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WO1997019173A1 - Procede de traitement de maladies infectieuses - Google Patents

Procede de traitement de maladies infectieuses Download PDF

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Publication number
WO1997019173A1
WO1997019173A1 PCT/US1996/018616 US9618616W WO9719173A1 WO 1997019173 A1 WO1997019173 A1 WO 1997019173A1 US 9618616 W US9618616 W US 9618616W WO 9719173 A1 WO9719173 A1 WO 9719173A1
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WIPO (PCT)
Prior art keywords
chemokine
seq
protein
groβ
association
Prior art date
Application number
PCT/US1996/018616
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English (en)
Inventor
Peter Lawrence Demarsh
Kyung O. Johanson
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Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU10209/97A priority Critical patent/AU1020997A/en
Priority to JP9519868A priority patent/JP2000504310A/ja
Priority to EP96940554A priority patent/EP0871732A4/fr
Priority to US08/846,966 priority patent/US6042821A/en
Publication of WO1997019173A1 publication Critical patent/WO1997019173A1/fr
Priority to US09/513,153 priority patent/US6413510B1/en

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Classifications

    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/521—Chemokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Sepsis is broadly defined to mean situations when the invasion of a host by a microbial agent is associated with the clinical manifestations of infection including but not limited to (1) temperature >38°C or ⁇ 36°C, (2) heart rate >90 beats per minute, (3) respiratory rate >20 breaths per minute or PaC0 2 ⁇ 32 mm Hg, (4) white blood cell count >12,000/cu mm, ⁇ 4,000/cu mm, or >10% immature (band) forms, (5) organ dysfunction, hypoperfusion, or hypotension Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oligu ⁇ a, or an acute alteration in mental stales (Chest 1992, i0_L 1644- 1566) Sepsis can occur in hospitalized patients having underlying diseases or conditions that render them susceptible to bloodstream invasion or in burn, trauma or surgical patents In many cases of sepsis, the predominant pathogen is Escherichia coli, followed by othei Gram-negative bacteria such as the
  • Septic shock occurs because bacterial products react with cells and components of the coagulation, complement, fibrinolytic and bradykinin systems to release proteases which ⁇ n
  • ARDS' adult respiratory distress syndrome
  • Septic shock is a major cause of death in intensive care units
  • mortality for established septic shock has decreased very little since the comprehensive description by Waisbren (Arch Intern Med 88 467-488 (! Q 5!) Although effective antibiotic ai .
  • This invention relales to a method of preventing or treating sepsis comprising administering to a human or non-human animal in need thereof an effective amount of a protein derived from a chemokine selected from KC, gro-a, gro ⁇ , and gro ⁇
  • chemokines used in the method of the invention include modified KC [amino acids 5-72 of the full length protein, SEQ ID NO 1 J, modified human gro ⁇ [amino acids 5-73 of the full length protein, SEQ ID NO 3] or modified human gro ⁇ [amino acids 5-73 of the full length protein, SEQ ID NO 4] or multimers thereof
  • the mature chemokines may be utilized in the method of the invention
  • the method of the invention may be performed alone, or in conjunction with administration of an anti-infective agent
  • chemokines useful in the method of the invention include mature KC [SEQ ID NO 1 ].
  • Particularly desirable are the modified KC [amino acids 5-72 of SEQ ID NO 2], modified gro ⁇ [amino acids 5-73 of SEQ ID NO 3], modified gro ⁇ [amino acids 5- 73 of SEQ ID NO 4], and a dimeric modified gro ⁇ [ammo acids 5-73 of SEQ ID NO 3]
  • proteins useful in preparing medicaments and in the methods of the invention include the mature chemokines, modified chemokines, and multimers thereof
  • ' mature chemokines also known as ' lnterc ⁇ nes
  • the amino acid sequences of the murine protein KC which contains 72 residues is provided in SEQ ID NO 1
  • SEQ ID NO 2 amino acid sequences of the human protein groa
  • SEQ ID NO 3 amino acids 1-73
  • SEQ ID NO 4 The sequences of the human protein groy are provided in SEQ ID NO 4
  • the cDNA and amino acid sequences of groy are also provided in International Patent Application, Publication No WO 92/00326 (Jan 9, 1992) These groy sequences have further been published lnjnternational Patent Application, Publication No WO 94/29341 (December 22, 1994), which is incorporated by reference herein
  • the N terminal nictlnoni ⁇ e wluJi is uiseited into tne protein tor expression purposes, may be cleaved, either during the processing of the protein by a host cell or synthetically, using known techniques Alternatively, if so desired, this ammo acid may be cleaved through enzyme digestion or other known means
  • Particularly desirable modified chemokines include modified KC [amino acids 5 - 72 of SEQ ID NO 1], modified human gro ⁇ [amino acids 5-73 of SEQ ID NO 3] and modified human gro ⁇ [amino acids 5-73 of SEQ ID NO 4]
  • modified chemokine are other analogs or derivatives of KC, gro ⁇ , gro ⁇ , or gro ⁇ which share the biological activity of the mature protein
  • analogs and derivatives include modified proteins also characterized by alterations made in the known amino sequence of the proteins, e g , the proteins provided in SEQ ID NOS 1-4
  • Such analogs are characterized by having an amino acid sequence differing from that of the mature protein by 8 or fewer amino acid residues, and preferably by about 5 or fewer residues. It may be preferred that any differences in the amino acid sequences of the proteins involve only conservative amino acid substitutions
  • amino acid substitutions occur when an amino acid has substantially the same charge as the amino acid for which it is substituted and the substitution has no significant effect on the local conformation of the protein or its biological activity Alternatively, changes such as the introduction of a certain ammo acid in the sequence which may alter the stability of the protein, or permit it to be expressed in a desired host cell may be preferred Another characte ⁇ stic of these modified proteins may be enhanced biological activity in comparison to the mature protein By the term "multime ⁇ c protein' .
  • multime ⁇ c forms of the mature and/or modified proteins useful in this invention e g , dimers, t ⁇ mers, tetramers and other aggregated forms
  • Such multime ⁇ c forms can be prepared by synthesis or recombinant expression and can contain chemokines produced by a combination of synthetic and recombinant techniques as detailed below Multimers may form naturally upon expression or may be constructed into such multiple forms
  • Multime ⁇ c chemokines may include multimers of the same modified chemokine
  • Another multimer may be formed by the aggregation of different modified proteins
  • Still another multimer is formed by the aggregation of a modified chemokine of this invention and a known, mature chemokine
  • a dimer or multimer useful in the invention would contain at least uiie dcsdiniii ⁇ chemokine protein and at least one ottier chemokine or other protein characterized by having the same type of biological activity
  • This other protein may be an additional desamino chemok
  • the chemokines useful in the method of the invention are used in the preparation of medicaments and or are useful in the form of a pharmaceutical composition
  • the chemokines can be formulated into pharmaceutical compositions and administered in the same manner as described in, e g , International Patent Applications, Publication No WO 90/02762 (Mar 22, 1990) and Publication No W094/29341 (Dec 22, 1994)
  • medicaments or pharmaceutical compositions useful in the method of the invention for preventing or treating sepsis contain an effective amount of a mature, modified or multime ⁇ c chemokine protein derived from KC [SEQ ID NO 1 ], human gro-a [SEQ ID NO 2], human gro ⁇ [SEQ ID NO 3], and human gro ⁇ [SEQ ID NO 4] which is administered to an animal in need thereof
  • Particularly desired embodiments utilize the modified chemokines, or multimers thereof
  • These chemokine compositions may be administered alone or in combination with administration of other anti-infective agents
  • a pharmaceutical composition is prepared using one or more of proteins derived from the KC [SEQ ID NO 1], gro ⁇ [SEQ ID NO 2], gro ⁇ [SEQ ID NO 3] or gro ⁇ [SEQ ID NO 4] proteins Suitable pharmaceutical earners are well known to those of skill in the art and may be readily selected Currently, the preferred carrier is saline
  • the pharmaceutical compositions of the invention may contain other active ingredients or be administered in conjunction with other therapeutics
  • the compositions of the invention are particularly well suited for administration in conjunction with anti- infective agents
  • Suitable anti-infective agents include, without limitation, anti-microbial agents routinely used for the treatment of sepsis such as amino-glycosides (such as amikacin, tobramycin, netilmicin, and gentamicin), cephalosponns such as ceftazidime, related beta lactam agents such as maxalactam, carbopenems such as lmipenem, monobactam agents such as aztreonam, ampicillin and broad- spectrum penicillins, (e g , penicillinase-resistant penicillins, ureidopenicillins or antipseudomonal penicillin or Augmentin) that are active against P aeruginosa, Enterobacter species, indole-positive Proteus species, and Serratia Also included within the definition of anti-infective agents are antifungal agents, amphotericin and tne like as well as anti-viral agents such as famvir and acyclovir
  • chemokines desc ⁇ bed herein are useful in the treatment and prevention of sepsis in humans and other animals such as dairy cattle, horses, calves or poultry
  • a mature, modified or multime ⁇ c KC [SEQ ID NO 1 ], gro ⁇ [SEQ ID NO 2], gro ⁇ [SEQ ID NO 3] or human gro ⁇ [SEQ ID NO 4] or their multimers e.g , a dimeric, truncated gro ⁇ , amino acids 5-73 of SEQ ID NO 3
  • the dose may be in the range of about 10 to about 10,000 fg/kg/dose, or orally in the dose range of about 10 to about 10,000 fg/kg body weight per dose, if administered by infusion or similar techniques, the dose may be in the range of about 10 to about 10,000 fg kg/dose, if administered subcutaneously the dose may be in tne range of about 10 to about 10,000 fg/kg/dose
  • the compounds of this invention can be administered for prophylactic and/or therapeutic treatments
  • the compound is administered to a patient already suffenng from a disease in an amount sufficient to cure or at least partially arrest the disease and its complications It may be given at any time after surgery, preferably pnor to 24 hours after surgery
  • a composition containing mature, modified or multime ⁇ c KC [SEQ ID NO 1 ], gro ⁇ [SEQ ID NO 2J, gro ⁇ [SEQ ID NO 3] or gro ⁇ [SEQ ID NO 4] or a multimer thereof is administered to a patient not already in a disease state to enhance the patient's resistance. It may be given one day or one week pnor to surgery, preferably one to two days prior to surgery It may be administered parenteral iy or orally
  • Single or multiple administrations of the compounds can be carried out with dose levels and pattern being selected by the treating physician In any event, a quantity of the compounds of the invention sufficient to effectively treat the patient should be administered
  • chemokines useful in the methods of this invention may also be administered in conjunction with a separately administered conventional anti-infective as disclosed herein above, such a gentamicin, augmentin or ceftazidime
  • a separately administered conventional anti-infective as disclosed herein above, such a gentamicin, augmentin or ceftazidime
  • the particular anti-infective chosen should be one to which the infective organism is susceptible and is selected or modified during therapy as the infecting microorganism is more particularly identified
  • adjunctive agents in the treatment of septic shock also may be useful in combination with the components of this invention They include sympathomimetic amines (vasopressors) such as norepineph ⁇ ne, epineph ⁇ ne, isoproterenol, dopamine, and dobutamine, anti-inflammatory agents such as methylprednisolone anti-inflammatory agents such as lndomethacin and phenylbutazone, and corticosteroids such as betamethasone, hydrocortisone, methylprednisolone, or dexamethasone, anti-coagulants such as hepa ⁇ n, anti-thrombin III or couma ⁇ n type drugs for certain conditions and schedules, diuretics such as furosemide or ethacrynic acid, and antagonist of opiates and beta-endorphins such as naloxone; an antagonist of tumor necrosis factor or of interleukin- 1 , phenothiazines, antivaso
  • E. coli A clinical isolate of £ coh isolated from sputum was utilized The organisms were tested for antibiotic sensitivity by the disc agar diffusion technique and found to be sensitive to gentamicin, ampicillin, cephalothin, chloramphenicol, kanamycin tetracycline, t ⁇ methop ⁇ n/sulfamethoxazole and resistant to penicillin G, erythromycin, and vancomycin The organism was animal passed in mice and subsequently recovered and plated onto MacConkey's agar The reisolated organisms were grown overnight in brain- heart infusion broth, and then stored frozen at -70°C The inoculate the fibrin clot, organisms from thawed stocks were inoculated into brainheart infusion broth and incubated overnight on a rotary shaker (120 rpm ⁇ an 37°C The F coh was harvested by cent ⁇ fugation, washed 3X and finally resuspended in normal saline The number or organisms was quantified by
  • Fibrin Clot The E colt infected fibrin clots were made from a 1 % solution of bovine fibrinogen (Type 1 -S, Sigma) in sterile saline The clot was formed by adding sequentially human thrombin (Hanna Pharma ) bacteria, and fibrinogen solution to 24 well plastic plates Bacte ⁇ al numbers of 2 0 to 3 0 x I0 9 were used in inoculate the fibrin clots The resulting mixture was then incubated at room temperature for 30 minutes before implantation Animal Model.
  • Bovine fibrinogen Type 1 -S, Sigma
  • the clot was formed by adding sequentially human thrombin (Hanna Pharma ) bacteria, and fibrinogen solution to 24 well plastic plates Bacte ⁇ al numbers of 2 0 to 3 0 x I0 9 were used in inoculate the fibrin clots The resulting mixture was then incubated at room temperature for 30 minutes before implantation Animal Model.
  • the rats were anesthetized with ketamine/xylazine (40 mg/kg/5 mg/kg) after which the abdominal surfaced were shaved and a midlme laparotomy performed Bacterial peritonitis was induced by implanting a fib ⁇ n-thrombin clot containing E co into the abdominal cavity After implantation the muscle layers were closed with 4 0 silk suture, and the wound closed with surgical staples The animals were closely observed, any animals obviously moribund were euthanized
  • Gentamicin Rats were treated subcutaneously with gentamicin sulfate (Elkins Sinn, NJ) 5 mg/kg twice a day for five days
  • E colt cell pellet was lysed in pH 6 0 buffer containing 20 mM dithiothreitol (DTT) to avoid the nonspecific air oxidation
  • the majority of truncated gro ⁇ was m the insoluble lysate pellet which was solubilized in 2 M GdnHCI, pH 8 0 buffer containing 20mM DTT
  • the solubilized truncated gro ⁇ was dialyzed against pH 6 0 buffer containing 2 mM EDTA
  • the majo ⁇ ty of £ colt proteins were precipitated during dialysis while truncated gro ⁇ stayed in solution as a monomeric form at >95 % purity
  • the truncated gro ⁇ solution was adjusted to pH 8 5, stirred overnight for air oxidation
  • the refolded truncated gro ⁇ solution was adjusted to 0 1 % TFA solution, and applied to
  • DET-DDDDK chemokines were purified and refolded as described for truncated gro ⁇
  • the refolded DET-DDDDK chemokines were digested with enterokinase to remove the N-terminal DET-DDDDK and the undigested molecules were removed using anti DET Mab column
  • the digested molecules were further purified using C18 RP-HPLC as described above D Characterization
  • N-termmal sequencing and MALD-MS for molecular weight were performed and confirmed that the molecules are intact from N-terminus to C-termmus, either monomeric or dime ⁇ c form Concentration of each chemokine was determined by amino acid analysis and endotoxin level of each prep was ⁇ 0 05 U/ml
  • E coh LW cells 400 g were lysed in 4 liters of lysis buffer containing 50 mM sodium citrate pH 6.0, 40 mM NaCl, 2 M EDTA, 5% glycerol, 005% Tween 80, 0 2 mM PMSF, 1 mg/ml each of leupeptin and pepstatm A, by two passages through a
  • Typical yield of truncated gro ⁇ dimer was 0 15 mg/g of ⁇ ells when refolding was performed at 0 1 mg/ml or 0 7 mg/g of cells when refolding at 3 mg/ml E Characterization
  • the molecular weight of the truncated gro ⁇ dimer as determined on nonreducing SDS PAGE was approximately twice that of truncated gro ⁇ Upon reduction, both forms migrated to the same spot indicating that truncated gro ⁇ dimer is a disulfide linked dimer
  • the molecular weight of truncated gro ⁇ dimer, as determined b> MALD-MS analysis was 15,069 Da (predicted 15,073 Da), while that of truncated gro ⁇ dimer was 7,536 Da (predicted 7,537 Da) N-terminal sequencing of truncated gro ⁇ dimer showed that 5-10% of the final products retained the initiatory Met Disulfide pairing pattern of truncated gro
  • mice were dosed intraperitoneally with truncated KC [ammo acids 5-72 of SEQ ID NO 1] at doses of 10, 33, 100 or 333 fg/kg 24 hours and 2 hours before infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin On day 0 the rats were implanted with an E coh containing fib ⁇ n-thrombin clot Starting two hours after infection the rats were treated with gentamicin twice daily
  • the rats prophylactically treated with truncated KC at 33 or 100 fg kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rat receiving gentamicin therapy alone
  • the rats were implanted with an E coh containing fib ⁇ n-thrombin clot
  • the animals were dosed intraperitoneally with truncated KC [amino acids 5-72 of SEQ ID NO.1] at doses of 33, 100, 333, or 1,000 fg/kg as a single injection 2 hours after infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats therapeutically treated with truncated KCat 100 or 333 fg/kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rat receiving gentamicin therapy alone Results
  • Example 5 Therapeutically Administered Truncated KC in S. aureus Sepsis.
  • mice On day 0 the rats were implanted with a S. aureus containing fib ⁇ n-thrombin clot The animals were dosed intraperitoneally with truncated KC [amino acids 5-72 of SEQ ID NO 1 ] at doses of 33, 100, 333, or 1 ,000 fg/kg as a single injection 2 hours after infection Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin The rats therapeutically treated with truncated KC at 100 or 333 fg/kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rat receiving gentamicin therapy alone. Results
  • the rats were implanted with an E co containing fib ⁇ n-thrombin clot
  • the animals were dosed mtrape ⁇ toneally with truncated gro ⁇ [amino acids 5-73 of SEQ ID NO.3] at doses of 33, 100, 333, or 1,000 fg/kg as a single injection 2 hours after infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats therapeutically treated with t ⁇ lesed gro ⁇ at 100 or 333 fg/kg followed by gentamicin treatment demonstrated signi ificantly improved survival rates over the diluent treated control rats receiving gentamicin therapy ⁇ one
  • the rats were implanted with an S aureus containing fib ⁇ n-thrombin clot
  • the animals were dosed intrape ⁇ toneally with truncated gro ⁇ [amino acids 5-73 of SEQ ID NO 3] at doses of 33, 100, 333, or 1 ,000 fg/kg as a single injection 2 hours after infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats therapeutically treated with truncated gro ⁇ at 100 or 333 fg/kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rats receiving gentamicin therapy alone
  • Results Results
  • Example 8 Therapeutical Subcutaneously Administered Truncated gro ⁇ in E. coli Sepsis On day 0 the rats were implanted with an E. coh containing fib ⁇ n-thrombin clot
  • mice were dosed subcutaneously with truncated gro ⁇ [amino acids 5-73 of SEQ ID N0.3J at doses of 0 1 , 0.3, 1 0, or 3.3 pg/kg as a single injection 2 hours after infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats therapeutically treated with truncated gro ⁇ at 0.3 or 1.0 pg/kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rats receiving gentamicin therapy alone.
  • Example 9 Therapeutical Subcutaneously Administered Truncated gro ⁇ in S. aureus Sepsis On day 0 the rats were implanted with an S. aureus containing fibrin-thrombin clot
  • mice were dosed subcutaneously with truncated gro ⁇ [amino acids 5-73 of SEQ ID NO.3] at doses of 0.1 , 0 3, 1.0, or 3.3 pg/kg as a single injection 2 hours after infection
  • Control animals were dosed with dilution buffer on the same schedule Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats therapeutically treated with truncated gro ⁇ at 0.3 or 1.0 pg/kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rats receiving gentamicin therapy alone.
  • mice were dosed subcutaneously with dimer formed of two truncated gro ⁇ proteins [amino acids 5-73 of SEQ ID NO:3] at doses of 0 1, 0.3, 1.0 or 3.3 pg/kg 24 hours before infection
  • Control animals were doses with dilution buffer on the same schedule
  • the rats were implanted with an E colt containing fib ⁇ n-thrombin clot Starting two hours after infection the rats were treated twice daily with subcutaneous gentamicin
  • the rats prophylactically treated with truncated gro ⁇ dimer at 0 3 or 1 0 pg kg followed by gentamicin treatment demonstrated significantly improved survival rates over the diluent treated control rats receiving gentamicin therapy alone
  • mice On day 0 the rats were implanted with an S aureus containing fib ⁇ n-thrombin clot The animals were dosed subcutaneously with a dimer formed of two truncated groB proteins [ammo acids 5-73 of SEQ ID NO 3] at doses of 0 03, 0 1, 0 3, 1 0, 3 3, or 10 pg/kg as a single injection 2 hours after infection Control animals were doses with dilution buffer on the same schedule
  • Ala Pro lie Ala Asn Glu Leu Arg Cys Gin Cys Leu Gin Thr Met 1 5 10 15
  • Lys lie Val Gin Lys Met Leu Lys Gly Val Pro Lys
  • Lys lie lie Glu Lys Met Leu Asn Ser Asp Lys Ser Asn 65 70
  • Lys lie lie Glu Lys Met Leu Lys Asn Gly Lys Ser Asn
  • Lys lie lie lie Glu Lys lie Leu Asn Lys Gly Ser Thr Asn

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Abstract

L'invention concerne un procédé de prévention et de traitement de maladies infectieuses au moyen de chemokines sélectionnées entre des KC [SEQ ID NO:1], groα [SEQ ID NO:2], groβ [SEQ ID NO:3] ou groη [SEQ ID NO:4] matures ou modifiés ou dans leurs multimères, seules ou conjuguées à un agent anti-infectieux.
PCT/US1996/018616 1995-11-21 1996-11-20 Procede de traitement de maladies infectieuses WO1997019173A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU10209/97A AU1020997A (en) 1995-11-21 1996-11-20 Method of treating sepsis
JP9519868A JP2000504310A (ja) 1995-11-21 1996-11-20 敗血症の治療方法
EP96940554A EP0871732A4 (fr) 1995-11-21 1996-11-20 Procede de traitement de maladies infectieuses
US08/846,966 US6042821A (en) 1995-11-21 1997-04-29 Method of treating sepsis with chemokines
US09/513,153 US6413510B1 (en) 1995-11-21 2000-02-25 Dimeric modified groβ protein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US742595P 1995-11-21 1995-11-21
US60/007,425 1995-11-21

Related Child Applications (1)

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US08/846,966 Continuation-In-Part US6042821A (en) 1995-11-21 1997-04-29 Method of treating sepsis with chemokines

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WO1997019173A1 true WO1997019173A1 (fr) 1997-05-29

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JP (1) JP2000504310A (fr)
AU (1) AU1020997A (fr)
WO (1) WO1997019173A1 (fr)
ZA (1) ZA969721B (fr)

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WO2002045750A1 (fr) * 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Medicaments combines
US6406688B1 (en) 1996-05-14 2002-06-18 Human Genome Sciences, Inc. Method of treating sepsis and ARDS with chemokine β-4
EP0981361A4 (fr) * 1997-04-29 2004-06-16 Smithkline Beecham Corp Methode de traitement de l'etat septique
US6852508B1 (en) 1997-02-28 2005-02-08 Genetics Institute, Llc Chemokine with amino-terminal modifications
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7067117B1 (en) 1997-09-11 2006-06-27 Cambridge University Technical Services, Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7238711B1 (en) 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
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US6406688B1 (en) 1996-05-14 2002-06-18 Human Genome Sciences, Inc. Method of treating sepsis and ARDS with chemokine β-4
EP0807439B1 (fr) * 1996-05-14 2003-04-23 Smithkline Beecham Corporation Utilisation de Chimiokine beta-9 humaine pour le traitement du syndrome de detresse respiratoire chez l'adulte
US6852508B1 (en) 1997-02-28 2005-02-08 Genetics Institute, Llc Chemokine with amino-terminal modifications
US7396911B2 (en) 1997-02-28 2008-07-08 Genetics Institute, Llc Chimeric polypeptides containing chemokine domains
US6100387A (en) * 1997-02-28 2000-08-08 Genetics Institute, Inc. Chimeric polypeptides containing chemokine domains
US6730296B1 (en) 1997-02-28 2004-05-04 Wyeth Chimeric polypeptides containing chemokine domains
EP0981361A4 (fr) * 1997-04-29 2004-06-16 Smithkline Beecham Corp Methode de traitement de l'etat septique
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7067117B1 (en) 1997-09-11 2006-06-27 Cambridge University Technical Services, Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7700087B2 (en) 1997-09-11 2010-04-20 Cambridge Enterprise Limited Compounds and methods to inhibit or augment an inflammatory response
US6838435B1 (en) 1997-09-25 2005-01-04 Academisch Ziekenhuis Bij De Universiteit Van Amsterdam Isolated and recombinant antimicrobial peptides thrombocidin-1 (TC-1) and thrombocidin-2(TC-2) or variants thereof
WO1999015548A3 (fr) * 1997-09-25 1999-06-17 Az Univ Amsterdam Peptides antimicrobiens isoles et de recombinaison thrombocidine-1 (tc-1) et thrombocidine-2 (tc-2) ou variants desdits peptides
US7238711B1 (en) 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
WO2002045750A1 (fr) * 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Medicaments combines
CN106632616A (zh) * 2016-07-18 2017-05-10 复旦大学附属妇产科医院 具有卵巢肿瘤靶向d构型多肽及其基因递释系统
CN106632616B (zh) * 2016-07-18 2020-12-25 复旦大学附属妇产科医院 具有卵巢肿瘤靶向d构型多肽的基因递释系统

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EP0871732A1 (fr) 1998-10-21
EP0871732A4 (fr) 2002-01-16
JP2000504310A (ja) 2000-04-11
AU1020997A (en) 1997-06-11
ZA969721B (en) 1997-11-28

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