WO1990008195A1 - Anticorps monoclonal se liant au collagene humain de type ix - Google Patents
Anticorps monoclonal se liant au collagene humain de type ix Download PDFInfo
- 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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- Prior art keywords
- collagen
- ala
- human type
- monoclonal antibody
- human
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Links
- 102000004427 Collagen Type IX Human genes 0.000 title abstract description 22
- 108010042106 Collagen Type IX Proteins 0.000 title abstract description 22
- 102000015636 Oligopeptides Human genes 0.000 claims abstract description 15
- 108010038807 Oligopeptides Proteins 0.000 claims abstract description 15
- 239000012634 fragment Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 11
- 102000008186 Collagen Human genes 0.000 claims description 10
- 108010035532 Collagen Proteins 0.000 claims description 10
- 229920001436 collagen Polymers 0.000 claims description 10
- 210000004408 hybridoma Anatomy 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 210000004027 cell Anatomy 0.000 claims description 3
- 238000002372 labelling Methods 0.000 claims 1
- 239000000427 antigen Substances 0.000 abstract description 4
- 102000036639 antigens Human genes 0.000 abstract description 4
- 108091007433 antigens Proteins 0.000 abstract description 4
- 239000013060 biological fluid Substances 0.000 abstract description 4
- 210000001179 synovial fluid Anatomy 0.000 abstract description 3
- 210000002966 serum Anatomy 0.000 abstract description 2
- 108020004635 Complementary DNA Proteins 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 4
- 210000000845 cartilage Anatomy 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000012286 ELISA Assay Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 208000015100 cartilage disease Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 108090000819 Chondroitin-sulfate-ABC endolyases Proteins 0.000 description 1
- 102000037716 Chondroitin-sulfate-ABC endolyases Human genes 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 208000017568 chondrodysplasia Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 108060003552 hemocyanin Proteins 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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.
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 |
Family
ID=23144858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1990/000283 WO1990008195A1 (fr) | 1989-01-13 | 1990-01-11 | Anticorps monoclonal se liant au collagene humain de type ix |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1990008195A1 (fr) |
Cited By (19)
| 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 |
| EP0710251A1 (fr) * | 1993-07-09 | 1996-05-08 | The Regents Of The University Of 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 |
-
1990
- 1990-01-11 WO PCT/US1990/000283 patent/WO1990008195A1/fr unknown
Non-Patent Citations (1)
| 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 (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6143511A (en) * | 1987-11-06 | 2000-11-07 | Washington Research Foundation | Sandwich immunoassays for collagen type II degradation products |
| US5320970A (en) * | 1987-11-06 | 1994-06-14 | Washington Research Foundation | Detection of collagen degradation in vivo |
| US5300434A (en) * | 1987-11-06 | 1994-04-05 | Washington Research Foundation | Hybridoma cell line producing an antibody to type-I collagen amino-terminal telopeptide |
| US5912131A (en) * | 1987-11-06 | 1999-06-15 | Washington Research Foundation | Detection of type 1 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 |
| US6153732A (en) * | 1987-11-06 | 2000-11-28 | Washington Research Foundation | Kit for detecting analyte indicative of type II collagen resorption in vivo |
| 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 |
| US5919634A (en) * | 1987-11-06 | 1999-07-06 | Washington Research Foundation | Methods of detecting collagen type II degradation in vivo |
| US5688652A (en) * | 1987-11-06 | 1997-11-18 | Washington Research Foundation | Detection of collagen degradation in vivo |
| US5140103A (en) * | 1987-11-06 | 1992-08-18 | Washington Research Foundation | Peptide fragments containing HP and LP cross-links |
| 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 |
| US6100379A (en) * | 1987-11-06 | 2000-08-08 | Washington Research Foundation | Synthetic peptides corresponding to telopeptide sequences of cross-linked type II collagen metabolites |
| US6048705A (en) * | 1987-11-06 | 2000-04-11 | Washington Research Foundation | Sandwich immunoassays for collagen type I degradation products |
| 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 |
| US5939274A (en) * | 1987-11-06 | 1999-08-17 | Washington Research Foundation | Methods of monitoring patient responses to anti-resorptive therapies |
| 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 |
| 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 |
| EP0710251A1 (fr) * | 1993-07-09 | 1996-05-08 | The Regents Of The University Of California | Dosage de ykl-40 en tant que marqueur de la degradation de matrices de tissus conjonctifs de mammiferes |
| 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 |
| US8580529B2 (en) | 2007-03-02 | 2013-11-12 | Anamar Ab | Diagnosis of collagen IX destruction |
| 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 |
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