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WO1986005687A1 - Procede de prevention de maladies causees chez les mammiferes par l'endotoxine gram-negatif - Google Patents

Procede de prevention de maladies causees chez les mammiferes par l'endotoxine gram-negatif Download PDF

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Publication number
WO1986005687A1
WO1986005687A1 PCT/US1986/000651 US8600651W WO8605687A1 WO 1986005687 A1 WO1986005687 A1 WO 1986005687A1 US 8600651 W US8600651 W US 8600651W WO 8605687 A1 WO8605687 A1 WO 8605687A1
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WIPO (PCT)
Prior art keywords
lipid
gram
endotoxin
mice
lipopolysaccharide
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Application number
PCT/US1986/000651
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English (en)
Inventor
Christian H. R. Raetz
Richard A. Proctor
James A. Will
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Wisconsin Alumni Research Foundation
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Wisconsin Alumni Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to a method for treating mammals so as to prevent clinical complications and death arising from the presence of gram-negative endotoxin (lipopolysaccharide) in their bodies, by administering to mammals a compound having lipid X activity in an amount sufficient to induce said protection.
  • gram-negative endotoxin lipopolysaccharide
  • Lipopolysaccharide is a major constituent of the outer membranes of gram-negative bacteria. Structural studies have shown that it consists of the following three distinct domains: 1) the 0-antigen region, which is a strain-specific polysaccharide moiety and determines the antigenic specificity of the organism; 2) the core region, which is relatively conserved with respect to its sugar composition and may play a role in maintaining the integrity of the outer membrane; and 3) the lipid A region, which is also conserved and functions as a hydro- phobic anchor holding lipopolysaccharide in place. The lipid A portion of lipopolysaccharide constitutes most of the outer monolayer of the outer membrane in gram-nega ⁇ tives.
  • Lipopolysaccharide is known to trigger many patho- physiological events in mammals, either when it is injected or when it accumulates due to gram-negative infection.
  • the hydrophobic lipid A moiety is responsible for these pathophysiological effects, which tend to be either i munostimulatory or toxic.
  • events such as B-lymphocyte mitogenesis, macro- phage activation, and the induction of tumor necrosis in certain experimental systems.
  • In the latter (toxic) category there are responses such as peripheral vascular collapse ("endotoxic" shock), pulmonary hypertension, pulmonary edema, disseminated intravascular coagulopathy and pyrogenicity.
  • lipid A has been confirmed in Escherichia coli, Salmonella typhimurium and Salmonella minnesota.
  • the discovery of the monosaccharide precursor, lipid X, has also led to the elucidation of the biosynthetic pathway for the formation of lipid A in E. coli and ⁇ . typhimurium.
  • the availability of these various novel lipid A precursors and substructures has made it possible to dissect the chemical and structural requirements for the numerous biological effects of lipid A.
  • the method of the present invention comprises treating mammals to protect them from gr m-negative endotoxins by administering to said mammals a safe and effective amount of a compound having lipid X activity.
  • the monosaccharide, lipid X mimics many of the immunostimulatory effects of lipid A, but does not have its extreme toxicity.
  • the compound, lipid X is administered to an animal in a safe and effective amount to protect it from the toxic effects of gram-negative endotoxins.
  • Lipid X is a B cell mitogen which is capable of activating macrophages with release of protaglandin E,, it can activate macrophage protein kinase C, and it is capable of inducing regression of experimental tumors in guinea pigs.
  • Lipid X may be represented by the following formula:
  • lipid X has the "endotoxic" activity of lipopolysaccharide and lipid A has been examined in sheep, which display sensitivity similar to that of man, and in mice, which are relatively resistant.
  • the LD 5Q for the lipopolysaccharide in sheep is about 10-20 ⁇ _g/kg (intravenous), while in mice it is about 5 mg/kg.
  • lipopolysaccharide causes death by triggering pulmonary hypertension, pulmonary edema, and peripheral vascular collapse. Death usually occurs within 8 to 48 hours after injection of lipopolysaccharide or lipid A. Occa ⁇ sionally, death will occur at 1-2 weeks. This is usually the result of disseminated intravascular coagulopathy leading to renal cortical necrosis and uremic death.
  • lipid X (40 ⁇ g/kg cumulative dose) causes a transient (3-5 min) increase in pulmonary arterial pressure, that may be attributed to prostaglandin release, or stimulated synthesis.
  • endotoxin i.e. lipopolysac ⁇ charide
  • the increase in pulmonary blood pressure is much more prolonged with lipopolysaccharide than with lipid X, persisting over several hours.
  • lipid X The only significant symptoms observed after injection of lipid X alone are transient lethargy and shortness of breath (15-30 min), without significant distress or obvious adverse long-term consequences.
  • mammals such as sheep or mice
  • lipid X makes them immediately resistant to the lethal effects of injection of gram-negative endotoxin.
  • This apparent antagonism between lipid X and endotoxin may have useful applications in clinical situations and disease states that are caused by endotoxin, such as gram-negative sepsis following surgery in humans and animals, bovine or porcine mastitis, and other endotoxin-related veterinary diseases listed in Tables I and II.
  • endotoxin such as gram-negative sepsis following surgery in humans and animals, bovine or porcine mastitis, and other endotoxin-related veterinary diseases listed in Tables I and II.
  • endotoxin such as gram-negative sepsis following surgery in humans and animals, bovine or porcine mastitis,
  • Lipid X that possess lipid X activity i.e. the ability to protect against gram-negative endo-toxin
  • Such derivatives possess the ester linked ⁇ -hydroxymyristoyl moiety at position 3 but may have substitutents at other ' positions that do not interfere with lipid X activity.
  • a and B are the same or different, and are H, a hydrocarbon structure, a fatty acyl chain, or another functional group;
  • R 2 is a fatty acyl chain, n is an alkyl group of 2 to 24 carbon atoms, and substituent Z is a water solubilizing group.
  • E. coli lipid X The 2,3-diacylglucosa- mine 1-phosphate (E. coli lipid X) was isolated from E. coli strain MN7 (ATCC #39328) as described previously. Lipid X obtained in this manner is a solid white powder. Stock solutions (1-10 mg/ml) are usually prepared in aqueous 1 mM EDTA titrated to pH 8 with Tris-free base. Other monovalent counter ions, such as (NH.) , Na , K , etc., may also be used, but divalent cations such as Mg and Ca cause the lipid to precipitate.
  • monovalent counter ions such as (NH.) , Na , K , etc.
  • lipid X forms a clear viscous solution, that may be sterilized by filtration without prior sonic irradiation.
  • solid lipid X was first dissolved in 0.9% saline (instead of water) and titrated with Tris-free base to pH 8 in the same manner.
  • Stock solutions of lipid X (5-10 mg/ml) could be stored frozen at -20°C for many months without evidence of significant deterioration.
  • Escherichia coli lipopolysaccharide (sero-type E. coli 011:B4) was prepared by a phenol-water method. Stock solutions of 5 mg/ml were prepared in sterile 0.9% saline. The LD of this material in sheep is approxi- mately 10-20 ⁇ g/kg when administered intravenously.
  • mice the LD is about 5 mg/kg intravenously and about 10 mg/kg injected intraperitoneally.
  • the lethal dose of E. coli 011:B4 endotoxin was determined in 8-10 week old, C57BL/10 mice weighing 20-25 gm. Mice were injected either intraperitoneally (x), or they were ether-anesthe ⁇ tized and injected intravenously with a total volume of 0.05-0.2 ml via the retroorbital plexus (o). Endotoxin was dissolved in sterile, phosphate-buffered saline. All deaths occurred within 72 hours of challenge; however, the animals were observed for at least 7 days. Dose- response curves were generated for each lot of endotoxin and mouse population employed.
  • mice Eight week old mice (strain C57BL/10) were used as were mixed bred sheep weighing 30-70 kg. Sheep were prepared as follows: at least 24 hours before each experiment catheters were percutaneously placed in the pulmonary artery. Any other catheteriza- tions that were required for infusion were done at this time. All studies were performed on awake, unrestrained sheep placed in portable stanchions with food and water _____ libitum. Electronically calculated pulmonary artery pressures as well as heart rates were recorded at various intervals on a polygraph. To ensure a stable baseline prior to the injection of test compounds, approximately 1 hour of baseline measurements were recorded.
  • mice were allowed to rest for at least 7 days follow- ing their arrival and were sexually segregated and housed at 5 per cage with food and water ad libitum.
  • Intravenous injection of lipid X (dissolved in saline as described above) and/or lipopolysaccharide was achieved by the retroorbital sinus route using a 27 gauge needle. No more than 0.1 ml of fluid was injected at a time. Just prior to injection, the mice were lightly anesthetized with ether. Following the injection, mice were observed every 0.5-6 hours and the time of death was recorded. In a few experiments, mice were injected by the intraperi- toneal route with solutions of lipid X and/or lipopolysac ⁇ charide similar to those described above.
  • Lipid X protects mice against lethal endotoxemia. Since lipid X may be considered a substructure of lipid A but appears to be nontoxic, it was examined to see if it might act as an endotoxin antagonist. To do a statisti ⁇ cally controlled study of the ability of lipid X to pre ⁇ vent lethal endotoxemia, mice were initially employed, despite the inherent drawback that mice are far more re- sistant to the deleterious effects of lipopolysaccharide than are sheep, cattle or humans.
  • mice C57BL/10 mice were challenged with 750, 2000 or 5000 ⁇ g of lipid X intraperitoneally (12 mice) or with 750, 1500 or 3000 ⁇ g intravenously (7 mice). All these mice lived. Consequently, lipid X appeared to be nontoxic in mice, as in sheep. As discussed more fully below, 40 sheep have been injected with lipid X and no serious adverse complications of lipid X administration have been observed so far.
  • mice were given 750 ⁇ g of lipid X from 24 hours prior to 6 hours after endotoxin challenge with 1-2 LD n doses. Forty-one percent of mice receiving 500 ⁇ g lipid X from 6 hours prior to endotoxin challenge through 1 hour after LPS challenge survived. When a lower endo ⁇ toxin challenge dose (250 ⁇ g) was used, 81% of the mice survived if treated with lipid X from 1 hour prior to through 4 hours post LPS challenge.
  • LPS lipopolysaccharide
  • the LD of lipopolysaccharide in sheep is in the vicinity of 10-20 ⁇ g/kg, injected intravenously. Sheep respond to lipopolysaccharide in a manner that more closely resembles the situation encountered in human diseases.
  • Lipid X by itself (40-1000 ⁇ g/kg) does not create marked illness or fever. A period of transient pulmonary hypertension and slight shortness of breath subsides after 30 minutes. About 30 sheep were examined with regard to lipid X toxicity.
  • lipo ⁇ polysaccharide In contrast to lipid X, a single injection of lipo ⁇ polysaccharide (10-20 ⁇ g/kg) causes more serious pulmonary hypertension, and after 15-30 minutes, an animal treated with lipopolysaccharide will begin to tremble, cough and lay down. The symptoms become more severe over the next few hours and are accompanied by fever. About half the animals die by 24 hours.
  • the sheep system has the important advantage of permitting the administra ⁇ tion of much larger doses of lipid X relative to LPS. It is the ratio of lipid X to endotoxin that is critical for survival. As shown in Table III, all the sheep receiving 100-200 ⁇ g/kg of lipid X during the pretreatment period survived subsequent LPS challenge. It is evident that a 5-10 fold excess of lipid X (on a weight basis) over LPS is required to ensure survival. (Because of the inherent LPS resistance of mice, their small body volume, and the limited solubility of lipid X in water, it is impossible to achieve 5-10 fold excess of lipid X relative to LPS in the mouse system. )
  • lipid X In addition to rescuing sheep from lethal effects of LPS, pretreatment with lipid X also alleviates some of the serious clinical symptoms, including shortness of breath, weakness, diarrhea, etc. However, lipid X does not prevent pulmonary hypertension or fever induced by LPS-. Implications for therapy. Previous work on the lethal endotoxicity of gram-negative lipopolysaccharide showed that limited prevention of the complications of injection of this material could be achieved through the administration of glucocorticoids, prostaglandins, naloxone, pressors, ..fluid replacement therapy or anti-LPS antibodies. The possibility of using a lipid A fragment, such as lipid X, as an endotoxin antagonist was not considered. In addition, all existing therapies against LPS lethality are dependent upon their being given prior to or very shortly after the administration of the LPS challenge.
  • lipid X appears to prevent lethal endotoxi ⁇ city even when given 4 hours after lipopolysaccharide.
  • the acute protection afforded by lipid X may have some relationship to the biological phenomenon of lipopoly ⁇ saccharide tolerance described in the clinical literature.
  • lipid X-induced protection against lipopolysac- charide is immediate and wears off after several hours, whereas classical tolerance does not appear for many days and may, in part, be mediated by antibodies.
  • lipid X may ameliorate patho ⁇ logical conditions created by many of the endotoxin-induced diseases listed in Table I. Furthermore, protection by lipid X can be obtained even after endotoxin had been administered. This is a unique and extremely important therapeutic consideration, since the signs and symptoms of a disease are almost always manifest before therapy is initiated. Although the mechanism(s) of protection by lipid X against lipopolysaccharide challenge remain unknown, the data fit best with competition for a common target molecule, such as membrane receptor(s) on endo- the.lial or vascular cells. The action of lipid X is much too fast to have an immunological cause.
  • lipid X by itself is not seriously toxic to animals, it may be useful for treatment of other diseases which lipopolysaccharide is known to ameliorate, but cannot be employed because of its toxicity. Thus, it might be anticipated that lipid X would protect mammals from skatole toxicity, oxygen toxicity, and drugs that enhance the production of free radicals (e.g. bleomycin, nitrofurantoin, adria ycin, etc.). It is known that LPS stimulates the activity of various enzymes that protect animals against oxidant stresses, and it can be antici ⁇ pated that lipid X will have these beneficial effects as well.
  • free radicals e.g. bleomycin, nitrofurantoin, adria ycin, etc.
  • lipid X is chemically defined and highly purified, it will be a very valuable agent with which to standardize the Limulus amebocyte lysate assay, a widely used test for endotoxin. Endotoxin per se is not a good standard because it is not chemically defined or chemically homogeneous.
  • the compound lipid X and its various modified deriva ⁇ tives possessing lipid X activity may be introduced into the circulation of an animal by intravenous, intraperi- toneal or intramuscular routes, and appear to induce a state of relative resistance to the deleterious effect of lipopolysaccharide.
  • lipid X and related compounds may be administered in the .form of parenteral solutions containing the selected protective compound, in a sterile liquid suitable for intravenous or other administration.
  • the exact route, dose, and adminis ⁇ tration interval of the active compound will vary with the size and weight of the animal, and the species, and the desired level of protection.
  • Pet Animal and Livestock Endotoxemias and Other Patho- physiological Entities with High Probability of Being Prevented or Treated by Administration of Lipid X or Compounds Having Lipid X Activity are the following:
  • Gastrointestinal parasites including coccidiosis and sarcosporidiosis
  • infectious etiology is intended to include bacterial, viral and parasitic etiologies. Hepatitis of infectious or parasitic etiologies

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Méthode de traitement vétérinaire destiné à protéger les animaux contre les effets toxiques de l'endotoxine gram-négatif et consistant à administrer auxdits animaux une quantité sûre et efficace d'un composé présentant une activité de lipide X.
PCT/US1986/000651 1985-04-03 1986-03-31 Procede de prevention de maladies causees chez les mammiferes par l'endotoxine gram-negatif Ceased WO1986005687A1 (fr)

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US71932885A 1985-04-03 1985-04-03
US719,328 1985-04-03

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309411A2 (fr) 1987-09-23 1989-03-29 Sandoz Ag Dérivés de saccharides
US5219843A (en) * 1987-09-23 1993-06-15 Sandoz Ltd. Saccharide derivatives
EP0466838A4 (fr) * 1989-07-21 1995-02-22 Wisconsin Alumni Res Found
US7820627B2 (en) 2002-05-09 2010-10-26 Oncothyreon Inc. Lipid A and other carbohydrate ligand analogs
US8329639B2 (en) 2011-02-24 2012-12-11 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant

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* Cited by examiner, † Cited by third party
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US3089821A (en) * 1959-10-28 1963-05-14 Merck & Co Inc Process for the preparation of lipids
US3119741A (en) * 1962-04-10 1964-01-28 Princeton Lab Inc Non-specific immunizing agent
US3185624A (en) * 1962-03-26 1965-05-25 Taisho Pharmaceutical Co Ltd Preparation of purified lipid a from crude lipid a derived from lipopolysaccharides of gram-negative bacteria
FR2316964A1 (fr) * 1975-07-11 1977-02-04 Pasteur Institut Medicament contenant, a titre de principe actif, un produit a base de polysaccharides, notamment obtenu a partir de lipopolysaccharides bacteriens
US4323561A (en) * 1977-09-06 1982-04-06 Temple University Of The Commonwealth System Of Higher Education Process of enhancing immmunogenic response in mammals by the administration of synthetic glycolipid adjuvants
US4454119A (en) * 1981-06-29 1984-06-12 Mitsubishi Chemical Industries Limited Therapeutic agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0143840B1 (fr) * 1983-05-06 1990-08-29 Wisconsin Alumni Research Foundation Composes de monosaccharide dotes d'une activite immunostimulatrice

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3089821A (en) * 1959-10-28 1963-05-14 Merck & Co Inc Process for the preparation of lipids
US3185624A (en) * 1962-03-26 1965-05-25 Taisho Pharmaceutical Co Ltd Preparation of purified lipid a from crude lipid a derived from lipopolysaccharides of gram-negative bacteria
US3119741A (en) * 1962-04-10 1964-01-28 Princeton Lab Inc Non-specific immunizing agent
FR2316964A1 (fr) * 1975-07-11 1977-02-04 Pasteur Institut Medicament contenant, a titre de principe actif, un produit a base de polysaccharides, notamment obtenu a partir de lipopolysaccharides bacteriens
US4323561A (en) * 1977-09-06 1982-04-06 Temple University Of The Commonwealth System Of Higher Education Process of enhancing immmunogenic response in mammals by the administration of synthetic glycolipid adjuvants
US4454119A (en) * 1981-06-29 1984-06-12 Mitsubishi Chemical Industries Limited Therapeutic agents

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 100, No. 25, issued 1984 (Columbus, Ohio, U.S.A.), (C.E. BULAWA), "The Biosynthesis of Gram-negative Endotoxin Identification and Function of UDP-2, 3-Diacylglucosamine in Escherichia Coli", Abstract No. 206338h. *
CHEMICAL ABSTRACTS, Volume 101, No. 1, issued 1984 (Columbus, Ohio, U.S.A.), (M. MATSUURA), "Interferon-Inducing, Pyrogenic and Proclotting Enzyme of Horseshoe Crab Activation Activities of Chemically Synthesized Lipid A Analogs", Abstract No. 2631j. *
CHEMICAL ABSTRACTS, Volume 101, No. 17, issued 1984 (Columbus, Ohio, U.S.A.), (K. TAKAYAMA), "Influence of Fine Structure of Lipid A on Limulus Amebocyte Lysate Clotting and Toxic Activities", Abstract No. 145589n. *
CHEMICAL ABSTRACTS, Volume 101, No. 3, issued 1984 (Columbus, Ohio, U.S.A.), (B.L. Ray), "The Biosynthesis of Gram-Negative-Endotoxin. Formation of Lipid A Disacchardies from Monosaccharide Precursors in Extracts of Escherichia Coli", Abstract No. 20336w. *
CHEMICAL ABSTRACTS, Volume 104, No. 9, issued 1985 (Columbus, Ohio, U.S.A.), (K. E. BURHOP), "Pulmonary Pathophysiological Changes in Sheep Caused by Endotoxin Precursor, Lipid X" Abstract No. 63864w *
CHEMICAL ABSTRACTS, Volume 87, No. 17, issued 1977, (Columbus, Ohio, U.S.A.), (N. HAEFFNER), "Identification of 2-Methyl-3 Hydroxy-Decanoic Acid and 2-Methyl-3-Hydroxy-Tetradecanoic Acids in the 'Lipid X' Fraction of the Bordetella Pertussis Endotoxin", Abstract No. 129203u. *
CHEMICAL ABSTRACTS, Volume 88, No. 23, issued 1978, (Columbus, Ohio, U.S.A.), (A. LE DUR), "A Novel Type of Endotoxin Structure Present in Bordetalla Pertussis. Isolation of Two Different Polysaccharides Bound to Lipid A", Abstract No. 165751a. *
CHEMICAL ABSTRACTS, Volume 93, No. 5, issued 1980, (Columbus, Ohio, U.S.A.), (G. AYME), "Biological Activities of Fragments Derived from Bordetalla Pertussis Endotoxin: Isolation of a Nontoxic, Shwartzman-Negative Lipid A Possessing High Adjuvant Properties", Abstract No. 39049t. *
CHEMICAL ABSTRACTS, Volume 99, No. 25, issued 1983, (Columbus, Ohio, U.S.A.), (J.A. WILL), "Lung Metabolism, Function, and Morphology During Hyperoxic and Hyperbaric Exposure", Abstrat No. 210570F *
See also references of EP0219514A4 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309411A2 (fr) 1987-09-23 1989-03-29 Sandoz Ag Dérivés de saccharides
EP0309411A3 (fr) * 1987-09-23 1991-07-24 Sandoz Ag Dérivés de saccharides
AU614772B2 (en) * 1987-09-23 1991-09-12 Novartis Ag Saccharide derivatives
US5219843A (en) * 1987-09-23 1993-06-15 Sandoz Ltd. Saccharide derivatives
EP0466838A4 (fr) * 1989-07-21 1995-02-22 Wisconsin Alumni Res Found
US7820627B2 (en) 2002-05-09 2010-10-26 Oncothyreon Inc. Lipid A and other carbohydrate ligand analogs
US8097593B1 (en) 2002-05-09 2012-01-17 Oncothyreon Inc. Lipid A and other carbohydrate ligand analogs
US8329639B2 (en) 2011-02-24 2012-12-11 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant
US8889616B2 (en) 2011-02-24 2014-11-18 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant

Also Published As

Publication number Publication date
EP0219514A1 (fr) 1987-04-29
EP0219514A4 (fr) 1988-04-26

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