WO1999056775A1 - Emploi de l'interleukine 18 comme produit d'addition pour vaccin - Google Patents

Emploi de l'interleukine 18 comme produit d'addition pour vaccin Download PDF

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Publication number
WO1999056775A1
WO1999056775A1 PCT/EP1999/003098 EP9903098W WO9956775A1 WO 1999056775 A1 WO1999056775 A1 WO 1999056775A1 EP 9903098 W EP9903098 W EP 9903098W WO 9956775 A1 WO9956775 A1 WO 9956775A1
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Prior art keywords
canine
equine
vaccine
seq
pcr
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PCT/EP1999/003098
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English (en)
Inventor
Lesley Nicolson
Eric Onno Rijke
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Akzo Nobel N.V.
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Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to CA002328059A priority Critical patent/CA2328059A1/fr
Priority to JP2000546799A priority patent/JP2002513547A/ja
Priority to EP99920854A priority patent/EP1075275A1/fr
Priority to AU38276/99A priority patent/AU3827699A/en
Publication of WO1999056775A1 publication Critical patent/WO1999056775A1/fr

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    • 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
    • C07K14/54—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to the use of recombinant interleukin 18 (IL-18) as an adjuvant, adjuvant compositions and vaccines comprising said LL-18, and various recombinant LL-18 to be used in said compositions and vaccines.
  • IL-18 interleukin 18
  • Interleukin 18 is a novel cytokine, that can be isolated from the liver, and which is predominantly produced by activated marcophages. LL-18 has been reported to induce the production of interferon- ⁇ (INF.- ⁇ ) in established Thl cells, to stimulate NK cell cytotoxicity, and to activate the proliferation of Thl but not Th2 cells (Okamura et al., Nature vol. 378:88 (1995); Stoll et al., J. Immunol, vol. 159 (1):298 (1997)).
  • INF.- ⁇ interferon- ⁇
  • LL-18 was also found to augment granulocyte-macrophage-CSF production, decrease IL-10 production but was not found to have an effect on LL-4 production by Con A-stimulated PBMC (Ushio et al., J.Immunol, vol. 156 (1 1):4274 (1996); Kohno et al., J Immunol, vol. 158(4): 1541 (1997)).
  • the gene encodes for a precursor protein which contains a leader sequence which resembles the IL-1 signature-like sequence.
  • LL-18 and LL-l ⁇ proteins both contain this IL-1 signature-like sequences, the homology between the amino acid sequences of IL-18 and IL-1 is less than 20% and their biological activities were different in terms of induction of LNF.- ⁇ (Ushio, supra).
  • EP-A-712931 and EP-A- suggest the use of LL-18 as a therapeutic and/or prophylactic agent in case of INF.- ⁇ -susceptive diseases such as AIDS, and condyloma acuminatum; malignant tumours such as renal cancer, granuloma, mycosis fungoides and cerebral tumour, articular rheumatism and allergy.
  • INF.- ⁇ -susceptive diseases such as AIDS, and condyloma acuminatum
  • malignant tumours such as renal cancer, granuloma, mycosis fungoides and cerebral tumour, articular rheumatism and allergy.
  • LL-18 is suggested for use in so called “anti-tumour immunotherapy” using LL-2 to treat solid malignant tumours such as colonic cancer, rectal cancer, gastric cancer, thyroid carcinoma, cancer of the tongue, bladder carcinoma, choriocarcinoma, hepatoma, prostate cancer, carcinoma uteri, laryngeal lung cancer, breast cancer, malignant melanoma, Kaposi's sarcoma, cerebral tumour neuroblastoma, tumour of the ovary, testicular tumour, osteosarcoma, cancer of the pancreas, and others.
  • solid malignant tumours such as colonic cancer, rectal cancer, gastric cancer, thyroid carcinoma, cancer of the tongue, bladder carcinoma, choriocarcinoma, hepatoma, prostate cancer, carcinoma uteri, laryngeal lung cancer, breast cancer, malignant melanoma, Kaposi's sarcoma, cerebral tumour neuroblastoma, tumour of the ovary, testicular tumour, osteosarcoma,
  • Vaccination against an infectious disease aims to elicit an immune response that limits clinical symptoms associated with infection by a pathogen. It is important that the correct type of immune reaction is triggered, since many types of immune mechanisms that can be activated are inadequate for control of the particular pathogen.
  • Low responsiveness to vaccine antigens can be overcome by administering the antigens in combination with adjuvants.
  • Adjuvants are defined as those components of a vaccine formulation other than the antigen which contribute to enhanced immune responsiveness to the antigen, e.g. aluminium salts, oil emulsions, derivatives of muramyl peptide, monophosphoryl lipid A, liposomes, QS21, MF-59, Iscoms, and the like.
  • the cellular and molecular mechanisms that are activated following vaccination are strongly influenced by the choice of adjuvant that is administered together with the vaccine antigen. Hence the selection of adjuvants may be as critical as the choice of vaccine antigens themselves in providing optimal efficacy.
  • LL-18 has a potent adjuvant effect on the immune response of a subject to a vaccine. Because of this, LL-18 can be used as a vaccine adjuvant.
  • the invention provides for an adjuvant composition comprising an effective adjuvant amount of LL-18.
  • the adjuvant composition comprising LL-18 can be administered concomitantly or sequentially with a vaccine formulation.
  • LL-18 can be included in the vaccine formulation.
  • the present invention provides for a vaccine comprising at least one active agent, an effective adjuvant amount of LL-18, and a pharmaceutical acceptable carrier or diluent.
  • IL-18 is closely related to the IL-18 naturally found in the subject animal or patient.
  • the IL-18 is derived from the same species as the vaccine is designed for, e.g. canine LL-18 in the event of a vaccine for use in canines, human LL- 18 in the event of a vaccine for use in humans, and so on.
  • the 11-18 is derived from equine or canine for use in vaccination of dogs and horses respectively.
  • LL-18 according to the present invention can be the whole molecule or fragments thereof, provided said fragments have retained their adjuvanting ability. It should be understood that functional equivalents of LL-18 can also be used in the present invention. Functional equivalents are defined as modified LL-18 proteins which differ in amino acid sequence from wild type IL-18 but nevertheless have substantially the same adjuvanting activity as wild type IL-18. These modifications can constitute insertions, deletions, or conservative substitutions of one or more amino acids in the amino acid sequence of wild type LL-18. Also within the scope of the invention is an LL-18 molecule conjugated to another molecule, either direct or via the use of a conjugating agent (a linker), provided that said conjugation does not prevent or hinder the adjuvating effect of LL-18.
  • a conjugating agent a linker
  • LL-18 of the present invention can be obtained via extraction or purification from natural sources, via organic chemical synthesis, or via recombinant DNA technology. Most preferred is the production of LL-18 via recombinant DNA technology. The recombinant production of 11-18 necessitates the use of genes or nucleotide sequences that encode said IL-18. LL-18 encoding nucleotide sequences have been published for murine, human and rat IL-18 respectively (Okamura, supra; Ushio, supra; B. Conti et al., J. Biol. Chem. 272 (4), pp. 2035-2037, 1997).
  • the present invention provides for nucleotide sequences that code for LL-18, more especially canine and equine IL-18.
  • the nucleotide sequences coding for canine IL- 18 and equine IL-18 are depicted in SEQ LD NO 1 and 3, respectively.
  • the primary deduced amino acid structure of canine and equine IL 18 is given in SEQ ID NO 2 and 4, respectively.
  • the cloning of the nucleotide sequences encoding canine and equine LL-18, respectively, enables the production of pure LL-18, free from other cytokines. This is especcially useful in case of the production of LL-18-specific antibodies.
  • These specific anti-LL-18-antibodies can be generated via techniques generally available.
  • the specific anti-IL-18-antibodies are monoclonal anti-IL-18-antibodies.
  • the present invention furthermore provides for LL-18-specific antibodies, more particularly canine and/or equine IL-18-specific antibodies.
  • the Il-18-specific antibodies according to the invention are suitable for use in diagnostics or for isolation and purification of LL-18 protein from crude preparations. Moreover, the antibodies can be used into develop assays for quantitative analysis of 11-18 production in vitro or for quantitaive measurements of LL-18 levels in vivo.
  • the adjuvant composition according to the present invention comprises LL-18 and a pharmaceutical acceptable carrier. Suitable pharmaceutical carriers are water, saline, and the like. Additionally, the adjuvant composition may comprises one or more other adjuvants such as oil emulsions, aluminium salts, derivatives of muramyl dipeptide, monophosphoryl lipid A, liposomes, QS21, MF-59, Iscoms, and the like. Preferably, 11-18 is used in conjunction with other cytokines such as for example IL-12. In a preferred embodiment, the adjuvant composition according to the invention comprises a DNA plasmid capable of expressing said LL-18. Said DNA plasmid comprises DNA sequences encoding LL-18 operably linked to transcriptional regulatory sequences.
  • Nucleotide sequences encoding for other cytokines that are used in conjunction with IL-18 can be present on the same DNA plasmid or on a separate plasmid. Upon administration of such a DNA adjuvant composition to a subject, host cells take up and express encoded genes on the inoculated DNA, resulting in in vivo expression of said LL-18.
  • Vaccines according to the invention can be used for immunisation of humans and animals, such as for example swine, sheep, birds, cattle, dogs, cats, equines, fish and shell fish.
  • a vaccine according to the invention comprises at least one active agent and an effective adjuvant amount of LL-18, i.e. an amount of LL-18 which will cause the vaccinated subject to produce an enhanced immunological response as compared to the vaccine without said LL-18.
  • the required effective amount of LL-18 in an adjuvant composition or vaccine according to the invention is dependent on the type of active agent used, the type of pathogen immunised against, as well as the type of vaccinated subject. Determination of the effective amount is well within the routine skills of the practitioner, and will generally be in the amount of 0.001 to 500 ⁇ g/dose. Preferably the amount will be between 0.01 and 50 ⁇ g/dose, more preferably 0.1 to 5 ⁇ g/dose.
  • the active agent for use a vaccine according to the invention can be of viral, bacterial or parasitic origin.
  • the active agent may either be the whole pathogen which causes the disease, or may consist of components derived from said pathogen.
  • said pathogen may be a live pathogen or an inactivated pathogen.
  • Live pathogens are considered to be either attenuated or naturally occurring mild strains of said pathogen.
  • Inactivated pathogens are pathogens killed by chemical or physical means, that is, the inactivate or "killed" pathogen is no longer capable of replication. Suitable means for chemical inactivation are formaldehyde, glutaraldehyde, ⁇ -propiolactone, ethyleneimine and derivatives, and the like.
  • Suitable means for physical inactivation are UV radiation, ⁇ -radiation, "heat-shock", X- radiation, and the like.
  • the active agent may constitute one or more components derived from said diseases causing pathogen, e.g. purified protein, protein-polysaccharide, protein-lipopolysaccharides, lipopolysaccharides, and the like.
  • the active agent is a DNA plasmid capable of in vivo expression of a pathogen or selected components derived from said pathogen.
  • the vaccine may comprise a DNA plasmid capable of expressing the LL-18 adjuvant in vivo.
  • the DNA encoding said IL 18 adjuvant and the DNA encoding said pathogen or selected components may be present on one and the same plasmid, or may be present on separate plasmids.
  • host cells Upon administration of the DNA vaccine to a subject, host cells will take up and express in vivo said active agent as well as said LL-18.
  • DNA vaccines are for example described in US 5,580,859.
  • compositions that can be used to formulate an adjuvant composition or a vaccine composition according to the invention are sterile and physiological compatible such as for example an aqueous buffer, a saline solution and the like.
  • stabilisers, preservatives and the like may be added to these compositions.
  • DNA plasmids that may be used in the adjuvant composition or vaccine according to the invention contain a carrier DNA fragment and a suitable expression cassette including transcriptional regulatory sequences, the target gene and other regulatory sequences, if desired.
  • suitable plasmids include pBR322, pUC18 and pUC19, pNeo, pSVL, pMSG (commercially available from Pharmacia Biotech) and pMClneo, pSG5, pXTl and pBX (commercially available from Stratagene).
  • Suitable transcriptional regulatory sequences comprise promoters such as the (human) cytomegalovirus immediate early promoter (Seed, B. et al., Nature 329, 840-842, 1987; Fynan, E.F. et al., PNAS 90, 11478-11482,1993; Ulmer, J.B. et al., Science 259, 1745- 1748, 1993), Rous sarcoma virus LTR (RSV, Gorman, CM. et al., PNAS 79, 6777-6781, 1982; Fynan et al., supra; Ulmer et al., supra), the MPSV LTR (Stacey et al., J.
  • promoters such as the (human) cytomegalovirus immediate early promoter (Seed, B. et al., Nature 329, 840-842, 1987; Fynan, E.F. et al., PNAS 90, 11478-11482,19
  • the regulatory sequences may also include terminator and polyadenylation sequences. Amongst the sequences that can be used are the well known bovine growth hormone polyadenylation sequence, the SV40 polyadenylation sequence, the human cytomegalovirus (hCMV) terminator and polyadenylation sequences.
  • any transcriptional regulatory sequence can be used that is able to regulate the transcription of a gene in an eucaryotic cells as for example described in Sambrook et al, Molecular Cloning, a Laboratory Manual, second edition, Cold Spring Harbor Laboratory Press, 1989.
  • the regulatory sequences may include an intron, for example hCMV intron A (Chapman, B.S. et al., Nucleic Acid Research 19, 3979-3986, 1991), the effect of which is to increase the expression of the encoded protein.
  • compositions of the present invention may take any form that is suitable for oral or parenteral administration.
  • the adjuvant or vaccine compositions according to the invention may be formulated as solutions, syrups, suspensions, tablets, capsules and the like.
  • the compositions according to the present invention may be formulated in a form suitable for injection such as suspensions, solutions, dispersions, emulsions, and the like. Preparation of the compositions according to the present invention is carried out by means conventional for the skilled person.
  • Preferred administration routes are parenteral routes, e.g. intramuscular injection, intravenous injection, intradermal injection, subcutaneous injection, and mucosal routes, e.g. nasal drops, eye drops, (aerosol) sprays, and the like.
  • parenteral routes e.g. intramuscular injection, intravenous injection, intradermal injection, subcutaneous injection, and mucosal routes, e.g. nasal drops, eye drops, (aerosol) sprays, and the like.
  • Lung macrophages were extracted from the lungs of a horse or dog (post mortem) by filling the lungs with tissue culture medium (equine - HBSS, canine RPMI) and recovering the medium and cells by pouring the fluid into centrifuge bottles (this procedure was performed several times to maximise recovery of cells from the lungs e.g. up to 3 litres of equine 'lung wash' was recovered).
  • tissue culture medium equine - HBSS, canine RPMI
  • this procedure was performed several times to maximise recovery of cells from the lungs e.g. up to 3 litres of equine 'lung wash' was recovered.
  • this procedure was performed in a laminar flow hood to minimise the potential for bacterial contamination from the environment. Every effort was made to minimise contamination by red blood cells by gentle handling and avoidance of contamination from the external surface of the lung.
  • Cells recovered from the lung wash material by centrifugation of 'lung wash' at 1700 rpm for 10 minutes were resuspended in 20 ml medium (wash step), centrifliged at 1700 rpm for 10 minutes and the cell pellet resuspended in 20 ml or 40 ml medium depending on pellet size.
  • Cell suspensions were transferred to tissue culture flasks; 10ml per 25cm 2 flask. Flasks were gassed with CO2 and incubated at 37°C for 4 hours to allow adherence of macrophages. The medium was then changed to remove non-adherent contaminating red blood cells and cultures incubated overnight at 37°C. Cultures were stimulated with PMA (5ng/ml) for 4 hours. Cells were recovered byremoving medium, washing with PBS then lysing cells as per Pharmacia Biotech Quick prep mRNA purification kit.
  • Dulbecco's Modified Eagles Medium (Gibco cat number 31966-021) with added: 10% FCS 20 mM Hepes lOOU/ml penicillin 1 OOug/ml streptomycin
  • HBSS Hank's Buffered saline
  • mRNA from stimulated cultures mRNA was isolated using Pharmacia Quick Prep ® kit. Freshly recovered, or previously prepared cell pellets (the latter stored at -70°C) were used as the starting material for preparation of mRNA. mRNAs were prepared according to the manufacturer's protocols with minor modifications.
  • O. ⁇ ug mRNA was used as template for first strand cDNA synthesis using Pharmacia 1st strand cDNA synthesis kit according to manufacturer's instructions.
  • the primer used was a Notl- d(T)18 bifunctional primer of sequence:
  • 0.5ug treated mRNA was used as template for first strand cDNA synthesis using Pharmacia 1st strand cDNA synthesis kit according to manufacturer's instructions.
  • the primer used was a NotI-d(T)18 bifunctional primer of sequence : 11
  • PCR reactions using cDNA as target were performed. Some primer combinations produced no significant product after primary PCR and PCR products from this reaction were used in a secondary PCR reaction using identical or different primer conditions to that used in the primary PCR. 5ul cDNA was used in primary PCR's and I ul of primary PCR product in secondary PCRs. Annealing temperatures and cycling conditions were optimised for amplification of parts or whole equine and canine LL-18 cDNAs - examples of PCR reaction conditions are detailed below. PCR machine Perkin Elmer model 9600 was used for equine PCR reactions and Perkin Elmer Geneamp PCR system 2400 for canine reactions.
  • canine LL-18 clones were recovered by secondary PCRs using primary PCRs with primer A in combination with primers B, D and E as target for secondary PCR using A+B, A+E and C+B.
  • PCR reaction products from a minimum of three independent PCR reactions [primary and secondary] using the primer sets A+B, C+B, A+E (canine only), and C+D were cloned into Invitrogen TA cloning vector pCR2.1.
  • LL-18 clones were sequenced using Amersham's Thermo Sequenase cycle sequencing kit and LI-COR automated DNA sequencer model 4000L. and sequenced. Consensus sequences of the equine and canine LL-18 cDNAs were derived by 14
  • mice Groups of C57 BL/6 mice (female, 6 week-old) were injected intramuscularly (i.m) on day 0 in the upper leg muscle with a vaccine formulation containing as antigen inactivated Pseudorabies virus (PRV plus 0.1 LF tetanus toxoid (TT); 10 6 7 TCID 50 per dose), .
  • the antigen preparation was mixed together with 0.1 ⁇ g recombinant murine IL-18, expressed in E.coli (Pepro Tech, cat. no. 315-04) shortly, 1-2 hours before immunisation.
  • vaccine antigen PRV plus TT; 10 6 7 TCID50 per dose
  • ADV phylaxia A25H, A- 1015 1:600 diluted Naive unvaccinated animals all succumbed to the infection within 3-4 days. Among animals vaccinated with antigen only 30 % (3 out of 10) survived the infection, while among animals receiving the same amount of antigen together with only 0.1 ⁇ g LL-18 80 % (8 out of 10 ) survived the infection.
  • FIGURE 1 Survival rates of mice immunized with antigen and 0.1 ⁇ g LL-18 or antigen only after infection with virulent PRV.

Abstract

Cette invention, qui a trait à l'emploi de l'interleukine 18 (IL-18) en tant que produit d'addition pour vaccin, concerne également des compositions adjuvantes et des vaccins renfermant cette IL-18 ainsi que différentes IL-18 de recombinaison à utiliser dans lesdites compositions et dits vaccins.
PCT/EP1999/003098 1998-05-07 1999-05-04 Emploi de l'interleukine 18 comme produit d'addition pour vaccin WO1999056775A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002328059A CA2328059A1 (fr) 1998-05-07 1999-05-04 Emploi de l'interleukine 18 comme produit d'addition pour vaccin
JP2000546799A JP2002513547A (ja) 1998-05-07 1999-05-04 ワクチン・アジュバントとしてのインターロイキン−１８の使用
EP99920854A EP1075275A1 (fr) 1998-05-07 1999-05-04 Emploi de l'interleukine 18 comme produit d'addition pour vaccin
AU38276/99A AU3827699A (en) 1998-05-07 1999-05-04 Use of interleukin-18 as vaccine adjuvant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98201451.6 1998-05-07
EP98201451 1998-05-07

Publications (1)

Publication Number Publication Date
WO1999056775A1 true WO1999056775A1 (fr) 1999-11-11

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PCT/EP1999/003098 WO1999056775A1 (fr) 1998-05-07 1999-05-04 Emploi de l'interleukine 18 comme produit d'addition pour vaccin

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EP (1) EP1075275A1 (fr)
JP (1) JP2002513547A (fr)
AU (1) AU3827699A (fr)
CA (1) CA2328059A1 (fr)
WO (1) WO1999056775A1 (fr)

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EP1013763A1 (fr) * 1997-08-07 2000-06-28 Toray Industries, Inc. INTERLEUKINE 18 CANINE, INTERLEUKINE-1 $g(b)-CONVERTASE CANINE, SEQUENCES D'ADN CODANT CETTE ENZYME, PROCEDE DE PRODUCTION DE L'INTERLEUKINE 18, ET REMEDES CONTRE LES MALADIES IMMUNOLOGIQUES CHEZ LE CHIEN
WO2005039630A2 (fr) * 2003-10-13 2005-05-06 Glaxosmithkline Biologicals Sa Compositions immunogenes
WO2005039634A1 (fr) * 2003-10-13 2005-05-06 Glaxosmithkline Biologicals Sa Compositions vaccinales comprenant une interleukine 18 et un systeme adjuvant a base de saponine
WO2008060219A1 (fr) * 2006-11-13 2008-05-22 Theravac Pharmaceuticals Ab Vaccin à il-18 pour le traitement de diverses affections inflammatoires
US7556963B2 (en) * 2000-08-04 2009-07-07 Heska Corporation Feline IL-18 nucleic acid molecules

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US20110098656A1 (en) 2005-09-27 2011-04-28 Burnell Rosie L Auto-injection device with needle protecting cap having outer and inner sleeves
GB2438591B (en) 2006-06-01 2011-07-13 Cilag Gmbh Int Injection device
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Cited By (9)

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Publication number Priority date Publication date Assignee Title
EP1013763A1 (fr) * 1997-08-07 2000-06-28 Toray Industries, Inc. INTERLEUKINE 18 CANINE, INTERLEUKINE-1 $g(b)-CONVERTASE CANINE, SEQUENCES D'ADN CODANT CETTE ENZYME, PROCEDE DE PRODUCTION DE L'INTERLEUKINE 18, ET REMEDES CONTRE LES MALADIES IMMUNOLOGIQUES CHEZ LE CHIEN
EP1013763A4 (fr) * 1997-08-07 2005-01-26 Toray Industries INTERLEUKINE 18 CANINE, INTERLEUKINE-1 $g(b)-CONVERTASE CANINE, SEQUENCES D'ADN CODANT CETTE ENZYME, PROCEDE DE PRODUCTION DE L'INTERLEUKINE 18, ET REMEDES CONTRE LES MALADIES IMMUNOLOGIQUES CHEZ LE CHIEN
EP2184358A3 (fr) * 1997-08-07 2010-07-21 Toray Industries, Inc. Interleukine canine et remèdes contre les maladies immunologiques chez le chien
US7556963B2 (en) * 2000-08-04 2009-07-07 Heska Corporation Feline IL-18 nucleic acid molecules
WO2005039630A2 (fr) * 2003-10-13 2005-05-06 Glaxosmithkline Biologicals Sa Compositions immunogenes
WO2005039634A1 (fr) * 2003-10-13 2005-05-06 Glaxosmithkline Biologicals Sa Compositions vaccinales comprenant une interleukine 18 et un systeme adjuvant a base de saponine
WO2005039630A3 (fr) * 2003-10-13 2005-07-21 Glaxosmithkline Biolog Sa Compositions immunogenes
JP2007508273A (ja) * 2003-10-13 2007-04-05 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム 免疫原性組成物
WO2008060219A1 (fr) * 2006-11-13 2008-05-22 Theravac Pharmaceuticals Ab Vaccin à il-18 pour le traitement de diverses affections inflammatoires

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EP1075275A1 (fr) 2001-02-14
AU3827699A (en) 1999-11-23
JP2002513547A (ja) 2002-05-14
CA2328059A1 (fr) 1999-11-11

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