9 monoclonal antibody that can neutralize circulating DNAJB9 and/or clear DNAJB9 from glomeruli).
  • the administered inhibitor(s) can reduce the severity of one or more symptoms of FGN.

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Abstract

La présente invention concerne des matériels et des méthodes permettant de traiter une glomérulonéphrite fibrillaire (par exemple, une glomérulonéphrite fibrillaire non amyloïde) et/ou une complication associée à une glomérulonéphrite fibrillaire (par exemple, une pression artérielle élevée, un déséquilibre en phosphore et/ou une anémie). Par exemple, l'invention concerne des méthodes d'utilisation d'un ou plusieurs inhibiteurs de l'expression ou de l'activité du polypeptide DNAJB9 pour traiter un mammifère ayant une glomérulonéphrite fibrillaire.
PCT/US2017/062318 2016-11-18 2017-11-17 Évaluation et traitement d'une glomérulonéphrite fibrillaire Ceased WO2018094221A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080318803A1 (en) * 2004-05-27 2008-12-25 Vertex Pharmaceuticals Biomarkers for Monitoring Impdh Pathway Inhibition
CN102713632A (zh) * 2009-12-23 2012-10-03 希尔氏宠物营养品公司 用于诊断和治疗犬肾脏病症的组合物和方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080318803A1 (en) * 2004-05-27 2008-12-25 Vertex Pharmaceuticals Biomarkers for Monitoring Impdh Pathway Inhibition
CN102713632A (zh) * 2009-12-23 2012-10-03 希尔氏宠物营养品公司 用于诊断和治疗犬肾脏病症的组合物和方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DONG ET AL.: "ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C", MOLECULAR BIOLOGY OF THE CELL, vol. 19, no. 6, 1 June 2008 (2008-06-01), pages 2620 - 2630, XP055511027 *
JI ET AL.: "Cystatin C Attenuates Insulin Signaling Transduction by Promoting Endoplasmic Reticulum Stress in Hepatocytes", FEBS LETTERS, vol. 589, no. 24, 22 November 2015 (2015-11-22), pages 3938 - 3944, XP029347122 *
NASR ET AL.: "DNAJB9 Is a Specific Immunohistochemical Marker for Fibrillary Glomerulonephritis", KIDNEY INTERNATIONAL REPORTS, vol. 3, no. 1, 1 January 2018 (2018-01-01), pages 56 - 64, XP055511025 *
NEZVITSKY ET AL.: "Complement-mediated glomerular injury is reduced by inhibition of protein-tyrosine phosphatase 1B", AMERICAN JOURNAL OF PHYSIOLOGY, RENAL PHYSIOLOGY, vol. 307, no. 5, 1 September 2014 (2014-09-01), pages F634 - 647, XP055511019 *

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