WO1995015179A1 - Procede pour traiter des troubles intestinaux - Google Patents

Procede pour traiter des troubles intestinaux Download PDF

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Publication number
WO1995015179A1
WO1995015179A1 PCT/AU1994/000745 AU9400745W WO9515179A1 WO 1995015179 A1 WO1995015179 A1 WO 1995015179A1 AU 9400745 W AU9400745 W AU 9400745W WO 9515179 A1 WO9515179 A1 WO 9515179A1
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WO
WIPO (PCT)
Prior art keywords
tnf
agent
bile
production
group
Prior art date
Application number
PCT/AU1994/000745
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English (en)
Inventor
Graham Douglas Fischer Jackson
Original Assignee
Unisearch Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from AUPM8325A external-priority patent/AUPM832594A0/en
Application filed by Unisearch Limited filed Critical Unisearch Limited
Priority to EP95902712A priority Critical patent/EP0732938A4/fr
Priority to JP7515299A priority patent/JPH09505812A/ja
Priority to AU11879/95A priority patent/AU1187995A/en
Publication of WO1995015179A1 publication Critical patent/WO1995015179A1/fr

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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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

  • the present invention relates to a method of treating intestinal disorders.
  • the method involves the use of procedures or agents that reduce the production or block the action of tumour necrosis factor ⁇ (TNF), produced in the liver and released into the bile of humans or animals. Since TNF released into the bile may in some circumstances be taken up from the gut and act systemically, the invention also relates to a method of treatment of disorders due to elevated circulating TNF, by blocking TNF release to or action in the bile.
  • TNF tumour necrosis factor ⁇
  • endotoxic shock results from the action of lumenal agents.
  • LPS lipopolysaccharide
  • the present inventors have demonstrated that infusion of recombinant human TNF into the bile diverted from and then reintroduced to the gastrointestinal tract, results in similar symptoms to those observed in animals challenged with LPS. Furthermore, addition of antibodies directed against murine TNF (which also recognise rat TNF) to the bile of LPS-treated animals partially or fully blocked the gastrointestinal lesions seen in animals not treated with antibody, including haemorrhage and fluid accumulation, diarrhoea and gross intestinal damage. As well, the constitutional symptoms associated with LPS treatment and elevation of bile TNF levels (fever, hypotension, general malaise and tissue damage) were reduced.
  • the present invention consists in a method of treating or preventing in a subject an intestinal disorder caused by an elevated level of TNF in the lumen of the intestine of the subject the method comprising administering to the subject an agent which reduces the action of the intralumenal TNF or reduces the production or accumulation of intralumenal TNF.
  • the present invention consists in a method of treating or preventing in a subject constitutional symptoms resulting from increased uptake into the circulation of TNF produced by the liver and secreted into the bile, the method comprising administering to the subject an agent which reduces the production or action of biliary TNF.
  • an agent which reduces the production or action of biliary TNF.
  • These syndromes or conditions include sepsis, diarrhoea (viral, bacterial), diarrhoea (induced by stress, alcohol, antibiotics, chemotherapy, or radiation), gay bowel syndrome, graft versus host disease (e.g., after bone marrow transplantation), colon cancer, HIV infection, AIDS and AIDS related infections (e.g., icrosporidium) , colic, ulcers initiated by non-steroidal anti-inflammatory drugs (NSAIDS), inflammatory bowel diseases (Crohns disease, ulcerative colitis, irritable bowel syndrome), graft versus host disease, gastrointestinal ulcers, gastrointestinal inflammation, bacterial translocation following surgery, multi-organ failure and food allergy.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • the intestinal disorder in the subject is as a result of one or more of these syndromes or conditions.
  • the subject is suffering from sepsis, diarrhoea (viral, bacterial), diarrhoea (induced by stress, alcohol, antibiotics, chemotherapy, or radiation), HIV infection, AIDS and AIDS related infections (e.g., Microsporidium), bacterial translocation following surgery, and bowel ischemia/reperfusion injury
  • the elevated level of TNF in the lumen of the intestine is of bile origin.
  • the agent which reduces the action of the intralumenal TNF or reduces the production or accumulation of the intralumenal TNF may be any of a number of agents such as:- a) antibodies to TNF or to its receptors, e.g., a TNF- blocking antibody; b) the soluble forms of TNF receptors; c) peptides or other molecules that block TNF action at its receptors; d) peptides that reduce TNF production; e) agents that block TNF production, such as thalidomide, anti-inflammatory inhibitors of 5-lipoxygenase and 5-cyclooxygenase, e.g., Tepoxalin (Johnson & Johnson), Tenidap (Pfizer),
  • agents that block TNF production such as thalidomide, anti-inflammatory inhibitors of 5-lipoxygenase and 5-cyclooxygenase, e.g., Tepoxalin (Johnson & Johnson), Tenidap (Pfizer),
  • CGP47 969A (Ciba Geigy) , agents that reduce TNF production by elevating cAMP levels including pentoxyfy11ine; f) lipid molecules, such as polyunsaturated fatty acids that block TNF production.
  • the agent is an antibody, either polyclonal or monoclonal.
  • a preferred monoclonal antibody is MAb47.
  • the hybridoma cell line which produces MAb47 was deposited with the European Collection of Animal Cell Cultures (ECACC), Vaccine Research Production Laboratory, Public Health Laboratory Service, Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire SP4 OJG, United Kingdom on 14 December 1989 and was accorded Accession No 89121402.
  • Other antibodies which may find use in the method of the present invention are those disclosed in International Patent Application Nos WO 90/01950, WO 89/08460 and WO 90/10707.
  • the agent is a peptide, preferably peptide 492 or peptide T.
  • peptide 492 can be found in Australian Patent Application No 22731/92 "Peptide which abrogates TNF and/or LPS toxicity" .
  • peptide T may be found in EP0249390, EP0249394 and WO88/09338. The disclosures of these references are included herein by reference.
  • An agent reducing the production of TNF could be delivered via a number of routes including: oral, parenteral, transdermal etc., or in combination with a second agent that would enhance accumulation of the agent in the liver.
  • An agent reducing the action of biliary TNF could be delivered by a number of routes including:- a) direct delivery to a relevant region of the bile duct or gastrointestinal tract via a cannula or needle, or b) delivered orally and have its effect in the gut (i.e., formulated to be protected from degradation until released at the required site in the gut), or c) delivered parenterally and be excreted through the liver into the bile, or d) delivered parenterally and block transport of TNF to bile, or e) delivered via the rectum for lower bowel diseases, or f) any combination of these routes.
  • the agent is delivered directly to the gastrointestinal tract or bile duct.
  • METHOD The small intestine of each rat was tied at each end and freed from the abdominal tissues and the contents expressed by gentle squeezing from the duodenum to ileum. The solid material, including the mucus, was removed by centrifugation (500 g, 15 min) and the volume of clear fluid measured.
  • FIG. 1 Levels of biologically active TNF in the sera of Salmonella infected rats before, or 20hr after, treatment with 1ml of polyclonal rabbit anti-TNF ⁇ which was administered either intra-duodenally (I/Duo) or intravenously (I/V).
  • Escherlchla coll B04:lll LPS into adult Wistar rats results in 100% mortality 12-24hrs later. Examination at 4hrs post inoculation revealed macroscopic evidence of haemorrhage and fluid accumulation within the small bowel. Neither of these events were apparent in similarly treated rats which had had the common bile duct cannulated to prevent bile from entering the gut. No intestinal damage was apparent in normal animals or in bile duct cannulated animals (not treated with LPS). Less haemorrhage and no fluid accumulation was observed in bile duct-ligated, LPS-treated rats.
  • TNF tumour necrosis factor ⁇
  • LPS bacterial lipopolysaccharide
  • a further group of animals was infused with physiological saline (controls). After 4 hours the animals were killed and H&E stained sections of duodenum, jejunum and ileum were prepared.
  • a further group of LPS treated animals was infused with normal rabbit serum (NRS) .
  • the rate of infusion of serum was lml/hour and at a dilutions (in saline) as follows:
  • Tissues from the animals infused with anti-TNF ⁇ serum appeared as normal. No haemorrhage occurred at any site although occasional villi in the duodenum and ileal regions showed a small degree of oedema. No breaching of the epithelium was observed. The intestinal tracts of the rats infused with normal serum were damaged in the same fashion (necrosis, severe haemorrhage, villus damage or heavy oedema) as for non-infused animals injected with LPS. These results are consistent with hypothesis b) .
  • biliary TNF most likely arises from the Kupffer cells of the liver and also further implicates TNF as the damaging agent following LPS treatment.
  • biliary tumour necrosis factor ⁇ in the intestinal effects of bacterial lipopolysaccharides (LPS, endotoxin) a constituent of Gram-negative bacterial pathogens, prompted experiments which tested the hypotheses that a) biliary factors induced by LPS alter the intestinal epithelium to permit early entry of organisms through this barrier and b) in the later stages of an infection, bile (and in particular the tumour necrosis factor ⁇ component) is responsible for the development of diarrhoea.
  • LPS bacterial lipopolysaccharides
  • the infection of rats with Se is regarded as one of the standard animal models of human typhoid fever.
  • Control groups (c) and (d) animals were indistinguishable in terms of health status and diarrhoea, i.e., signs of endotoxaemia (fur ruffling, loss of interest in food, inactivity) , with excessive diarrhoea.
  • Group (b) animals were assessed to be in better health than Groups (c) and (d) . Diarrhoea had ceased in all animals .
  • Group (b) animals had significantly lower numbers of Se in the mesenteric lymph nodes than group (a) animals. Numbers of organisms in Peyers patches of group (b) animals were also lower but not statistically different from numbers in group (a) (Table 3). Table 3
  • Faecal samples were prepared for assay by published methods.
  • the assay system - Enzyme Linked Immunoabsorbent Assay - was established according to a published protocol (8) .
  • the present inventors have demonstrated a strong correlation between gastrointestinal lesions and elevated levels of TNF in the bile. Furthermore, they have effectively demonstrated that addition to the bile of an agent able to block the action of TNF also blocks the associated gastrointestinal lesions.
  • the present inventors have also observed a reduction in general constitutional symptoms (fur ruffling. disinterest in food, inactivity, isolation from other animals) associated with elevated bile TNF levels, either by diversion of the bile from the gut following cannulation of the bile duct, or in LPS-treated animals given antibody to TNF into the gastrointestinal tract.
  • Many toxaemias in man, including that associated with the septic shock syndrome, are associated with excessive production of TNF in a number of tissues and organs including the liver.
  • a number of publications report a causal associated between TNF production and various pathological symptoms.
  • TNF bacterial cell wall lipopolysaccharide fraction
  • TNF in the G.I. tract The bile duct discharges its contents into the upper part of the G.I. tract in the duodenum adjacent to and distal to the pyloric sphincter of the stomach.
  • the contents of the duodenum are approximately neutral in pH, and antibodies delivered directly into the duodenum are reasonably stable. Consequently, one effective way of neutralising TNF in the duodenum is to inject an antibody able to bind TNF directly, for example, via insertion of a stomach tube into the lumen of the gut passing through the stomach and the pyloric sphincter directly into the duodenum, or by passing a needle through the duodenal wall from the exterior guided by a keyhole surgical device.
  • the animal sources of the polyclonal anti-TNF antibodies could be horses, cows, sheep, camels, goats or rabbits. Monoclonal antibodies could also be effective. Whilst human monoclonal antibodies able to block the biological activity of human TNF would be less likely to produce immunological side-effects, in practice, monoclonal antibodies from other animals delivered into the G.I. tract could be as effective. Apart from delivering antibodies or other therapeutic agents able to inactivate TNF directly into the duodenum or other parts of the G.I. tract distal to the duodenum and where the gut wall damage occurs, it is obvious that indirect inactivation methods could also be effective.
  • anti-TNF antibody or other TNF inhibitors could be delivered orally in a suitable formulation, to be released at the required site.
  • inflammation may be caused by localised production of TNF by TNF secreting cells in the gut (10, 11).
  • a number of simple formulations and coatings are in use to protect labile pharmaceuticals from degradation in the stomach whilst allowing the active component to be available lower down the G.I. tract.
  • the use of such coatings and/or formulations could have benefit to enable the oral therapeutic use of antibodies, peptides, etc., for treatment of the less traumatic toxaemias where the patient is conscious and able to swallow tablets and where the urgency for a rapid resolution of the disease is not so pressing.
  • TNF TNF and could also be used when delivered in the fashion indicated.
  • TNF ⁇ in stool as a marker of intestinal inflammation. Lancet, 339 , 89. 10. Tan, X., Hsueh, W. , Gonzalez-Crussi, F. (1993). Cellular localisation of tumor necrosis factor (TNF)- alpha transcripts in normal bowel and in necrotising enterocolitis. TNF gene expression by Paneth cells, intestinal eosinophils, and macrophages . Am. J. Pathol. 142, 1858.
  • Tumor necrosis factor- ⁇ mediates the early pathology in Salmonella infection of the gastrointestinal tract. Microb. Pathog. 14 , 217.
  • Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.- host disease. J.Exp. Med. 166, 1280.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Biochemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • AIDS & HIV (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne une méthode popur traiter ou prévenir chez un sujet les troubles intestinaux provoqués par un niveau élevé de facteur de nécrose des tumeurs (FNT) à l'intérieur de l'intestin. Cette méthode fait appel à l'administration au sujet d'un agent qui diminue l'action du FNT endoluminal ou limite la production et l'accumulation de FNT endoluminal. Cet agent peut être l'un des nombreux agents anti-FNT connus. Toutefois, il est préférable que l'agent soit un anticorps anti-FNT. On préfère également que l'agent soit administré directement dans l'intestin.
PCT/AU1994/000745 1993-12-01 1994-12-01 Procede pour traiter des troubles intestinaux WO1995015179A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95902712A EP0732938A4 (fr) 1993-12-01 1994-12-01 Procede pour traiter des troubles intestinaux
JP7515299A JPH09505812A (ja) 1993-12-01 1994-12-01 腸疾患の治療方法
AU11879/95A AU1187995A (en) 1993-12-01 1994-12-01 Method of treating intestinal disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AUPM274093 1993-12-01
AUPM2740 1993-12-01
AUPM8325A AUPM832594A0 (en) 1994-09-21 1994-09-21 Bile tnf
AUPM8325 1994-09-21

Publications (1)

Publication Number Publication Date
WO1995015179A1 true WO1995015179A1 (fr) 1995-06-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1994/000745 WO1995015179A1 (fr) 1993-12-01 1994-12-01 Procede pour traiter des troubles intestinaux

Country Status (4)

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EP (1) EP0732938A4 (fr)
JP (1) JPH09505812A (fr)
CA (1) CA2177570A1 (fr)
WO (1) WO1995015179A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0729360A1 (fr) * 1993-09-24 1996-09-04 Peptide Technology Ltd Traitement ou prevention de la maladie de crohn et/ou de la colite ulcerative
US5616321A (en) * 1992-08-28 1997-04-01 Bayer Corporation Method of treating bacterial meningitis with anti-tumor necrosis factor antibody
US9028822B2 (en) 2002-06-28 2015-05-12 Domantis Limited Antagonists against TNFR1 and methods of use therefor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023471A2 (fr) * 1998-10-20 2000-04-27 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Utilisation de souche de lactococcus produisant de la cytokine pour traiter la colite
WO2011158904A1 (fr) 2010-06-18 2011-12-22 株式会社林原生物化学研究所 Agent thérapeutique pour des maladies inflammatoires contenant de l'adénosine n1-oxyde en tant que principe actif

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989008460A1 (fr) * 1988-03-11 1989-09-21 Celltech Limited Anticorps utilises dans le traitement faisant intervenir des anticorps anti-lymphocytes
AU4182289A (en) * 1988-08-19 1990-03-23 Celltech Limited Pharmaceutical products for anti-neoplastic therapy
AU5263490A (en) * 1989-03-09 1990-10-09 Margreet Jonker Pharmaceutical product for the treatment of immunoregulatory disorders
AU2273192A (en) * 1991-07-05 1993-02-11 Peptide Technology Limited Peptide which abrogates tnf and/or lps toxicity

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1531492A (en) * 1991-02-14 1992-09-15 Rockefeller University, The Method for controlling abnormal concentration tnf alpha in human tissues
IL99120A0 (en) * 1991-08-07 1992-07-15 Yeda Res & Dev Multimers of the soluble forms of tnf receptors,their preparation and pharmaceutical compositions containing them

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989008460A1 (fr) * 1988-03-11 1989-09-21 Celltech Limited Anticorps utilises dans le traitement faisant intervenir des anticorps anti-lymphocytes
AU4182289A (en) * 1988-08-19 1990-03-23 Celltech Limited Pharmaceutical products for anti-neoplastic therapy
AU5263490A (en) * 1989-03-09 1990-10-09 Margreet Jonker Pharmaceutical product for the treatment of immunoregulatory disorders
AU2273192A (en) * 1991-07-05 1993-02-11 Peptide Technology Limited Peptide which abrogates tnf and/or lps toxicity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SCHERINGA M. et al., (1992), "Anti-Tumor Necrosis Factor Alpha Antibodies Prolong Allograft Survival in Rats", INTERNATIONAL CONFERENCE ON TUMOR NECROSIS FACTOR AND RELATED CYTOKINES, (3rd: 1990: Chiba-shi Japan), Tumor Necrosis Factor: Structure-Function Relationship and Clinical Application, OSAWA, T., BONAVIDA, *
See also references of EP0732938A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616321A (en) * 1992-08-28 1997-04-01 Bayer Corporation Method of treating bacterial meningitis with anti-tumor necrosis factor antibody
EP0729360A1 (fr) * 1993-09-24 1996-09-04 Peptide Technology Ltd Traitement ou prevention de la maladie de crohn et/ou de la colite ulcerative
EP0729360A4 (fr) * 1993-09-24 1998-11-11 Peptide Technology Ltd Traitement ou prevention de la maladie de crohn et/ou de la colite ulcerative
US9028822B2 (en) 2002-06-28 2015-05-12 Domantis Limited Antagonists against TNFR1 and methods of use therefor

Also Published As

Publication number Publication date
EP0732938A1 (fr) 1996-09-25
EP0732938A4 (fr) 1997-03-19
CA2177570A1 (fr) 1995-06-08
JPH09505812A (ja) 1997-06-10

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