WO1999059632A1 - Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions - Google Patents
Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions Download PDFInfo
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- WO1999059632A1 WO1999059632A1 PCT/IB1998/000761 IB9800761W WO9959632A1 WO 1999059632 A1 WO1999059632 A1 WO 1999059632A1 IB 9800761 W IB9800761 W IB 9800761W WO 9959632 A1 WO9959632 A1 WO 9959632A1
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- tnf
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- rii
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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
- C07K16/2866—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 cytokines, lymphokines, interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Asthma is a complex inflammatory disease of the airways that is 5 characterized by recurrent exacerbations due to exposure to specific allergens, exercise, cold air or stress.
- the hallmarks of inflammation associated with asthmatic condition are the presence of activated eosinophils, an increased sensitivity of the airways to non-specific stimuli (airways hyperresponsiveness: AHR), edema, mucus hypersecretion and cough.
- AHR airways hyperresponsiveness
- edema airways hyperresponsiveness
- mucus hypersecretion mucus hypersecretion and cough.
- This inflammatory process is 10 believed to be mediated, in part, by the generation and activation of Th2-type lymphocytes which secrete a variety of cytokines.
- allergic conditions other than asthma may be associated with similar generation and activation of Th2-type lymphocytes and cytokines secretion, such as rhinoconjuctivitis, conjuctivitis, rhinitis, dermatitis, urticaria, anaphylaxis, and others.
- Th2-type lymphocytes and cytokines secretion such as rhinoconjuctivitis, conjuctivitis, rhinitis, dermatitis, urticaria, anaphylaxis, and others.
- Tumor Necrosis Factor TNF ⁇ exerts a key role in the cytokine network with regard to the pathogenesis of many infectious and inflammatory 25 diseases. TNF ⁇ was purified, sequenced and cloned in the mid 1980s. Since then, several biological properties of this cytokine have been demonstrated.
- TNF ⁇ forms a non-covalently bound cone-shaped homotrimer.
- TNF effects are transmitted via cross-linking of the membrane-bound receptor molecules TNF-Receptor I (TNF-RI, p55) and TNF Receptor II (TNF- Rll,p75).
- TNF-RI, p55 membrane-bound receptor molecules
- TNF- Rll,p75 TNF Receptor II
- the extracellular portions of both TNF receptors can be shed, and these soluble receptors retain the ability to bind TNF.
- TNF mediates diverse effects in different organs and tissues.
- TNF Although several cell types produce TNF, the main source for the cytokine is monocytes/macrophages. TNF induce a number of proinflammatory changes in endothelial cells, including cytokine production, expression of adhesion molecules, and release of procoagulatory substances. These alterations may lead to septic shock.
- TNF ⁇ The actions of TNF ⁇ are known to promote asthmatic conditions; therefore, different groups have determined that blocking the action of soluble circulating TNF ⁇ provides means for relieving these conditions. This issue has been addressed by different approaches in published patent literature.
- WO 97/41895 relates to the treatment of asthma by administering a preparation of a chimeric protein comprising the soluble portion of TNFRI(p55) fused to IgG.
- This composition is claimed to block the action of TNF ⁇ and reverse inflammation in the lung.
- prolonged exogenous administration of the soluble portion of TNFRI receptor could cause an alteration in the immune response of the organism.
- mTNF membrane-bound TNF
- p55 and p75 TNF receptors seem to represent a balancing system for TNF action.
- a deficit in p55 activation or in p55 receptor leads to deficits in several inflammatory responses.
- a deficit in p75 activation or in p75 receptor leads to exacerbated pulmonary inflammation.
- the present application is based on the assumption that the binding of TNF-RII(p75) receptor with an agonist triggers a TNF-RI(p55)-independent signal to the cell which causes a decrease in Th2-mediated inflammation, notably in allergic bronchial asthma and other allergic conditions.
- This assumption is based on the findings reported in the examples that selective TNF-RII(p75) activation has a protective role in lung inflammation and hyperreactivity in a murine model of allergic bronchial asthma. Therefore, the main object of the present invention is a method for treating allergic bronchial asthma by administering an effective amount of a product having TNF-RII(p75) agonist properties.
- a further object of the invention is a method for treating other allergic conditions such as rhinoconjuctivitis, conjuctivitis, rhinitis, dermatitis, urticaria, anaphylaxis, and others by administering an effective amount of a product having TNF-RII(p75) agonist properties.
- a still further object of the invention is a method for treating Th2- mediated inflammation conditions by administering an effective amount of a product having TNF-RII(p75) agonist properties.
- product having TNF-RII(p75) agonist properties means any molecule that is able to bind and activate the receptor, for example a monoclonal antibody, such as those described by the group of Prof. Wallach in Bigda et al.(J. Exp. Med., 180, 445-460, 1994), and, in particular, those which bind to epitopes A, B and C of the p75 receptor , as well as those described in WO 94/09137.
- This term also encompasses polyclonal antibodies, proteins, peptides, peptoids, nucleic acids, chemical analogues of peptides and nucleic acids, as well as any organic molecule having a molecular weight similar to other organic molecules having pharmaceutical properties, and preferably between 100 and 30000 daltons.
- This term also encompasses prokaryotic or eukaryotic living cells, viruses, or any other TNF-RII(p75) agonist particles.
- the TNF-RII(p75) agonist used in the present invention has essentially no TNF-RI(p55) agonist properties.
- an “effective amount” refers to an amount of the TNF-RII(p75) agonist that is sufficient to affect the course and the severity of the allergic condition, bronchial asthma or Th2-mediated inflammation and to improve the patient's conditions, leading to the reduction or remission of the disease.
- the effective amount will depend on the route of administration and the condition of the patient.
- administration of the product having TNF- Rll(p75) agonist properties can be enteral, parenteral, or preferably topical such as in aerosol formulations.
- the product having TNF- Rll(p75) agonist properties is administered during an asthmatic, allergic, or Th2- mediated inflammation attack or exacerbation and said product is administered in an amount sufficient to alleviate the effects of said attack or exacerbation.
- Rll(p75) agonist properties is administered to a human or animal having an underlying asthmatic, allergic, or Th2-mediated inflammation condition prior to the onset of an attack or exacerbation of the condition, in an amount effective to prevent or retard the onset of said attack or exacerbation.
- a further object of the present invention is a method for treating an asthmatic, allergic, or Th2-mediated inflammation condition in a human or an animal, comprising modifying the balance between TNF-RII(p75) and TNF- Rl(p55) effectors.
- a still further object of the present invention is the use of the product having TNF-RII(p75) agonist properties together with a pharmaceutically acceptable carrier in the preparation of pharmaceutical compositions for the treatment of allergic bronchial asthma, allergic conditions, and Th2-mediated inflammation conditions.
- compositions of the invention can also comprise minor amounts of additives, such as stabilizers, excipients, buffers and preservatives.
- a further object of the present invention relates to the use of a product having TNF-RII(p75) agonist properties for modifying the balance between TNF-RII(p75) and TNF-RI(p55) effectors.
- a still further object of the present invention relates to a method for screening products having TNF-RII(p75) agonist properties comprising monitoring the inhibition of pulmonary inflammation occurring in humans or animals having pulmonary inflammation. Inhibition of pulmonary inflammation can be assessed by determining the level of cellular (eosinophils) and soluble (leukotriene) markers in broncho-alveolar lavage or in any other suitable body fluid, by indirect measures of airway resistance, or any other suitable means.
- the determination of the levels of cellular (eosinophils) and soluble (leukotriene) markers in broncho-alveolar lavage or in any other suitable body fluid of the human or the animal may help to establish a suitable dosage of products having TNF-RII(p75) agonist properties for said human or animal.
- Figure 1 shows the lung hyperreactivity of OVA-treated BALB/c mice receiving increasing doses of MCh via a nebulizer.
- Figure 2 shows that no lung hyperreactivity can be demonstrated in p55TNFR and WT mice after OVA-sensitization.
- Figure 3A Total cell counts in BAL
- 3B Dermatal cell counts in BAL
- Figure 4 shows lung hyperreactivity in p75TNFR and WT mice after OVA-sensitization.
- Figure 5A Total cell counts in the BAL fluid
- 5B Dermatal cell counts in BAL
- Table 1 presents a summary of the data obtained using TNF ⁇ -/- and tmTNFk/l mice tested for lung hyperreactivity and inflammation.
- mice Female BALB/c or C57BL/6 mice (6-8 wk of age) were purchased from Centre d'Elevage Janvier, Le Genest Saint-Isle, France. P55- deficient mice were obtained from Dr. K. Pfeffer (Munich); p75-deficient mice were purchased from Jackson laboratory. TNF ⁇ and tmTNFk/l mice were obtained from G. Kollias (Athens). Wild-type mice (C57BL 6) of the same genetic background, sex and age, were used as controls.
- Sensitization was performed using the method described by Hessel et al. ⁇ Hessel, van Oosterhout, et al. 1993 ID: 17 ⁇ . Mice were immunized by intraperitoneal (i.p.) injection of 10 mg ovalbumin (OVA; A-5503, Sigma Chemical Corp., St Louis, MO) in 0.1 ml NaCI (0.9% wt vol) every other day for fourteen days. Sham-sensitized mice received 0.1 ml of NaCI using the same protocol.
- OVA ovalbumin
- mice were challenged by intranasal instillation of OVA, 50 ml of a 0.3 mg/ml solution. For this, mice were anaesthetized by inhaled 2% FORENE TM (isofluran, Abbott, Cham, Switzerland). Control mice were treated with 50 ⁇ l of PBS alone. This procedure was repeated daily for 5 days. Lung hyperreactivity was assessed 24h after the last provocation, bronchoalveolar lavage (BAL) were done 2 days later.
- FORENE TM isofluran, Abbott, Cham, Switzerland
- Airway responsiveness was measured by recording respiratory pressure curves by whole body plethysmography (Buxco®, EMKA Technologies, Paris, France) in response to inhaled MCh (Aldrich-Chemie, Steinhein, Germany) at concentrations indicated in the figure legends. The period of nebulization was 20s. After each dose lung hyperreactivity was allowed to returned to baseline. This was typically in the order of 15 min. This method allowed the measurement of spontaneous breathing in a non-restrained mouse. The airway reactivity was expressed in enhanced pause (Penh), a calculated value, which correlated with the measurement of airway resistance, impedance and intrapleural pressure in the same mouse.
- Prenh enhanced pause
- Tr relaxation time. The time it took for the box pressure to change from a maximum to a user defined percentage of the maximum. In this study, Tr measurement began at the maximum box pressure and ended at 40% ⁇ Chvatchko, Kosco-Vilbois, et al. 1996 ID: 331 ⁇ .
- Figure 1 shows the lung reactivity of OVA-treated BALB/c mice receiving increasing doses of MCh via a nebulizer.
- Hyperresponsiveness was monitored by plethismography and was expressed as maximum Penh values over 15 min after Mch exposure. p ⁇ 0.05.
- Figure 2 shows lung reactivity in p55TNFR and WT mice after either NaCI or OVA-sensitization and challenge. Penh was monitored as described in material and methods in response to 6 x10 M Mch. Results show that p55TNFR " " animals do not develop lung hyperreactivity to MCh challenge.
- Figure 3 shows total and differential cell counts in BAL fluid in p55TNFR " " and WT mice after either NaCI or OVA-sensitization and challenge.
- MAC macrophages
- EOS eosinophils
- LYM lymphocytes
- NEUT neutrophils.
- NaCI challenge animals did not have eosinophilic infiltrates, in their lung. Eosinophils were present in large number in the lungs of C57BL/6 WT mice after challenge, but were absent in p55TNFR " " animals lavage fluid.
- Figure 4 shows lung reactivity in p75TNFR and C57BL 6 WT mice after either NaCI or OVA-sensitization and challenge. Penh was monitored as described in material and methods in response to indicated doses of MCh.
- Results show that p75TNFR mice developed lung hyperreactivity in the model of allergic asthma.
- Figure 5 shows total and differential cell counts in BAL from p75TNFR "/_ and C57BL/6 WT mice after either NaCI or OVA-sensitization and challenge.
- MAC macrophages
- EOS eosinophils
- LAM lymphocytes
- NEUT neutrophils
- Results show that there are more eosinophils in BAL from p75TNFR " when compared to C57BL/6 WT mice indicating that there is more inflammation.
- the p75 TNF-R may have a protective role for lung inflammation. Table 1 :
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Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1998/000761 WO1999059632A1 (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
EP98917548A EP1077723A1 (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
AU70738/98A AU7073898A (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
CA002328509A CA2328509A1 (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
IL13957498A IL139574A0 (en) | 1998-05-18 | 1998-05-18 | TNF-RII (p75) AGONISTS FOR TREATING ASTHMA AND OTHER ALLERGIC CONDITIONS |
JP2000549296A JP2002515459A (en) | 1998-05-18 | 1998-05-18 | Method for treating asthma and other allergic conditions and use of a composition comprising a TNF-RII (P75) agonist |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1998/000761 WO1999059632A1 (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
Publications (1)
Publication Number | Publication Date |
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WO1999059632A1 true WO1999059632A1 (en) | 1999-11-25 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/IB1998/000761 WO1999059632A1 (en) | 1998-05-18 | 1998-05-18 | Methods and use of compositions comprising tnf-rii(p75) agonists for treating asthma and other allergic conditions |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1077723A1 (en) |
JP (1) | JP2002515459A (en) |
AU (1) | AU7073898A (en) |
CA (1) | CA2328509A1 (en) |
IL (1) | IL139574A0 (en) |
WO (1) | WO1999059632A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2853588A1 (en) * | 2002-06-27 | 2015-04-01 | The General Hospital Corporation | Methods of organ regeneration |
US9821010B2 (en) | 2013-02-07 | 2017-11-21 | The General Hospital Corporation | Methods for expansion or depletion of T-regulatory cells |
US9840556B2 (en) | 2004-11-25 | 2017-12-12 | Ucb Biopharma Sprl | Anti-TNF alpha antibodies which selectively inhibit TNF alpha signalling through the p55R |
US10500273B2 (en) | 2015-03-02 | 2019-12-10 | 180 Therapeutics Lp | Method of treating a localized fibrotic disorder using an IL-33 antagonist |
US10906982B2 (en) | 2015-05-15 | 2021-02-02 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor 2 antibodies |
US11266730B2 (en) | 2015-09-29 | 2022-03-08 | The General Hospital Corporation | Methods of treating and diagnosing disease using biomarkers for BCG therapy |
US11859002B2 (en) | 2016-05-13 | 2024-01-02 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor 2 antibodies |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2950095B1 (en) * | 2014-05-28 | 2018-08-29 | Technische Universität Dresden | Cell-based assay and screening methods for modulators of p75NTR signaling |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0398327A1 (en) * | 1989-05-18 | 1990-11-22 | Yeda Research And Development Company Limited | Tumor necrosis factor binding protein II, its purification and antibodies thereto |
EP0585939A2 (en) * | 1992-09-03 | 1994-03-09 | YEDA RESEARCH AND DEVELOPMENT CO., Ltd. | TNF ligands |
WO1994009137A1 (en) * | 1992-10-15 | 1994-04-28 | Genentech, Inc. | Antibodies against type 2 tumor necrosis factor receptor |
EP0648783A1 (en) * | 1993-10-12 | 1995-04-19 | Yeda Research And Development Co. Ltd. | TNF inhibitors |
-
1998
- 1998-05-18 WO PCT/IB1998/000761 patent/WO1999059632A1/en not_active Application Discontinuation
- 1998-05-18 AU AU70738/98A patent/AU7073898A/en not_active Abandoned
- 1998-05-18 JP JP2000549296A patent/JP2002515459A/en active Pending
- 1998-05-18 EP EP98917548A patent/EP1077723A1/en not_active Withdrawn
- 1998-05-18 IL IL13957498A patent/IL139574A0/en unknown
- 1998-05-18 CA CA002328509A patent/CA2328509A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0398327A1 (en) * | 1989-05-18 | 1990-11-22 | Yeda Research And Development Company Limited | Tumor necrosis factor binding protein II, its purification and antibodies thereto |
EP0585939A2 (en) * | 1992-09-03 | 1994-03-09 | YEDA RESEARCH AND DEVELOPMENT CO., Ltd. | TNF ligands |
WO1994009137A1 (en) * | 1992-10-15 | 1994-04-28 | Genentech, Inc. | Antibodies against type 2 tumor necrosis factor receptor |
EP0648783A1 (en) * | 1993-10-12 | 1995-04-19 | Yeda Research And Development Co. Ltd. | TNF inhibitors |
Non-Patent Citations (3)
Title |
---|
BIGDA J ET AL: "TNF receptors --how they function and interact.", ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, (1997) 45 (4) 263-70. REF: 78 JOURNAL CODE: 79O. ISSN: 0004-069X., Poland, XP002089651 * |
FINLAY, A. ET AL: "TNF-alpha downregulates broncho-hypersensitivity in a murine model of allergic asthma", IMMUNOLOGY, vol. 92, no. supp1, December 1997 (1997-12-01), pages 107, XP002089650 * |
PESCHON J. ET AL: "TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation", THE JOURNAL OF IMMUNOLOGY, vol. 160, 15 January 1998 (1998-01-15), pages 943 - 952, XP002089649 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2853588A1 (en) * | 2002-06-27 | 2015-04-01 | The General Hospital Corporation | Methods of organ regeneration |
US9840556B2 (en) | 2004-11-25 | 2017-12-12 | Ucb Biopharma Sprl | Anti-TNF alpha antibodies which selectively inhibit TNF alpha signalling through the p55R |
US9821010B2 (en) | 2013-02-07 | 2017-11-21 | The General Hospital Corporation | Methods for expansion or depletion of T-regulatory cells |
US10765700B2 (en) | 2013-02-07 | 2020-09-08 | The General Hospital Corporation | Methods for expansion or depletion of t-regulatory cells |
US11844814B2 (en) | 2013-02-07 | 2023-12-19 | The General Hospital Corporation | Methods for expansion or depletion of T-regulatory cells |
US10500273B2 (en) | 2015-03-02 | 2019-12-10 | 180 Therapeutics Lp | Method of treating a localized fibrotic disorder using an IL-33 antagonist |
US11400154B2 (en) | 2015-03-02 | 2022-08-02 | 180 Therapeutics Lp | Method of treating a localized fibrotic disorder using an IL-33 antagonist |
US10906982B2 (en) | 2015-05-15 | 2021-02-02 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor 2 antibodies |
US11266730B2 (en) | 2015-09-29 | 2022-03-08 | The General Hospital Corporation | Methods of treating and diagnosing disease using biomarkers for BCG therapy |
US11859002B2 (en) | 2016-05-13 | 2024-01-02 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor 2 antibodies |
Also Published As
Publication number | Publication date |
---|---|
EP1077723A1 (en) | 2001-02-28 |
JP2002515459A (en) | 2002-05-28 |
IL139574A0 (en) | 2002-02-10 |
AU7073898A (en) | 1999-12-06 |
CA2328509A1 (en) | 1999-11-25 |
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