WO1999002178A1 - Mittel zur sepsistherapie, seine herstellung und seine verwendung - Google Patents

Mittel zur sepsistherapie, seine herstellung und seine verwendung Download PDF

Info

Publication number
WO1999002178A1
WO1999002178A1 PCT/DE1998/000964 DE9800964W WO9902178A1 WO 1999002178 A1 WO1999002178 A1 WO 1999002178A1 DE 9800964 W DE9800964 W DE 9800964W WO 9902178 A1 WO9902178 A1 WO 9902178A1
Authority
WO
WIPO (PCT)
Prior art keywords
lbp
composition according
sepsis
lps
therapy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DE1998/000964
Other languages
German (de)
English (en)
French (fr)
Inventor
Ralf Reiner Schumann
Norbert Lamping
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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
Application filed by Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Priority to DE59805440T priority Critical patent/DE59805440D1/de
Priority to EP98928139A priority patent/EP0999849B1/de
Priority to AT98928139T priority patent/ATE223227T1/de
Priority to DK98928139T priority patent/DK0999849T3/da
Priority to JP2000501768A priority patent/JP2001509488A/ja
Publication of WO1999002178A1 publication Critical patent/WO1999002178A1/de
Anticipated expiration legal-status Critical
Priority to US09/484,121 priority patent/US6949512B1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1751—Bactericidal/permeability-increasing protein [BPI]
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to an agent for sepsis therapy, its preparation and its use. Fields of application of the invention are the pharmaceutical industry and medicine.
  • the invention has for its object to develop a means for sepsis therapy.
  • LBP The structure of LBP is known, it is obtained by isolating a clone from an acute phase cDNA library, and then sequencing and deriving the amino acid sequence. Recombinant LBP is produced by cloning the cDNA into an expression vector and co-infecting insect cells with the baculovirus.
  • LBP The cloned LPS binding protein binds high affinity LPS and is released into the serum as an acute phase protein during sepsis.
  • LBP inhibits the LPS effects and, if given to mice, can suppress the sepsis triggered by LPS and reduce the lethality in a highly significant manner. This applies when used simultaneously with the triggering of sepsis, as well as beforehand, which makes LBP seem suitable for sepsis prophylaxis.
  • LPS Since LPS also plays a central role in sepsis triggered by gra positive bacteria, as well as in the * systemic inflammatory response syndrome ', a disease pattern triggered by trauma that is identical to sepsis, * translocation' of gram-negative intestinal bacteria, the inhibition of the LPS effects can LBP can also improve these dramatic clinical pictures.
  • Another basic way of realizing the invention is to clone the LBP gene into an adenoviral vector with high liver activity behind the strong one Cloning CMV promoters in order to achieve gene transfer in addition to hepatic expression of LBP.
  • the invention is applicable to
  • SIRS Systemic infla atory response syndrome
  • the complete LBP cDNA is cloned into the pACHLT-B vector (Pharmingen, San Diego, USA) behind the strong polyhedrin promoter and behind the glutathione S-transferase (GST) cDNA, so that a GST fusion protein is expressed.
  • GST glutathione S-transferase
  • a 500 ml cell culture of Sf-9 insect cells is then infected with this vector and the baculovirus DNA ( ⁇ Baculogold ', baculovirus DNA in linearized form, also from Pharmingen, San Diego, USA).
  • the cells are lysed after 2 days and the lysate is coupled to gluthation-Sepharose in the presence of Triton X-100 using the * baten 'method.
  • LBP is then cleaved from the fusion partner by thrombin digestion, followed by treatment with Calbiosorb for triton removal and treatment with benzamidine-Sepharose to remove thrombin residues.
  • concentrations of pure LBP are 0.3-0.5 mg / ml.
  • FIG. 1 A murine macrophage cell line is stimulated with different concentrations of the bacterial toxin LPS in vitro for the synthesis of the sepsis mediator TNF depending on LBP. At high LPS concentrations not found in the organism, LBP does not influence TNF synthesis. The stimulation of the macrophages by lower amounts of LPS is, however, inhibited by high LBP concentrations, such as occur in vivo during the acute phase and can also be achieved by exogenous addition.
  • FIG. 2 Here it can be seen that the addition of LBP in the presence of serum also suppresses the TNF production of the macrophage cell line. The LBP in the serum is responsible for this.
  • FIG. 4 It is shown here that the LBP levels of the mouse that are produced by exogenous administration correspond to the acute phase levels that are generated by high LPS administration and are therefore physiological.
  • FIG. 5 LPS-induced cytokine release can be suppressed in the mouse by simultaneous administration of LBP.
  • Figure 6 Furthermore, the liver damage triggered by LPS and detected by the increase in the ALT enzyme is suppressed by the simultaneous administration of LBP.
  • Figure 7 The administration of LBP significantly reduces the lethality in an LPS sepsis model, performed with 20 mice per group.
  • LBP sepsis mediator molecule

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/DE1998/000964 1997-07-11 1998-04-04 Mittel zur sepsistherapie, seine herstellung und seine verwendung Ceased WO1999002178A1 (de)

Priority Applications (6)

Application Number Priority Date Filing Date Title
DE59805440T DE59805440D1 (de) 1997-07-11 1998-04-04 Verwendung von lbp zur sepsistherapie
EP98928139A EP0999849B1 (de) 1997-07-11 1998-04-04 Verwendung von lbp zur sepsistherapie
AT98928139T ATE223227T1 (de) 1997-07-11 1998-04-04 Verwendung von lbp zur sepsistherapie
DK98928139T DK0999849T3 (da) 1997-07-11 1998-04-04 Anvendelse af LBP til sepsisbehandling
JP2000501768A JP2001509488A (ja) 1997-07-11 1998-04-04 敗血症治療薬、その製造及び使用
US09/484,121 US6949512B1 (en) 1997-07-11 2000-01-13 Therapeutic agent for the treatment of septicaemia its preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19729810.9 1997-07-11
DE19729810A DE19729810C2 (de) 1997-07-11 1997-07-11 Mittel zur Sepsistherapie, seine Herstellung und seine Verwendung

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/484,121 Continuation US6949512B1 (en) 1997-07-11 2000-01-13 Therapeutic agent for the treatment of septicaemia its preparation and use

Publications (1)

Publication Number Publication Date
WO1999002178A1 true WO1999002178A1 (de) 1999-01-21

Family

ID=7835437

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1998/000964 Ceased WO1999002178A1 (de) 1997-07-11 1998-04-04 Mittel zur sepsistherapie, seine herstellung und seine verwendung

Country Status (9)

Country Link
US (1) US6949512B1 (https=)
EP (1) EP0999849B1 (https=)
JP (1) JP2001509488A (https=)
AT (1) ATE223227T1 (https=)
DE (2) DE19729810C2 (https=)
DK (1) DK0999849T3 (https=)
ES (1) ES2183376T3 (https=)
PT (1) PT999849E (https=)
WO (1) WO1999002178A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2108372A1 (en) * 2008-04-09 2009-10-14 Forschungszentrum Borstel Leibniz-Zentrum für Medizin und Biowissenschaften Novel antimicrobial peptides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994025476A1 (en) * 1993-04-30 1994-11-10 Incyte Pharmaceuticals, Inc. Recombinant bpi-based and lbp-based proteins, nucleic acid molecules encoding same, methods of producing same, and uses thereof
WO1995008560A1 (en) * 1993-09-24 1995-03-30 Centocor, Inc. Novel peptides useful for inhibiting binding of lipopolysaccharides (lps) by lipopolysaccharide binding protein (lbp)
WO1995025117A1 (en) * 1994-03-15 1995-09-21 The Scripps Research Institute Polypeptides of lipopolysaccharide binding protein

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005393A2 (en) * 1993-08-18 1995-02-23 Morphosys Gesellschaft Für Proteinoptimierung Mbh Lipopolysaccharide-binding and neutralizing peptides
US5990082A (en) * 1997-10-22 1999-11-23 Xoma Corporation Uses of lipopolysaccharide binding protein

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994025476A1 (en) * 1993-04-30 1994-11-10 Incyte Pharmaceuticals, Inc. Recombinant bpi-based and lbp-based proteins, nucleic acid molecules encoding same, methods of producing same, and uses thereof
WO1995008560A1 (en) * 1993-09-24 1995-03-30 Centocor, Inc. Novel peptides useful for inhibiting binding of lipopolysaccharides (lps) by lipopolysaccharide binding protein (lbp)
WO1995025117A1 (en) * 1994-03-15 1995-09-21 The Scripps Research Institute Polypeptides of lipopolysaccharide binding protein

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABRAHAMSON S L ET AL: "Biochemical characterization of recombinant fusions of lipopolysaccharide binding protein and bactericidal/permeability- increasing protein. Implications in biological activity.", JOURNAL OF BIOLOGICAL CHEMISTRY, (1997 JAN 24) 272 (4) 2149-55, XP002077617 *
GALLAY P ET AL: "Lipopolysaccharide - binding protein as a major plasma protein responsible for endotoxemic shock.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, (1993 NOV 1) 90 (21) 9935-8, XP002077616 *
LAMPING N ET AL: "LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria.", JOURNAL OF CLINICAL INVESTIGATION, (1998 MAY 15) 101 (10) 2065-71, XP002077618 *

Also Published As

Publication number Publication date
DK0999849T3 (da) 2003-01-06
PT999849E (pt) 2003-01-31
ATE223227T1 (de) 2002-09-15
US6949512B1 (en) 2005-09-27
DE19729810A1 (de) 1999-01-14
JP2001509488A (ja) 2001-07-24
DE19729810C2 (de) 2000-01-13
DE59805440D1 (de) 2002-10-10
EP0999849A1 (de) 2000-05-17
ES2183376T3 (es) 2003-03-16
EP0999849B1 (de) 2002-09-04

Similar Documents

Publication Publication Date Title
DE69830582T2 (de) Verwendung von lactoferrin in der behandlung von beschwerden, die von allergenen verursacht sind
DE69433562T2 (de) Prosaposin und cytokinabhängige peptide als therapeutisch wirksame mittel
DE69736712T2 (de) Verfahren zur milderung von neuropatischen schmerz mit prosaposin verwandten peptiden
DE69905368T2 (de) Oxydiertes thymosin beta 4
DE69427970T2 (de) Medikament gegen atopische krankheiten
DE69914463T2 (de) Therapeutische chemokine rezeptor antagonisten
DE3853918T2 (de) Biologisch aktive bakterientötende/durchlässigkeitserhöhende proteinfragmente.
DE69519454T2 (de) Protein, das Interferon-Gamma Herstellung induziert und monoklonaler Antikörper dagegen
DE3856309T2 (de) DNS KODIEREND FÜR DIE IgE REZEPTOR A-UNTEREINHEIT ODER EIN FRAGMENT DAVON
DE69713485T2 (de) Medikamente für die Behandlung oder Vorbeugung von Thrombocytopenie
DE69033863T2 (de) Verwendung von 5-methyl-1-phenyl-2-(1H)-pyridon zur Vorbeugung fibrotischer Schädigungen
DE69535593T2 (de) Verwendung von hgf zur herstellung eines arzneimittels zur behandlung von lungenfibrose
DE3686794T2 (de) Reinigung des natuerlichen kolonie-stimulierenden faktors-1.
EP0209061A2 (de) Neue Polypeptide mit blutgerinnungshemmender Wirkung, Verfahren zu deren Herstellung bzw. Gewinnung, deren Verwendung und diese enthaltende Mittel
DE69637104T2 (de) Heilmittel für arthrosis deformans und entzündliche gelenkerkrankungen
EP1644028B1 (de) Substanzen mit biologischer aktivität des vasoaktiven intestinalen peptids für die behandlung von interstitiellen lungenerkrankungen
DE69902127T2 (de) Histon beinhaltende zusammenstellung zur behandlung von rheumatischer arthritis
DE3855747T2 (de) Biologische materialien, deren herstellung und verwendung in der therapie
DE69129563T2 (de) Epidermis-Wachstumsfaktor als Arzneimittel zur Wiederherstellung der Neuronen der Substantia nigra in der Behandlung nervenzerstörender Störungen
DE69735533T2 (de) Lösliche Polypeptide bestehend aus der ersten Coiled coil Domäne aus Mensch- und Maus-Epimorphin
DE3538619C2 (de) Pharmazeutische Verwendung eines Isomeren des 4-Hydroxyprolin
DE3436638C2 (de) Verwendung von Interferon-gamma (IFN-gamma) enthaltenden Präparationen zur Behandlung rheumatischer Erkrankungen
DE69019163T2 (de) Verwendung von Gamma-Interferon zur Herstellung eines Medikaments für die Behandlung von Steroid-abhängigem Asthma.
DE19729810C2 (de) Mittel zur Sepsistherapie, seine Herstellung und seine Verwendung
DE69634138T2 (de) HGF Mutant und dessen Verwendung als Antikrebsmittel

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09484121

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1998928139

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1998928139

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1998928139

Country of ref document: EP