WO2018167111A1 - Collagen type xviii assay - Google Patents

Collagen type xviii assay Download PDF

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Publication number
WO2018167111A1
WO2018167111A1 PCT/EP2018/056320 EP2018056320W WO2018167111A1 WO 2018167111 A1 WO2018167111 A1 WO 2018167111A1 EP 2018056320 W EP2018056320 W EP 2018056320W WO 2018167111 A1 WO2018167111 A1 WO 2018167111A1
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Prior art keywords
antibody
collagen type
type xviii
time point
seq
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PCT/EP2018/056320
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English (en)
French (fr)
Inventor
Tina MANON-JENSEN
Morten Karsdal
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Nordic Bioscience AS
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Nordic Bioscience AS
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Priority to ES18713147T priority Critical patent/ES2969042T3/es
Priority to EP18713147.9A priority patent/EP3596120B1/en
Priority to US16/494,441 priority patent/US20200087385A1/en
Priority to JP2019550764A priority patent/JP7275040B2/ja
Publication of WO2018167111A1 publication Critical patent/WO2018167111A1/en
Anticipated expiration legal-status Critical
Priority to US18/145,767 priority patent/US20230340092A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • 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
    • G01N33/6887—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from muscle, cartilage or connective tissue
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]

Definitions

  • the present invention relates to a method for detecting the short isoform of Collagen type XVIII, and the use of said method in evaluating haemophilic diseases.
  • HF haemophilic
  • ABR bleeding rate
  • Endothelial cell impairment and matrix quality may be associated with joint bleeds and later the development of HF arthropathy.
  • BM basement membrane
  • Extracellular matrix turnover is a central pathological feature in many diseases due to epithelial or endothelial cell damage. While the endothelial cell function is debated, no quantifiable methods are available for specifically quantifying the damage to the vascular endothelium, which, subsequent to bleeding, results in exposure of the BM underlying the endothelial cells.
  • Collagen IV, XV and XVIII represent the most well-known collagens of the vascular BMs, responsible for maintaining vessel wall structure and integrity of the membrane (Fig.lA) [5-7] .
  • Type XVIII collagen exists in three isoforms: short, intermediate, and long, localized in various basement
  • the short isoform is endothelial specific and is found in blood vessels and around muscular structures. Here, zero or only very low amounts of the intermediate and long isoforms are present [5]. Following remodelling, damage, and degradation of the vascular BM the short isoform of collagen type XVIII may be affected and degraded, releasing measurable fragments of type XVIII collagen, as have been undertaken with other types of collagen [8,9].
  • KS autosomal recessive disorder Knobloch syndrome
  • collagen XVIII is essential for controlling blood vessel formation in the eye, and possibly an important component in the BM zones of the entire vascular system [17] .
  • the Applicant has now developed an assay for detecting the short isoform of collagen type XVIII, and has used that assay to assess the clinical relevance of turnover of
  • the invention relates to an antibody specifically reactive with short isoform collagen type XVIII, wherein said antibody does not react with intermediate isoform collagen type XVIII or with long isoform collagen type XVIII.
  • the antibody is specifically reactive with short isoform collagen type XVIII, wherein said antibody does not react with intermediate isoform collagen type XVIII or with long isoform collagen type XVIII.
  • the antibody is specifically reactive with short isoform collagen type XVIII, wherein said antibody does not react with intermediate isoform collagen type XVIII or with long isoform collagen type XVIII.
  • the antibody is specifically reactive with short isoform collagen type XVIII, wherein said antibody does not react with intermediate isoform collagen type XVIII or with long isoform collagen type XVIII.
  • the antibody is specifically reactive with short isoform collagen type XVIII, wherein said antibody does not react with intermediate isoform collagen type XVIII or with long isoform collagen type XVIII.
  • the N-terminal epitope is an epitope that is exposed after cleavage and removal of the N-terminal signal peptide of short isoform collagen type XVIII.
  • the antibody is specifically reactive with an N- terminal epitope comprised in the N-terminal amino acid sequence of 3 ⁇ 4N-EPERI SEEVG... (SEQ ID NO: 1) .
  • the antibody is specifically reactive with an N-terminal epitope comprising the N-terminal amino acid sequence H 2 N-EPERIS... (SEQ ID NO: 2) .
  • the antibody does not specifically recognise or bind an N-extended elongated version of said N-terminal amino acid sequence which is 3 ⁇ 4N-AEPERI SEEVG (SEQ ID NO: 3) and/or does not specifically recognise or bind an N-truncated version of said N-terminal amino acid sequence which is 3 ⁇ 4N- PERI SEEVG (SEQ ID NO: 4) .
  • the antibody may be a monoclonal or polyclonal antibody.
  • the antibody is a monoclonal antibody.
  • the invention in a second aspect, relates to a method of immunoassay for detecting or quantitating in a sample short isoform collagen type XVIII, wherein said method comprises contacting a sample comprising said short isoform collagen type XVIII with an antibody as described supra, and
  • the present invention may be directed to a method of detecting short isoform collagen type XVIII in a human patient, said method comprising:
  • the method comprises detecting or
  • the N-terminal epitope is preferably comprised in the N-terminal amino acid sequence 3 ⁇ 4N-EPERI SEEVG... (SEQ ID NO: 1) .
  • the N-terminal epitope comprises the N- terminal amino acid sequence H 2 N-EPERIS... (SEQ ID NO: 2) .
  • the sample is a biofluid.
  • the biofluid may be, but is not limited to, serum, plasma, urine,
  • the immunoassay may be a competition assay or a sandwich assay.
  • the immunoassay may be a radioimmunoassay or an enzyme-linked immunosorbent assay.
  • the method may further comprise correlating the quantity of said short isoform collagen type XVIII determined by said method with standard haemophilic disease samples of known disease severity to evaluate the severity of a haemophilic disease.
  • standard haemophilic disease samples means samples obtained from subjects known to have a haemophilic disease of a known severity.
  • the method may be any suitable method.
  • the method may be any suitable method.
  • standard values associated with healthy subjects means standardised quantities of short isoform collagen type XVIII determined by the method described supra for subjects considered to be healthy, i.e. without a haemophilic disease. The standardisation will depend on the height, weight, gender, etc. of the healthy subject.
  • the method may further comprise quantifying the amount of collagen type XVIII in at least two samples obtained from a subject at a first time point and at at least one subsequent time point, wherein an increase in the quantity of collagen type XVIII from the first time point to the at least one subsequent time point is indicative of a deterioration in a haemophilic disease from the first time point to the at least one subsequent time point, or wherein a decrease in the quantity of collagen type XVIII from the first time point to the at least one subsequent time point is indicative of an improvement in a haemophilic disease from the first time point to the at least one subsequent time point.
  • the haemophilic disease may be haemophilic arthropathy.
  • the method described supra may also be used to evaluate
  • the present invention is directed to a method for evaluating the efficacy of a drug for treating a haemophilic disease.
  • the method comprises using the method as described above to quantify the amount of collagen type XVIII in at least two biological samples obtained from a subject at a first time point and at at least one subsequent time point during a period of administration of the drug to the subject. A reduction in the quantity of collagen type XVIII from the first time point to the at least one
  • the invention relates to an assay kit for determining the quantity of short isoform collagen type
  • XVIII comprising an antibody as described supra and at least one of:
  • a peptide which is reactive with said antibody which may be a biotinylated peptide 3 ⁇ 4N-EPERI SEEVG-L-Biotin (SEQ ID NO: 5), wherein L is an optional linker
  • a calibrator peptide comprising the N-terminal sequence 3 ⁇ 4N-EPERI SEEVG... (SEQ ID NO: 6)
  • FIG. 1A Structure of the vascular BM.
  • the capillary subendothelial layer is composed of a BM and an interstitial matrix (IM) .
  • the main components of vascular BMs include type IV collagen, laminin and nidogen. Minor components include type XV collagen and type XVIII collagen.
  • the components of the BM self-assemble into sheet-like structures.
  • the BM is tightly connected to the IM through interactions between collagen type I and VI and collagen type IV and XV.
  • Figure IB Isoforms of Type XVIII collagen.
  • Collagen type XVIII exists in three isoforms, which differ in their N- terminus.
  • the COL18A1 gene encodes these variants by the use of two promoters and alternative splicing.
  • the short isoform has a different signal peptide from the other two, and is coded by promoter 1, while the others have the same signal peptide and are both coded by promoter 2. All isoforms include a thrombospondin-like domain, heparin sulphate chains and a globular C-terminal containing the type XVIII collagen fragment, endostatin.
  • FIG. 1 COL-18N antibody specific reactivity against type XVIII collagen. Monoclonal NB632-13H11/G5 antibody reaction towards standard peptide, truncated, elongated and de-selection peptides is shown. The antibody has high
  • N-terminal epitope refers to an N-terminal peptide sequence at the extremity of a
  • polypeptide i.e. at the N-terminal end of the polypeptide, and is not to be construed as meaning in the general
  • competitive ELISA refers to a competitive enzyme-linked immunosorbent assay and is a technique known to the person skilled in the art.
  • the term "sandwich immunoassay” refers to the use of at least two antibodies for the detection of an antigen in a sample, and is a technique known to the person skilled in the art.
  • short isoform of collagen type XVIII refers to the isoform of collagen type XVIII generated by promoter 1 wherein the N-terminal non-collagenous region includes the thrombospondin-1 like domain (TSP-1), but does not contain the Domain of Unknown Function (DUF) or the
  • Frizzled Domain FZ
  • intermediate isoform of collagen type XVIII refers to the alternatively spliced isoform of collagen type XVIII generated by promoter 2 wherein the N-terminal non-collagenous region includes the TSP-1 and DUF, but does not comprise the FZ .
  • long isoform of collagen type XVIII refers to the alternatively spliced isoform of collagen type XVIII generated by promoter 2 wherein the N-terminal non-collagenous region includes the TSP-1, the DUF and the FZ .
  • the term "COL-18N” is used as shorthand to describe the herein disclosed specific assay for the N-terminal sequence EPERI SEEVG (SEQ ID NO: 1) of the short isoform of collagen type XVIII.
  • parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
  • Serum was collected from 35 male HF patients aged 26 and over. This cut-off age was chosen as collagen turnover wears off at the closure of the growth plate at the age of approximately 25 years [21] .
  • the patients had a treatment history of either on-demand medication upon bleeding episodes or intake of a low dosage of prophylaxis of 5-10 IU/kg recombinant FVIII, 2-3 times/week.
  • Patients had varying degrees of HF arthropathy defined by the World Federation of Haemophilia Physical Examination Score (Gilbert Score) and by radiologic evaluation according to the Pettersson score.
  • the patients' average ABR was 18.1 ranging from 2-46.
  • Exclusion criteria were bleeding disorders other than haemophilia, human immunodeficiency virus infection, chronic obstructive pulmonary disease, medical history of joint disease or liver fibrosis, and treatment with anti-inflammatory biologies or steroids. Study participants were enrolled at the Department of Haematology, Peking Union Medical College Hospital,
  • a peptide corresponding to the first 10 amino acids of the N- terminal epitope of the short isoform of human type XVIII collagen l chain (excluding signal peptide, 34 'EPERISEEVG' 43 ) was used to generate monoclonal neo-epitope specific
  • the hybridomas were grown in 96-well plates and monoclonal growth was ensured by limited dilution. Clones were screened against the specific epitope (EPERISEEVG; SEQ ID NO: 1), elongated peptide (AEPERI SEEVG; SEQ ID NO: 3) and truncated peptide (PERISEEVG; SEQ ID NO: 4) .
  • EPERISEEVG specific epitope
  • AEPERI SEEVG elongated peptide
  • PERISEEVG truncated peptide
  • the competitive COL-18N ELISA was performed as follows.
  • a 96-well streptavidin-coated plate (Roche cat.: 11940279) was coated with ⁇ /well 1.25ng/mL biotinylated synthetic peptide EPERI SEEVG-K-Biotin (SEQ ID NO: 7) dissolved in coating buffer (20mM Na 2 HP0 4 , 3.7mM KH 2 P0 4 , 137mM NaCl, 2.7mM KCL, 0.1% Tween20, 1% BSA, pH7.4) and incubated for 30 min. at 20°C. The plate was washed five times with washing buffer (20mM Tris, 50mM NaCl, pH 7.2).
  • TMB ⁇ tetramethylbenzidine
  • the upper limit of detection was determined as the mean - 3xSD of 10 measurements of standard A (lOOOng/ml) .
  • the lower limit of quantification was determined by the lowest possible concentration with an imprecision of less than 30%.
  • the intra- and inter-assay variations were calculated as the mean of the variation of seven human samples by 10
  • hemoglobin, lipemia, biotin, and human antibodies against mouse antigens by human anti-mouse antibody was determined by adding two-fold dilutions to a serum sample of known concentration. Concentrations started at 0.500 mmol/1 hemoglobin, 0.56 mmol/1 lipemia, 160 yg/l biotin and
  • the NB632-13H11/G5 antibody specially recognized the first 10 amino acids of N-terminus type XVIII collagen l chain, short isoform (selection) (Fig. 2) .
  • the antibody showed no or minimal reactivity towards related peptides, indicating a high specificity (Fig. 2) .
  • Possible cross- reactivity with N-terminus of intermediary and long forms of collagen type XVIII is not plausible.
  • the three isoforms of collagen type XVIII are encoded by the COL18A1 gene by the use of two different promoters and alternative splicing
  • N-terminus of the short isoform becomes entirely different from N-terminus of the other two isoforms .
  • the technical evaluation of the competitive COL-18N ELISA revealed a stable sensitive assay with high specificity towards the N-terminus of vascular form of type XVIII collagen including high accuracy and precision of the assay.
  • COL-18N correlates to annual bleeding rate in HF patients.
  • the haemorrhagic disorder haemophilia manifests clinically by repeated haemarthrosis resulting in unavoidable arthropathy in the absence of adequate treatment.
  • haemophilia The bleeding severity of haemophilia is generally inversely proportional to the degree of FVIII/IX activity in the plasma, although substantial variability in bleeding tendencies is well-known. Reduced spontaneous bleeding and lower requirements of factor concentrates are reported in a subset of 10-15% of severe HF patients [23,24] . Also, development of inhibitors in non-severe HF patients may heighten the bleeding phenotype considerably [25].
  • Bleeding phenotype may be further compromised by large discrepancies amongst the FVIII assays caused by
  • Extracellular Matrix Remodeling The Common Denominator in Connective Tissue Diseases Possibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure. Assay Drug Dev Technol 2013; 11: 70-92.

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PCT/EP2018/056320 2017-03-16 2018-03-14 Collagen type xviii assay Ceased WO2018167111A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
ES18713147T ES2969042T3 (es) 2017-03-16 2018-03-14 Ensayo de colágeno tipo XVIII
EP18713147.9A EP3596120B1 (en) 2017-03-16 2018-03-14 Collagen type xviii assay
US16/494,441 US20200087385A1 (en) 2017-03-16 2018-03-14 Collagen Type XVIII Assay
JP2019550764A JP7275040B2 (ja) 2017-03-16 2018-03-14 Ｘｖｉｉｉ型コラーゲンアッセイ
US18/145,767 US20230340092A1 (en) 2017-03-16 2022-12-22 Collagen Type XVIII Assay

Applications Claiming Priority (2)

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GB1704182.3 2017-03-16
GBGB1704182.3A GB201704182D0 (en) 2017-03-16 2017-03-16 Collagen tye XVIII assay

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US16/494,441 A-371-Of-International US20200087385A1 (en) 2017-03-16 2018-03-14 Collagen Type XVIII Assay
US18/145,767 Continuation US20230340092A1 (en) 2017-03-16 2022-12-22 Collagen Type XVIII Assay

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020161242A1 (en) * 2019-02-07 2020-08-13 Nordic Bioscience A/S Type xxiii collagen assay

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GB202019578D0 (en) * 2020-12-11 2021-01-27 Nordic Bioscience As Assay for detecting Collagen XVIII biomarkers

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JPWO2007049749A1 (ja) 2005-10-28 2009-04-30 ディナベック株式会社 血液凝固異常の治療方法

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WO2020161242A1 (en) * 2019-02-07 2020-08-13 Nordic Bioscience A/S Type xxiii collagen assay

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