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WO1990008195A1 - Anticorps monoclonal se liant au collagene humain de type ix - Google Patents

Anticorps monoclonal se liant au collagene humain de type ix Download PDF

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Publication number
WO1990008195A1
WO1990008195A1 PCT/US1990/000283 US9000283W WO9008195A1 WO 1990008195 A1 WO1990008195 A1 WO 1990008195A1 US 9000283 W US9000283 W US 9000283W WO 9008195 A1 WO9008195 A1 WO 9008195A1
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WIPO (PCT)
Prior art keywords
collagen
ala
human type
monoclonal antibody
human
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US1990/000283
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English (en)
Inventor
Bjorn R. Olsen
Yoshifumi Ninomiya
Tomaotsu Kimura
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Harvard University
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Harvard University
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Publication of WO1990008195A1 publication Critical patent/WO1990008195A1/fr
Anticipated expiration legal-status Critical
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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]

Definitions

  • This invention relates to purified oligopeptides corresponding to fragments of human Type IX collagen and to monoclonal antibodies which bind specifically to human Type IX collagen.
  • Type IX collagen is one of a distinct class of extracellular matrix proteins -associated with the surface of collagen fibrils in cartilage. In patients suffering from degenerative cartilage diseases such as rheumatoid arthritis and osteoarthritis, the Type IX collagen is disrupted, so that it or fragments of it are no longer in their normal location and can instead be found in the intra-joint fluid, for example. This abnormal condition of Type IX collagen is symptomatic of the disease.
  • a number of earlier publications describe the structure and composition of chicken Type IX collagen, such as Konomi, et al., J. Biol. Chemistry Vol. 261, 6742-67.46 (1986); McCormick, et al., Proc. Natl. Acad. Sci. USA Vol.
  • human cartilage contains a similar molecular structure (Bruckner, et al., J. Biol. Chem. , Vol 263, 16911-16917 (1988).
  • human Type IX collagen differs in amino acid sequence and composition from chicken Type IX collagen to a significant extent; for example, probes containing cDNAs for chicken Type IX collagen do not cross hybridize well with human genomic DNA for the human Type IX collagen.
  • the antibodies can be labeled by conventional procedures with radioactive, fluorescent, enzyme or other labels and used in a procedure for assaying biological fluids such as synovial fluid for detecting the presence or absence of Type IX collagen, ⁇ l (IX) collagen chains or fragments thereof, thus serving as a diagnostic tool for the presence or absence of a degenerative cartilage disease.
  • biological fluids such as synovial fluid for detecting the presence or absence of Type IX collagen, ⁇ l (IX) collagen chains or fragments thereof, thus serving as a diagnostic tool for the presence or absence of a degenerative cartilage disease.
  • the antibodies can be used to screen drugs for use against such disease.
  • Figs 1A and IB show the amino acid sequence of the human ⁇ l (IX) collagen chain as deduced from the cloned cDNAs.
  • Fig. 1 were obtained by conventional extraction and isolation of RNA from chondrocytes derived from a costal cartilage specimen obtained from a female patient, followed by synthesis and cloning of the cDNA according to procedures well known in the art.
  • the human cDNA library was screened by filter hybridization, positive phages purified, and recombinant DNA isolated using standard procedures, and nucleotide sequence analysis was performed by the Maxam and Gilbert procedure as well as by the dideoxy chain termination technique.
  • oligopeptide 1 and oligopeptide 2 were then synthesized by conventional Merrifield solid phase synthesis, and there was added to the carboxyl end of each a cysteinyl residue to enable the oligopeptide to be coupled to a carrier protein. After purification, each of the synthetic peptides was coupled through the carboxy-terminal cysteinyl residue to keyhole limpet hemocyanin by conventional procedures. Lyophilized peptide (5 g) was coupled to 4 mg of hemocyanin (Polysciences) in about 2 ml of 20 mM sodium phosphate-buffer pH 7.5.
  • peptide-hemocyanin complexes were separated from uncoupled peptide by gel filtration on Sephadex G-50 (fine) (1x25cm) equilibrated with 20 mM sodium phosphate pH 7.5.
  • peptide-hemocyanin complex For generation of antibodies, 50-100 ⁇ g of peptide-hemocyanin complex was mixed in 0.5 ml of complete Freunds Adjuvant and injected intraperitoneally into Balb-C mice. Booster injections were given at two week intervals in incomplete Freunds Adjuvant. A total of 2-4 booster injections were given. Mice were periodically bled from the tail vein for screening of sera. When sera were positive in ELISA assays against peptide-BSA conjugates, subcutaneous injections of 10-20 ⁇ g without adjuvant were given twice, one 5 days before fusion and the second 3 days before fusion.
  • Example 1 and Example 2 oligopeptides were selected by such screening for each of the Example 1 and Example 2 oligopeptides.
  • a specimen of the culture of each of the ten strains was injected into a pristane-primed mouse, the ascites collected, and the monoclonal antibody purified from the ascites by precipitation in 40% ammonium sulfate, then chromatographed on a column containing DEAE Sephacel.
  • the antibodies were finally subjected to electrophoresis on SDS-polyacrylamide gels for assessment of purity. All monoclonal antibodies were determined to be of the IgG class. They were of various subclasses and types as follows:
  • the individual blots were then treated with a solution of each of the 20 antibodies in phosphate-buffered saline, and with an antibody concentration of 0.005 mg/ml.
  • a commercial enzyme-labeled second antibody was then employed to determine which of the individual monoclonal antibody specimens reacted with the intact ⁇ l(IX) collagen chain on the nitrocellulose blot .
  • hybridoma line 24-3G3 was deposited with the American Type Culture Collection under the Budapest Treaty on January 13, 1989, being identified as No. HB 9972. These results were corroborated and extended by subjecting each of the four immunoreactive monoclonal antibodies to a standard immunofluorescent assay for binding to Type IX collagen in a specimen of human articular cartilage. Antibodies 23-3E12, 23-5D1, and 23-2F6 were also found to bind to specimens of mouse and rat Type IX collagen, but not to chicken Type IX collagen. Oligopeptides containing the following sequences -1-
  • the oligopeptide can be coupled to a carrier protein by adding a single cysteinyl moiety to the carboxyl terminus, then using a conventional cross-linking agent. These carrier-supported oligopeptides can then be used as antigens in a manner analogous to that of Examples 1 and 2 to produce monoclonal antibodies.
  • the monoclonal antibodies immunoreactive with human Type IX collagen and human ⁇ (IX) collagen chains can be labeled by any conventional procedure with any suitable label and employed in a conventional assay procedure for detecting the presence or absence of human Type IX collagen, ⁇ l(IX) collagen chains or fragments thereof in a specimen of biological fluid such as serum, synovial fluid or the like.
  • the biological fluid to be assayed can assayed by ELISA assays, radioimmunoassays or any other conventional immunoassays using the monoclonal antibodies.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Les oligopeptides correspondants aux segments de collagène humain de type IX sont utiles en tant qu'antigènes pour produire des anticorps monoclonaux se liant de manière immunologique au collagène humain de type IX ainsi qu'à des fragments dérivés de celui-ci, et pouvant être utilisés pour détecter leur présence dans les liquides biologiques tels que le liquide synovial et le sérum.
PCT/US1990/000283 1989-01-13 1990-01-11 Anticorps monoclonal se liant au collagene humain de type ix Ceased WO1990008195A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29710089A 1989-01-13 1989-01-13
US297,100 1989-01-13

Publications (1)

Publication Number Publication Date
WO1990008195A1 true WO1990008195A1 (fr) 1990-07-26

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5140103A (en) * 1987-11-06 1992-08-18 Washington Research Foundation Peptide fragments containing HP and LP cross-links
WO1994003813A1 (fr) * 1992-07-29 1994-02-17 Boehringer Mannheim Gmbh Dosage immunologique servant a detecter la presence de collagene ou de fragments de collagene
US5300434A (en) * 1987-11-06 1994-04-05 Washington Research Foundation Hybridoma cell line producing an antibody to type-I collagen amino-terminal telopeptide
US5320970A (en) * 1987-11-06 1994-06-14 Washington Research Foundation Detection of collagen degradation in vivo
WO1995004282A1 (fr) * 1993-07-28 1995-02-09 Boehringer Mannheim Gmbh Immunodosage pour la detection du collagene ou de fragments de collagene
EP0710251A4 (fr) * 1993-07-09 1997-12-10 Univ California Dosage de ykl-40 en tant que marqueur de la degradation de matrices de tissus conjonctifs de mammiferes
US5702909A (en) * 1987-11-06 1997-12-30 Washington Research Foundation Methods of detecting collagen type II degradation in vivo
WO1999021011A1 (fr) * 1997-10-23 1999-04-29 Fibrogen, Inc. Anticorps anti-collagene de type ix et utilisations associees
US5962639A (en) * 1987-11-06 1999-10-05 Washington Research Foundation Synthetic peptides corresponding to telopeptide sequences of cross-linked type I collagen metabolites
US6027903A (en) * 1987-11-06 2000-02-22 Washington Research Foundation Kit for detecting analyte indicative of type I collagen resorption in vivo
US6107047A (en) * 1996-03-21 2000-08-22 Osteometer Biotech A/S Assaying protein fragments in body fluids
US6117646A (en) * 1997-09-22 2000-09-12 Osteometer Biotech A/S Assaying protein fragments in body fluids
US6153732A (en) * 1987-11-06 2000-11-28 Washington Research Foundation Kit for detecting analyte indicative of type II collagen resorption in vivo
US6210902B1 (en) 1994-03-24 2001-04-03 Osteometer Biotech A/S Estimation of the fragmentation pattern of collagen in body fluids and the diagnosis of disorders associated with the metabolism of collagen
US6300083B1 (en) 1996-08-22 2001-10-09 Osteometer Biotech A/S Assaying D-amino acids in body fluids
US6372442B1 (en) 1994-10-17 2002-04-16 Osteometer Biotech A/S Method of characterizing the degradation of type II collagen
US6660481B2 (en) 1996-12-09 2003-12-09 Osteometer Biotech A/S Sandwich assays for collagen type I fragments
WO2008108723A1 (fr) 2007-03-02 2008-09-12 Anamar Medical Ab Procédé de diagnostic de destruction de collagène ix
US7919456B2 (en) * 2003-06-17 2011-04-05 Proteobioactives Pty Ltd. Connective tissue derived polypeptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 263, No. 32, issued November 1988, P. BRUCKNER: "The Structure of Human Collagen Type IX and its Organization in Fetal and Infant Cartilage Fibrils", see pages 16911-16912. *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5912131A (en) * 1987-11-06 1999-06-15 Washington Research Foundation Detection of type 1 collagen degradation in vivo
US5919634A (en) * 1987-11-06 1999-07-06 Washington Research Foundation Methods of detecting collagen type II degradation in vivo
US5939274A (en) * 1987-11-06 1999-08-17 Washington Research Foundation Methods of monitoring patient responses to anti-resorptive therapies
US5320970A (en) * 1987-11-06 1994-06-14 Washington Research Foundation Detection of collagen degradation in vivo
US6916604B2 (en) 1987-11-06 2005-07-12 Washington Research Foundation Uses of synthetic peptides corresponding to telopeptide sequences of cross-linked type I collagen metabolites
US5455179A (en) * 1987-11-06 1995-10-03 Washington Research Foundation Method of detecting collagen degradation in vivo
US5472884A (en) * 1987-11-06 1995-12-05 Washington Research Foundation Detection of collagen degradation in vivo
US5473052A (en) * 1987-11-06 1995-12-05 Washington Research Foundation Antigen-binding fragments of an antibody to type-I collagen amino-terminal telopeptide
US5532169A (en) * 1987-11-06 1996-07-02 Washington Research Foundation Methods of detecting collagen degradation in vivo
US5576189A (en) * 1987-11-06 1996-11-19 Washington Research Foundation Antibody to type-I collagen amino-terminal telopeptide
US5607862A (en) * 1987-11-06 1997-03-04 Washington Research Foundation Assay for N-terminal type I collagen telopeptide that survives bone resorption in vivo
US5641687A (en) * 1987-11-06 1997-06-24 Washington Research Foundation Methods of detecting collagen degradation in vivo
US5641837A (en) * 1987-11-06 1997-06-24 Washington Research Foundation Method of detecting collagen degradation in vivo
US5656439A (en) * 1987-11-06 1997-08-12 Washington Research Foundation Antibody to type-I collagen carboxy-terminal telopeptide
US5677198A (en) * 1987-11-06 1997-10-14 Washington Research Foundation Assay for peptide metabolites from the amino-terminal telopeptide domain of type I collagen
US5688652A (en) * 1987-11-06 1997-11-18 Washington Research Foundation Detection of collagen degradation in vivo
US6153732A (en) * 1987-11-06 2000-11-28 Washington Research Foundation Kit for detecting analyte indicative of type II collagen resorption in vivo
US5702909A (en) * 1987-11-06 1997-12-30 Washington Research Foundation Methods of detecting collagen type II degradation in vivo
US5834221A (en) * 1987-11-06 1998-11-10 Washington Research Foundation Assay for type I collagen carboxy-terminal telopeptide analytes
US6143511A (en) * 1987-11-06 2000-11-07 Washington Research Foundation Sandwich immunoassays for collagen type II degradation products
US6100379A (en) * 1987-11-06 2000-08-08 Washington Research Foundation Synthetic peptides corresponding to telopeptide sequences of cross-linked type II collagen metabolites
US5140103A (en) * 1987-11-06 1992-08-18 Washington Research Foundation Peptide fragments containing HP and LP cross-links
US5300434A (en) * 1987-11-06 1994-04-05 Washington Research Foundation Hybridoma cell line producing an antibody to type-I collagen amino-terminal telopeptide
US5962639A (en) * 1987-11-06 1999-10-05 Washington Research Foundation Synthetic peptides corresponding to telopeptide sequences of cross-linked type I collagen metabolites
US6027903A (en) * 1987-11-06 2000-02-22 Washington Research Foundation Kit for detecting analyte indicative of type I collagen resorption in vivo
US6048705A (en) * 1987-11-06 2000-04-11 Washington Research Foundation Sandwich immunoassays for collagen type I degradation products
WO1994003813A1 (fr) * 1992-07-29 1994-02-17 Boehringer Mannheim Gmbh Dosage immunologique servant a detecter la presence de collagene ou de fragments de collagene
US7230086B2 (en) 1993-07-09 2007-06-12 The Regents Of The University Of California Assay for YKL-40 as a marker for degradation of mammalian connective tissue matrices
EP0710251A4 (fr) * 1993-07-09 1997-12-10 Univ California Dosage de ykl-40 en tant que marqueur de la degradation de matrices de tissus conjonctifs de mammiferes
US6794150B2 (en) 1993-07-09 2004-09-21 The Regents Of The University Of California Assay for YKL-40 as a marker for degradation of mammalian connective tissue matrices
WO1995004282A1 (fr) * 1993-07-28 1995-02-09 Boehringer Mannheim Gmbh Immunodosage pour la detection du collagene ou de fragments de collagene
US6210902B1 (en) 1994-03-24 2001-04-03 Osteometer Biotech A/S Estimation of the fragmentation pattern of collagen in body fluids and the diagnosis of disorders associated with the metabolism of collagen
US6372442B1 (en) 1994-10-17 2002-04-16 Osteometer Biotech A/S Method of characterizing the degradation of type II collagen
US6107047A (en) * 1996-03-21 2000-08-22 Osteometer Biotech A/S Assaying protein fragments in body fluids
US6300083B1 (en) 1996-08-22 2001-10-09 Osteometer Biotech A/S Assaying D-amino acids in body fluids
US6660481B2 (en) 1996-12-09 2003-12-09 Osteometer Biotech A/S Sandwich assays for collagen type I fragments
US6117646A (en) * 1997-09-22 2000-09-12 Osteometer Biotech A/S Assaying protein fragments in body fluids
WO1999021011A1 (fr) * 1997-10-23 1999-04-29 Fibrogen, Inc. Anticorps anti-collagene de type ix et utilisations associees
US7919456B2 (en) * 2003-06-17 2011-04-05 Proteobioactives Pty Ltd. Connective tissue derived polypeptides
WO2008108723A1 (fr) 2007-03-02 2008-09-12 Anamar Medical Ab Procédé de diagnostic de destruction de collagène ix
US7892768B2 (en) 2007-03-02 2011-02-22 Anamar Medical Ab Diagnosis of collagen IX destruction
US8580529B2 (en) 2007-03-02 2013-11-12 Anamar Ab Diagnosis of collagen IX destruction

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