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WO1992009631A1 - Immunoanalyse et anticorps monoclonaux utilises dans la detection de recepteur de facteur de croissance de nerfs tronques - Google Patents

Immunoanalyse et anticorps monoclonaux utilises dans la detection de recepteur de facteur de croissance de nerfs tronques Download PDF

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Publication number
WO1992009631A1
WO1992009631A1 PCT/US1991/008968 US9108968W WO9209631A1 WO 1992009631 A1 WO1992009631 A1 WO 1992009631A1 US 9108968 W US9108968 W US 9108968W WO 9209631 A1 WO9209631 A1 WO 9209631A1
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WIPO (PCT)
Prior art keywords
growth factor
nerve growth
factor receptor
deposit
hybridoma
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PCT/US1991/008968
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English (en)
Inventor
Peter S. Distefano
Margaret Clagett-Dame
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to JP4503325A priority Critical patent/JPH06503722A/ja
Priority to CA002097309A priority patent/CA2097309A1/fr
Publication of WO1992009631A1 publication Critical patent/WO1992009631A1/fr

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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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators

Definitions

  • the so-formed complexes then are contacted with an indicator reagent comprising a monoclonal antibody or fragment thereof which specifically binds to human nerve growth factor receptor and human truncated nerve growth factor receptor, and which also binds to monkey truncated nerve growth factor receptor, and which does not significantly bind to rat or chick nerve growth factor receptor has been bound, to form a second mixture.
  • This second mixture is incubated for a time and under conditions sufficient for antibody/antigen/antibody complexes to form.
  • the presence of human nerve growth factor receptor or human truncated nerve growth factor receptor is determined by detecting the measurable signal generated.
  • the amount of human nerve growth factor receptor present in the test sample is proportional to the amount of signal generated.
  • the signal generating compound can be selected from the group consisting of luminescent compounds, chemiluminescent compounds, enzymes, and radioactive elements.
  • FIGS. 5A-B are photographs of immunoblots of E9b cell NGF-R under non- reducing and reducing conditions.
  • FIG. 5A is a photograph of the solubilized preparation loaded directly on a non-reducing 10% SDS-polyacrylamide gel followed by electrophoresis and transfer to nitrocellulose membrane (non-reduced).
  • FIGS. 6A-6D are bar graphs of competition studies wherein the counts (cpm x 10- 3 /weII) of each monoclonal antibody labeled with 125 l were plotted against NGF-Rt bound to immobilized unlabeled antibody, as indicated on the graphs.
  • FIG. 6C is a graph of 1 5
  • FIG. 6D is a graph of 125
  • FIGS. 7A-B are bar graphs of two-site RISA using 125 l-labeled IIIG5 monoclonal antibody of the invention to detect NGF receptor and NGF-Rt bound to immobilized antibodies. Data are expressed as mean +/- SD. An average for the background binding when either Ltk- solubilized cells or conditioned medium was used in the assay is shown by the dotted line ( ).
  • FIG. 7A shows E9b cells (hatched bar) that were solubilized and use as a source of NGF receptor; Ltk- solubilized preparation (open bar) were examined in parallel to assess non-specific binding.
  • FIG. 7B shows E9b conditioned medium (solid bar) used as an assay source of NGF-Rt. Conditioned medium (open bar) was examined in parallel to assess non ⁇ specific binding.
  • FIG. 8A is a graph of the linearity of binding of 125 I-IIIG5 to increasing amounts of NGF-Rt immobilized on a solid support by antibody XIF1.
  • FIG. 8B is a graph of the correlation of relative values obtained for NGF-Rt in serial dilutions of E9b conditioned medium concentrated by ammonium sulfate precipitation using the two-site RISA assay of the invention and the CLIP assay. Data in each assay are expressed as a percent of the maximum value obtained for NGF-Rt.
  • FIG. 9A is a graph of the counts per minute of 1 2 5
  • FIG. 9B is a graph of the counts per minute of 125 I-IIIG5 bound per well versus urine volume added to the assay.
  • Urine sample from a 6-year old male was diluted with HEPES to a final volume of 50 ⁇ l.
  • FIG. 10 is a graph of urine NGF-Rt plotted as a function of age in humans.
  • the present invention provides novel cell lines (hybridomas) which produce (secrete) monoclonal antibodies to NGF receptor, immunoassays which use the monoclonal antibodies, and kits which contain these monoclonal antibodies.
  • These cell lines are identified as cell line IIIG5 which produces monoclonal antibody IIIG5, cell line VIID1 which produces monoclonal antibody VIID1 , cell line VIIIC8 which produces monoclonal antibody VIIIC8, and cell line XIF1 , which produces monoclonal antibody XI F1.
  • cell line IIIG5 which produces monoclonal antibody IIIG5
  • cell line VIID1 which produces monoclonal antibody VIID1
  • cell line VIIIC8 which produces monoclonal antibody VIIIC8
  • cell line XIF1 which produces monoclonal antibody XI F1.
  • the monoclonal antibodies of the invention can be employed in various assay systems to determine the presence, if any, of truncated NGF receptor in a test sample. Fragments of the monoclonal antibodies also can be used.
  • the present invention provides an assay to detect human NGF receptor and/or truncated NGF- receptor. We have discovered a distinct developmental regulation of NGF receptor in human urine which is similar to that seen in the rat. P. S. DiStefano and E. M. Johnson, Proc. Natl. Acad. Sci USA. Ibid. No sexual dimorphism was evident at any time during development, nor was there any diurnal variation associated with NGF receptor truncation in the adult.
  • NGF receptor truncation correlates well with the development of function in peripheral nerves, strengthening the hypothesis that the predominant cell type shedding NGF receptor is the Schwann cell. Furthermore, NGF receptor in test samples such as biological fluids can serve as a biochemical marker for abnormal development, regeneration and degeneration of peripheral neurons.
  • This second mixture is incubated for a time and under conditions sufficient to form antibody/antigen/a ⁇ tibody complexes.
  • the presence of NGF receptor and/or truncated nerve growth factor receptor in the test sample which is captured on the solid phase, if any, is determined by detecting the measurable signal generated by the signal generating compound.
  • the amount of NGF receptor present is proportional to the signal generated.
  • one or a combination of more than one monoclonal antibody of the invention or fragment thereof is employed as a competitive probe for the detection of antibodies to NGF receptor and/or truncated NGF receptor.
  • NGF receptor and/or truncated NGF receptor can be coated on a solid phase.
  • a test sample suspected of containing antibody to NGF receptor and/or truncated nerve growth factor receptor then is incubated with an indicator reagent comprising a signal generating compound attached to one or a combination of more than one monoclonal antibody of the invention or fragment thereof, for a time and under conditions sufficient to form antigen/antibody/complexes of either the test sample and indicator reagent to the solid phase or the indicator reagent to the solid phase.
  • the reduction in binding of the monoclonal antibody to the solid phase can be quantitatively measured.
  • a measurable reduction in signal compared to the signal generated from a confirmed negative NGF receptor and truncated NGF receptor test sample indicates the presence of anti-NGF receptor antibodies and/or anti-truncated NGF receptor antibodies in the test sample.
  • each of the monoclonal antibodies of the present invention can be employed in the detection of NGF receptor and/or truncated NGF receptor in fixed or fresh tissues or cells by immunochemical analysis.
  • these monoclonal antibodies can be bound to matrices and used for affinity purification of specific NGF receptor and truncated NGF receptor proteins from cell cultures.
  • Combinations of the monoclonal antibodies (and fragments thereof) provided herein also may be used together as components in a mixture or "cocktail" of anti-NGF receptor antibodies, with different binding specificities.
  • Test samples which can be tested by the methods of the present invention described herein include biological fluids such as urine, whole blood, plasma, serum, cerebrospinal fluid, saliva, sweat, semen, or conditioned medium of cultured human cells. It also is contemplated that cells and tissues which are fixed or fresh can be employed.
  • Solid supports are known to those in the art and include the walls of wells of a reaction tray, test tubes, polystyrene beads, magnetic beads, nitrocellulose strips, membranes, microparticles such as latex particles, Sepharose-like beads, and others.
  • the indicator reagent comprises a signal generating compound (label) which is capable of generating a measurable signal detectable by external means conjugated (attached) to a specific binding member for NGF receptor and/or truncated NGF receptor.
  • label a signal generating compound
  • Specific binding member means a member of a specific binding pair. That is, two different molecules where one of the molecules through chemical or physical means specifically binds to the second molecule.
  • the indicator reagent in addition to being an antibody member of a specific binding pair for NGF receptor and/or truncated nerve growth factor receptor, the indicator reagent also can be a member of any specific binding pair, including either hapten-anti-hapten systems such as biotin or anti-biotin, avidin or biotin, a carbohydrate or a lectin, a complementary nucleotide sequence, an effector or a receptor molecule, an enzyme cofactor and an enzyme, an enzyme inhibitor or an enzyme, and the like.
  • hapten-anti-hapten systems such as biotin or anti-biotin, avidin or biotin, a carbohydrate or a lectin, a complementary nucleotide sequence, an effector or a receptor molecule, an enzyme cofactor and an enzyme, an enzyme inhibitor or an enzyme, and the like.
  • the immunoreactive specific binding member can be an antibody, an antigen, or an antibody/antigen complex that is capable of binding either to NGF receptor and/or truncated NGF receptor as in a sandwich assay, to the capture reagent as in a competitive assay, or to the ancillary specific binding member as in an indirect assay.
  • the various signal generating compounds (labels) contemplated include chromogens, catalysts such as enzymes, luminescent compounds such as fluorescein and rhodamine, chemiluminescent compounds, radioactive elements, and direct visual labels.
  • enzymes include alkaline phosphatase, horseradish peroxidase, beta-galactosidase, and the like.
  • radioactive elements include 1 25 l, 3 H and 35 S. The selection of a particular label is not critical, but it will be capable of producing a signal either by itself or in conjunction with one or more additional substances.
  • the reagent(s) employed for the assay can be provided in the form of a kit with one or more containers such as vials or bottles containing a separate reagent such as a monoclonal antibody
  • Example 1 Immunization/Cell Fusion A partially purified preparation of NGF-Rt was prepared for use as an immunogen as follows. E9b cells were grown as described by M. V. Chao et al.. Science 232:518-521 [1986]). Conditioned medium was decanted from the cells, brought to 0.02% with sodium azide and stored at 4°C. An immunoaffinity chromatography resin was prepared by coupling affinity purified monoclonal antibody ME20.4 (A. H. Ross et al.. Proc. Natl. Acad. Sci. USA 81 :6681-6685
  • IV injection of approximately 40 ⁇ g total protein was administered seven (7) weeks after the three (3) week boost.
  • the hybridomas were maintained in Dulbecco's modified Eagle's medium supplemented with 15% fetal calf serum (FCS), glutamine (2 mM), sodium pyruvate (1 mM), nonessential amino acids (10 mM), 2-mercaptoethanol (50 ⁇ M) and n-(2- hydroxyethyI)1piperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.3 (10 mM).
  • FCS fetal calf serum
  • glutamine (2 mM
  • sodium pyruvate (1 mM
  • nonessential amino acids 10 mM
  • 2-mercaptoethanol 50 ⁇ M
  • HEPES n-(2- hydroxyethyI)1piperazine-N'-2-ethanesulfonic acid
  • Immulon 2 Removawell strips (available from Dynatech Labs, Alexandria, VA) were coated with goat anti-mouse IgG (50 ⁇ l, 50 ⁇ g/ml) in PBS (pH 8.0) overnight at 4°C or at room temperature for one (1 ) hour. After removal of the goat anti-mouse IgG, the wells were blocked with 1.5% BSA (150 ⁇ g/ml) in PBS for 30 minutes at room temperature. The wells were washed three (3) times with cold PBS followed by the addition of hybridoma supematants (50 ⁇ l) and incubation for approximately two hours at room temperature.
  • the wells were washed three (3) times with cold PBS, placed on ice, and 50 ⁇ l of NGF-R cross-linked to 1 25 I-NGF (approximately 25,000 cpm) was added to each well and incubated for 45 minutes at 4°C.
  • the wells were washed four (4) times with cold PBS containing 0.05% Tween-
  • Receptor-containing samples affinity labeled with 1 25 I-NGF (50 to 100 ⁇ l) were incubated with hybridoma supernatant (50 to 100 ⁇ l), mouse serum (50 ⁇ l of a 1 :100 dilution in PBS) or purified monoclonal antibodies (5 ⁇ g) for two to four hours at 4°C.
  • a suspension of goat anti-mouse IgG Sepharose in PBS was added (10%, v/v), and the mixture was incubated for one hour.
  • Membranes were incubated for one hour at room temperature in PBS containing 5% non-fat dry milk, followed by one rinse with PBS containing 0.5% non-fat dry milk, and incubation for two hours with affinity purified monoclonal antibody (25 ⁇ g/ml) in the same buffer. Membranes were rinsed three times each for five minutes with PBS containing 0.5% non-fat dry milk and 0.05% Tween-20. Membranes then were incubated for two hours in the presence of 1 2 5
  • Affinity purified antibodies were radiolabeled with 25 l-Bolton-Hunter reagent.
  • Cells (E9b or Ltk-) were solubilized as described hereinabove.
  • NGR-Rt in E9b cell conditioned medium was used directly or was purified by immunoaffinity chromatography on a resin constructed using an antibody (ME20.4) to the human NGR-R.
  • the column was washed sequentially with PBS, 20 mM sodium phosphate buffer (pH 7.4) containing 0.55 M NaCI, PBS, 50 mM CAPS buffer (pH 9.8).
  • NGF- Rt was eluted from the column using CPAS buffer (pH 11.5). Column fractions were brought to pH 7.4 by the addition of 1 M HEPES buffer, pH 7.0.
  • Example 8 General Procedures Protein concentration was determined by the method of M. M. Bradford, Anal. Biochem. 72:248-3454 (1976) using crystalline BSA as a standard. Laser densitometry was performed using an LKB UltroScan XL laser densitometer.
  • NGF-Rt from E9b conditioned medium was affinity labeled with 12 5
  • NGF- Rt was immunopur ⁇ fied from E9b conditioned medium and used to immunize a BALB/cByJ mouse. Serum from a mouse receiving a primary immunization and one booster injection of partially purified NGF-Rt was positive for antibody activity to intact NGF-Rt by RISA and immunoprecipitation assay. Spleen cells from this mouse were fused with NS-1 mouse myeloma cells.
  • Hybridomas which secreted antibody to the NGF-R were first identified using the RISA assay as described in Example 3. Wells with a signal two times above background radioactivity (34/1056 wells) were rescreened by immunoprecipitation, and 18 of 34 wells remained positive for the presence of antibody to the NGF-R using this assay. Five cell lines continued to screen positive for antibody to NGF-R after expansion of the cell lines, and these were cloned by limiting dilution. After cloning and expansion, four hybridoma lines remained positive for antibody to NGF-R.
  • hybridomas are identified as cell line IIIG5 which produces monoclonal antibody IIIG5, cell line VIID1 which produces monoclonal antibody VIID1 , cell line VIIIC8 which produces monoclonal antibody VIIIC8, and cell line XIF1 , which produces monoclonal antibody XIF1.
  • the four monoclonal antibodies produced were capable of immunoprecipitating a protein with an apparent molecular weight of 63,000 daltons from a preparation containing affinity labeled NGF-Rt, as shown in FIG. 3. Again, subtracting a monomer of NGF yields a net molecular weight of approximately 50,000 daltons for the truncated form of the receptor. The 125 l-NGF-NGF-Rt complex was not immunoprecipitated by the antibody MOPC21.
  • the CLIP assay as described in Example 4 was performed using affinity labeled NGF-R solubilized from SH-SY5Y cells.
  • SH-SY5Y cells are a clonal affinity form of the NGF-receptor (see K. H. Sonnenfeld and D. N. Ishii. J * Neurosci. 5:1717-1728 [1985]).
  • All four monoclonal antibodies of the invention, as well as the antibody ME20.4 immunoprecipitated the 90,000 Mr NGF-R 1 25 l- NGF-R complex from SH-SY5Y cells receptor, as shown in FIG. 4. No labeled material was immunoprecipitated by MOPC21.
  • Example 11 Species Cross- Reactivity Using the two-site RISA as described in Example 3, all of the monoclonal antibodies of the invention bound to NGF-Rt from monkey urine. However, antibodies did not bind to NGF-R from chick embryonic dorsal root ganglia, rat superior cervical ganglia or PC12 cells.
  • Example 13 Epitope Mapping and Selection of Monoclonal Antibodies for Assay Solid phase competition studies were performed to determine whether the monoclonal antibodies of the invention bound to distinct receptor epitopes. All of the monoclonal antibodies were tested on the solid phase, as well as serving as the radiolabeled (top) monoclonal antibody. In this assay, the retention of radiolabel in the well indicated that the top and bottom antibody recognized distinct epitopes on the receptor protein. The only exception to this occurred when a single antibody bound to repeated epitopes of the receptor.
  • Example 14 Sample Collection and Preparation Urine samples were collected from 70 normal human subjects ranging in age from 1 month to 68 years. Urine from 4 pregnant women in their third trimester
  • Urine was collected in polypropylene specimen containers (available from Scientific Products, McGaw Park, IL), immediately placed on ice, and frozen at -80°C within 2 hours of collection. Urine samples were routinely assayed within 2 weeks of collection. There was no reduction in assay values for NGF-Rt or for creatinine when samples were frozen at -80°C for at least three weeks when compared to fresh urine. For neonates, urine was collected from cloth diapers or by the use of U-bags (available from Hollister, Kirksville, MO).
  • II1G5 was iodinated to specific activities of 600-800 cpm/fmol and binding was performed at various concentrations of labeled IHG5 for 45 minutes as described herei ⁇ above.
  • KD and Bmax values were determined by Scratchard plot. Bmax was expressed as nanograms (ng) 125 I-NGF bound per ⁇ g of creatinine which had been determined as described in Example 15.

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Abstract

Anticorps monoclonaux se liant spécifiquement à un récepteur de facteur de croissance de nerfs humains, un récepteur de facteur de croissance de nerfs tronqués humains, un récepteur de facteur de croissance de nerfs tronqués simiesques, et ne se liant pas significativement à un récepteur de facteur de croissance de nerfs de rat ou de poussin, et hybridomes produisant ces anticorps monoclonaux. L'invention concerne également des analyses utilisant ces anticorps monoclonaux afin de déterminer la présence d'un récepteur de facteur de croissance de nerfs humains ou d'un récepteur de facteur de croissance de nerfs tronqués humains dans un échantillon de test, et matériels de dosage contenant ces anticorps monoclonaux.
PCT/US1991/008968 1990-11-30 1991-12-02 Immunoanalyse et anticorps monoclonaux utilises dans la detection de recepteur de facteur de croissance de nerfs tronques WO1992009631A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP4503325A JPH06503722A (ja) 1990-11-30 1991-12-02 末端欠失神経成長因子受容体の検出に有用なイムノアッセイおよびモノクローナル抗体
CA002097309A CA2097309A1 (fr) 1990-11-30 1991-12-02 Immuno-essais et anticorps monoclonaux, utiles pour detecter le recepteur du facteur de croissance nerveuse tronque

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US62111190A 1990-11-30 1990-11-30
US621,111 1990-11-30

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WO1995006723A1 (fr) * 1993-09-01 1995-03-09 Boehringer Mannheim Gmbh Procede de marquage de cellules eucariotes par utilisation d'un recepteur de surface cellulaire en tant que marqueur
WO1999020780A1 (fr) * 1997-10-20 1999-04-29 Roche Diagnostics Gmbh Selection par gene marqueur positif ou negatif lors d'une recombinaison homologue
US6268214B1 (en) 1996-04-04 2001-07-31 Roche Diagnostics Gmbh Vectors encoding a modified low affinity nerve growth factor receptor
WO2002096458A1 (fr) * 2001-05-30 2002-12-05 Genentech, Inc. Anticorps anti-ngf pour le traitement de divers troubles
WO2006077441A1 (fr) * 2005-01-24 2006-07-27 Cambridge Antibody Technology Limited Elements de liaison specifiques du ngf
WO2009097425A3 (fr) * 2008-01-29 2009-11-05 Spring Bioscience Corporation Procédé pour détecter des molécules tronquées
US8246956B2 (en) 2003-12-24 2012-08-21 Abbott Research B.V. Humanized anti-nerve growth factor antibodies
US8435523B2 (en) 2009-05-04 2013-05-07 Abbott Research B.V. Antibodies against nerve growth factor (NGF) with enhanced in vivo stability
US9505829B2 (en) 2010-08-19 2016-11-29 Zoetis Belgium S.A. Anti-NGF antibodies and their use
US9617334B2 (en) 2012-06-06 2017-04-11 Zoetis Services Llc Caninized anti-NGF antibodies and methods thereof
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US10982002B2 (en) 2018-03-12 2021-04-20 Zoetis Services Llc Anti-NGF antibodies and methods thereof

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Cited By (31)

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US6074836A (en) * 1993-09-01 2000-06-13 Boehringer Mannheim Gmbh Method of marking eukaryotic cells
WO1995006723A1 (fr) * 1993-09-01 1995-03-09 Boehringer Mannheim Gmbh Procede de marquage de cellules eucariotes par utilisation d'un recepteur de surface cellulaire en tant que marqueur
US6268214B1 (en) 1996-04-04 2001-07-31 Roche Diagnostics Gmbh Vectors encoding a modified low affinity nerve growth factor receptor
WO1999020780A1 (fr) * 1997-10-20 1999-04-29 Roche Diagnostics Gmbh Selection par gene marqueur positif ou negatif lors d'une recombinaison homologue
US6284541B1 (en) 1997-10-20 2001-09-04 Roche Diagnostics Gmbh Positive-negative selection for homologous recombination
WO2002096458A1 (fr) * 2001-05-30 2002-12-05 Genentech, Inc. Anticorps anti-ngf pour le traitement de divers troubles
JP2004536072A (ja) * 2001-05-30 2004-12-02 ジェネンテック・インコーポレーテッド 種々の疾患の治療のための抗−ｎｇｆ抗体
US8246956B2 (en) 2003-12-24 2012-08-21 Abbott Research B.V. Humanized anti-nerve growth factor antibodies
US8877491B2 (en) 2003-12-24 2014-11-04 Abbvie Inc. Polynucleotides encoding humanized anti-NGF antibodies
US8257710B2 (en) 2003-12-24 2012-09-04 Abbott Research, B.V. Method for the treatment of pain with humanized anti-nerve growth factor antibodies
WO2006077441A1 (fr) * 2005-01-24 2006-07-27 Cambridge Antibody Technology Limited Elements de liaison specifiques du ngf
NO343064B1 (no) * 2005-01-24 2018-10-22 Cambridge Antibody Tech Ltd Spesifikke bindingspartnere for NGF.
RU2406728C2 (ru) * 2005-01-24 2010-12-20 Медиммун Лимитэд Партнеры специфического связывания с ngf
US9315571B2 (en) 2005-01-24 2016-04-19 Elan Pharma International Limited Specific binding members for NGF
US9701746B2 (en) 2005-01-24 2017-07-11 Medimmune Limited Methods of treating neuropathic pain with specific binding members for NGF
AU2006207338B2 (en) * 2005-01-24 2011-12-08 Elan Pharma International Limited Specific binding members for NGF
US9688749B2 (en) 2005-06-07 2017-06-27 Abbvie Inc. Molecules that are able to inhibit the binding between NGF and the TrkA receptor as analgesics with prolonged effect
WO2009097425A3 (fr) * 2008-01-29 2009-11-05 Spring Bioscience Corporation Procédé pour détecter des molécules tronquées
US8435523B2 (en) 2009-05-04 2013-05-07 Abbott Research B.V. Antibodies against nerve growth factor (NGF) with enhanced in vivo stability
US9447181B2 (en) 2009-05-04 2016-09-20 Abbvie Research B.V. Antibodies against nerve growth factor (NGF) with enhanced in vivo stability
US9505829B2 (en) 2010-08-19 2016-11-29 Zoetis Belgium S.A. Anti-NGF antibodies and their use
US10125192B2 (en) 2010-08-19 2018-11-13 Zoetis Belgium S.A. Caninized anti-NGF antibodies and their use
US10093725B2 (en) 2010-08-19 2018-10-09 Zoetis Belgium S.A. Anti-NGF antibodies and their use
US9951128B2 (en) 2012-06-06 2018-04-24 Zoetis Services Llc Caninized anti-NGF antibodies and methods thereof
US9617334B2 (en) 2012-06-06 2017-04-11 Zoetis Services Llc Caninized anti-NGF antibodies and methods thereof
US10982002B2 (en) 2018-03-12 2021-04-20 Zoetis Services Llc Anti-NGF antibodies and methods thereof
US12049507B2 (en) 2018-03-12 2024-07-30 Zoetis Services Llc Felinized anti-NGF antibodies and methods of treating pain
US12049509B2 (en) 2018-03-12 2024-07-30 Zoetis Services Llc Nucleic acids encoding a canine antibody which binds nerve growth factor and vectors and host cells thereof
US12049508B2 (en) 2018-03-12 2024-07-30 Zoetis Services Llc Canine anti-NGF antibodies and methods of treating pain thereof
US12084507B2 (en) 2018-03-12 2024-09-10 Zoetis Services Llc Humanized anti-NGF antibodies and methods of treating pain thereof
US12084506B2 (en) 2018-03-12 2024-09-10 Zoetis Services Llc Methods of treating a canine and inhibiting NGF activity through use of anti-NGF antibodies

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CA2097309A1 (fr) 1992-05-31
AU9164991A (en) 1992-06-25
JPH06503722A (ja) 1994-04-28
EP0559834A4 (fr) 1993-06-18
EP0559834A1 (fr) 1993-09-15

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