EP1121148A2 - Immunstimulierende emulsion - Google Patents

Immunstimulierende emulsion

Info

Publication number
EP1121148A2
EP1121148A2 EP99942961A EP99942961A EP1121148A2 EP 1121148 A2 EP1121148 A2 EP 1121148A2 EP 99942961 A EP99942961 A EP 99942961A EP 99942961 A EP99942961 A EP 99942961A EP 1121148 A2 EP1121148 A2 EP 1121148A2
Authority
EP
European Patent Office
Prior art keywords
emulsion
emulsion according
molecule
polynucleotide
lipid
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.)
Withdrawn
Application number
EP99942961A
Other languages
English (en)
French (fr)
Inventor
Jean Haensler
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.)
Sanofi Pasteur Inc
Original Assignee
Aventis Pasteur SA
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 Aventis Pasteur SA filed Critical Aventis Pasteur SA
Publication of EP1121148A2 publication Critical patent/EP1121148A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59

Definitions

  • the invention relates to the field of vaccines and more particularly vaccine adjuvants.
  • Vaccines whether prophylactic or therapeutic, are intended to stimulate the immune system of the human or animal body to which they are administered, the immune system response can be either a humoral type response (production of antibodies), either a cell type response, or a combination of the two types of responses.
  • the immune system response can be either a humoral type response (production of antibodies), either a cell type response, or a combination of the two types of responses.
  • vaccination has consisted in administering to an organism a non-pathogenic version of a microorganism so as to prepare the immune system to react effectively in the event that the organism is subsequently caused to encounter the same microorganism, in its pathogenic version.
  • the antigen administered during vaccination can.
  • oligonucleotides that may immunostimuiatrice activity
  • these oligonucleotides can be administered as a vaccine adjuvant.
  • This reference also mentions the possibility of associating with these oligonucleotides by ionic, covalent bond or by encapsulation, means for targeting the administration of the oligonucleotide.
  • Such means can in particular consist of sterol, of lipid (for example a catiodic lipid, a virosome or a liposome) or of a binding agent specific to the target cell (for example a binder recognized by a receptor specific for the cell). target).
  • the invention relates to an immu ⁇ ostimulant emulsion of the oil in water type, comprising at least one aqueous phase and one oily phase, characterized in that it also comprises at least one immunostimulating polynucleotide of which at least a part is covalently coupled to at least one lipid molecule.
  • oil-in-water emulsion means a dispersion of oil droplets in an aqueous phase which may consist of a buffer such as the PBS buffer.
  • the oily phase consists of a pharmaceutically acceptable oil, which can be a mineral, animal or vegetable oil.
  • a metabolizable oil is used such as squalene, esters (in particular ethyl oleate, - j - isopropyl myristate), a vegetable oil (for example castor oil, sunflower oil, olive oil ...) or a modified vegetable oil (eg macrogol glycerides) .
  • a satisfactory emulsion by mixing 500 mg of squalene with 10 ml of PBS buffer in a device such as an ULTRA-TURRAX TM, then by microfluidizing the dispersion obtained using a microfluidizer such as Microfluidics TM, which allows to obtain oily particles whose diameter is less than 200 nm.
  • a surface-active agent in particular a surface-active agent whose HLB value (Hydrophilic / Lipophilic Balance) is between 6 and 14.
  • a surfactant chosen from the list of the following products: sorbitan esters and poiysorbates, ethoxylated castor oil hydrogenated or not, ethoxylated stearic acid, oleic alcohol 10 EO, cetostearyl alcohol 20 EO, glycerol stearate, propylene glycol stearate, lecithins, sodium lauryl sulfate, sodium stearate, ethoxylated glycerol cocoate. 70E, ethoxylated glycerol esters, ethoxylated oleic acids, l 'mannitan oleate. Particularly good results have been obtained using TWEEN TM 80.
  • the emulsion obtained is considered to be immunostimulatory if it is capable of causing or increasing the stimulation of the immune system, for example when it is administered together with a vaccine antigen.
  • the emulsion is used as an immunoadjuvant.
  • This immuno-adjuvant activity can be expressed in different ways:
  • - modify the nature of the response of the immune system to the administration of the antigen (for example, inducing a cellular response when the administration of the antigen alone provoked only a humoral response), - induce or increase the production of cytokines, or certain cytokines in particular
  • polynucleotide within the meaning of the present invention, is understood a single-stranded oligonucleotide having from 6 to 100 nuciéotides, preferably from 6 to 30 nuciéotides It can be oligonbonucleotide, or o godesoxy ⁇ bo-nucleotide preferably polynucleotides comprising basic sequences with reverse symmetry, as is the case in palindromic sequences (that is to say sequences of the ABCDEE'D'C'B'A 'type where A and A, B and B ', C and C, D and D' E and E 'are complementary bases in the sense of Watson and C ⁇ ck), and more particularly polynucleotides comprising at least one di ⁇ ucleotide sequence Cytosine, Guanme, in which Cytosine and Guanine are not methylated Any other polynucleotide known to be, by its very nature, immunostimulant, may be suitable for
  • At least one lipid molecule is covalently coupled to the polynucleotide.
  • This lipid molecule is preferably a cholesterol or cholesterol derivative molecule.
  • the coupling can be carried out by covalent bonding at one or at each end of the polynucleotide, or again by inserting at least one lipid molecule next to each base.
  • Antigens whose effect it is possible to potentiate thanks to the emulsion according to the present invention, can be of varied nature, it can in particular be proteins, glycoproteins, glycoconjugates, polysaccharides or polynucleotides comprising fractions of DNA likely to lead to the expression of molecules ules of interest, it can also be a mixture of different antigens. Particularly good results have been obtained with a composition comprising influenza antigens as they are present in the commercial vaccine VAXIGRIP TM
  • An emulsion according to the invention can be obtained by proceeding in the following manner, first mixing, with stirring, the oil with the aqueous phase optionally consisting of a buffer solution in which a surfactant has been incorporated.
  • the mixture obtained is homogenized. by means, for example, of a propeller stirrer, in order to lead to an emulsion of the type oil in water.
  • the emulsion obtained is then treated using a microfluidizer in order to reduce the oil droplets to a diameter less than 200 nm
  • this emulsion When this emulsion is intended to be used as an immunoadjuvant, it is mixed with stirring, to a composition comprising the antigen whose effect it is desired to potentiate.
  • the mixing can advantageously be carried out in a volume ratio of 1. verify the unexpected effect and in particular the synergistic effect obtained on the stimulation of the immune system by the simultaneous use of a polynucleotide coupled to at least one lipid molecule, and its incorporation into an oil-in-water emulsion
  • compositions comprising only the antigen or the mixture of antigens vis-à-vis which it is desired to test the immunostimulating effect of the emulsion according to the invention, - or a composition, comprising the antigen or antigens d interest to which has been added a solution comprising only polynucleotides coupled to at least one lipid molecule,
  • compositions comprising the antigen or antigens of interest to which has been added an oil-in-water type emulsion, without polynucleotide, or with a polynucleotide lacking immunostimulatory activity with respect to the antigens administered,
  • composition comprising the antigen or antigens of interest to which an emulsion according to the invention has been added
  • the results obtained showed a significant synergistic effect of the elements constituting the emulsion according to the invention.
  • the emulsion obtained according to the invention has increased stability compared to emulsions of the same nature, i.e. those consisting of an identical aqueous phase and an oily phase, but devoid of polynucleotides.
  • Oligonucleotides are prepared using a synthesizer automaton provided by Applied Biosystems which implements the standard chemical method with phosphoramidite and which includes an oxidation step at each cycle. This oxidation step is carried out using an iodine / water / tetrahydrofuran / acetonitrile solution to obtain a phosphodiester bond and using a tetraethylthiuram / acetonitrile solution to obtain a phosphorothioate bond.
  • a 3 Db (S) oligonucleotide is thus prepared, the sequence of which is reproduced under SEQ ID NO 1 and which comprises phosphorothioate bonds over its entire length.
  • An MGC (S) oligonucleotide is also prepared, the sequence of which is reproduced in SEQ ID NO 2, which comprises both phosphodiester bonds and phosphorothioate bonds.
  • the phosphorothiate bonds are located at each end; there are 2 phosphorothioate bonds in 3 'and 5 phosphorothioate bonds in 5'.
  • This oligonucleotide does not have a palindromic sequence, and in particular no CG sequence.
  • Oligonucleotides are prepared which are coupled to the ends of the cholesterol molecules.
  • the synthesis of these 3 Db (S) -chol oligonucleotides and MGC (S) -chol is carried out in the same manner as in Example 1, with the exception of the Phosphoramidite reagent which is replaced by a specific reagent, Cholesterol-ON TM Phosphoramidite supplied by the company CLONTECH Lab. Inc, (USA), during the first and last synthesis cycle in order to obtain a cholesterol molecule inserted before each of the end nucleotides.
  • the nucleotide sequences obtained are identical to those of the oligonucleotides described in the previous example.
  • An immunostimulatory emulsion according to the invention is prepared by mixing 435 ⁇ l of the 2.3 g / l solution of 3Db (S) coupled to the cholesterol obtained in Example 2 (ie 1 mg of oligonucleotide), with 2 ml of the squalene / PBS emulsion obtained in Example 3, kept stirring.
  • Another emulsion is prepared by mixing 263 ⁇ l of the 3.81 g / l solution of MGC (S) coupled with cholesterol obtained in Example 2 (ie 1 mg of oligonucleotide) with 2 ml of the squalene emulsion / PBS obtained in Example 3, kept stirring.
  • Example 5
  • Immunization doses of different natures are prepared by adding, with stirring, 2 ml of splitted vaccine against influenza NIB16 (monovalent A / Singapore H1 N1) containing 100 ⁇ g of hemagglutinin HA in PBS buffer to 2 ml of each of the following preparations •
  • mice There are groups of 6 Balb / c female mice aged 6 to 8 weeks, each group corresponding to one of the preparations carried out in Example 6
  • Each of the mice is immunized with 200 ⁇ l of the preparation corresponding to its group and therefore receives 5 ⁇ g of HA by immunization, each mouse being immunized 2 times 3 weeks apart, with the same preparation 2 weeks after the second injection, the response to specific anti-HA antibodies is measured, using an ELISA test, and the GMT for lgG1 as well as for lgG2a The results obtained are indicated below:
  • results obtained confirm that the oligonucleotide 3Db (S) is well endowed with immunostimulatory properties because it is capable of inducing an increase in the antibody response compared to what is obtained during the administration of the antigens alone.
  • results obtained with the oligonucleotide MGC (S) do not demonstrate immunostimulatory activity.
  • the emulsion containing an immunostimulating polynucleotide such as the polynucleotide 3Db (S) leads to a production of antibodies clearly greater than that obtained with an emulsion containing the polynucleotide MGC (S) -chol; this effect is even more remarkable with regard to the production of IgG2a; which is indicative of an orientation of the immune response towards a TH1 type, orientation sometimes desired in certain vaccine targets.
  • Vaccine compositions are prepared comprising the following elements:
  • the doses are 50 ⁇ litres and include 50 micrograms of oligonucleotides.
  • compositions are administered to mice at OJ and D28; 5 to 6 weeks after the booster injection, the spleens of the mice are removed in order to evaluate the amount of n ⁇ interferer produced.
  • Immunization doses are prepared identical to those of Example 7, with the exception of the RSV antigens which are not in the presence of aluminum gel.
  • the doses of 50 ⁇ litres are administered intramuscularly to groups of 6 mice.
  • mice 4 weeks after immunization, the mice are bled and the anti-F protein antibody levels are determined by ELISA titration. The results obtained are summarized in the following table:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP99942961A 1998-09-11 1999-09-13 Immunstimulierende emulsion Withdrawn EP1121148A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9811520A FR2783170B1 (fr) 1998-09-11 1998-09-11 Emulsion immunostimulante
FR9811520 1998-09-11
PCT/FR1999/002177 WO2000015256A2 (fr) 1998-09-11 1999-09-13 Emulsion immunostimulante

Publications (1)

Publication Number Publication Date
EP1121148A2 true EP1121148A2 (de) 2001-08-08

Family

ID=9530468

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99942961A Withdrawn EP1121148A2 (de) 1998-09-11 1999-09-13 Immunstimulierende emulsion

Country Status (7)

Country Link
US (1) US6610308B1 (de)
EP (1) EP1121148A2 (de)
AU (1) AU749282B2 (de)
CA (1) CA2342313A1 (de)
FR (1) FR2783170B1 (de)
NZ (1) NZ510419A (de)
WO (1) WO2000015256A2 (de)

Families Citing this family (29)

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US7935675B1 (en) 1994-07-15 2011-05-03 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6207646B1 (en) 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US20030026782A1 (en) * 1995-02-07 2003-02-06 Arthur M. Krieg Immunomodulatory oligonucleotides
US6239116B1 (en) * 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
SI1077722T1 (sl) 1998-05-22 2007-02-28 Ottawa Health Research Inst Metode in produkti za induciranje sluznicne imunosti
US20030022854A1 (en) 1998-06-25 2003-01-30 Dow Steven W. Vaccines using nucleic acid-lipid complexes
ES2572834T3 (es) 1999-02-17 2016-06-02 Csl Limited Complejos inmunogénicos y métodos relacionados con los mismos
NZ520976A (en) * 1999-11-19 2005-01-28 Csl Ltd Vaccine compositions
US7585847B2 (en) * 2000-02-03 2009-09-08 Coley Pharmaceutical Group, Inc. Immunostimulatory nucleic acids for the treatment of asthma and allergy
FR2814958B1 (fr) * 2000-10-06 2003-03-07 Aventis Pasteur Composition vaccinale
ATE411054T1 (de) 2001-08-17 2008-10-15 Coley Pharm Gmbh Kombinations-motif-immunstimulierende oligonukleotide mit verbesserter wirkung
US20050238660A1 (en) * 2001-10-06 2005-10-27 Babiuk Lorne A Cpg formulations and related methods
US7807803B2 (en) 2002-07-03 2010-10-05 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
US20040053880A1 (en) 2002-07-03 2004-03-18 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
US7605138B2 (en) 2002-07-03 2009-10-20 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
US7576066B2 (en) 2002-07-03 2009-08-18 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
US7569553B2 (en) 2002-07-03 2009-08-04 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
CN1753687A (zh) 2002-10-29 2006-03-29 科勒制药集团股份有限公司 Cpg寡核苷酸在治疗丙型肝炎病毒感染中的应用
CA2502015A1 (en) 2002-12-11 2004-06-24 Coley Pharmaceutical Group, Inc. 5' cpg nucleic acids and methods of use
AU2004275876B2 (en) 2003-09-25 2011-03-31 Coley Pharmaceutical Gmbh Nucleic acid-lipophilic conjugates
US20080113929A1 (en) * 2004-06-08 2008-05-15 Coley Pharmaceutical Gmbh Abasic Oligonucleotide as Carrier Platform for Antigen and Immunostimulatory Agonist and Antagonist
PT2078080E (pt) 2006-09-27 2015-09-18 Coley Pharm Gmbh Análogos dos oligonucleotídeos cpg que contêm análogos t hidrofóbicos com atividade imunoestimulante potenciada
EP2575878B1 (de) * 2010-05-28 2018-06-13 Zoetis Belgium S.A. Impstoffe mit cholesterin und cpg als einzige adjuvans-träger moleküle
EP3024936B1 (de) 2013-07-25 2019-09-04 Exicure, Inc. Sphärische nukleinsäurebasierte konstrukte als immunstimulatoren für prophylaktische und therapeutische verwendung
TR201908550T4 (tr) 2014-06-04 2019-07-22 Exicure Inc Profilaktik veya terapötik uygulamalar için lipozomal sferik nükleik asitler tarafından immün modülatörlerin çok değerlikli teslimi.
US11213593B2 (en) 2014-11-21 2022-01-04 Northwestern University Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates
WO2018039629A2 (en) 2016-08-25 2018-03-01 Northwestern University Micellar spherical nucleic acids from thermoresponsive, traceless templates
US11696954B2 (en) 2017-04-28 2023-07-11 Exicure Operating Company Synthesis of spherical nucleic acids using lipophilic moieties

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EP1167379A3 (de) * 1994-07-15 2004-09-08 University Of Iowa Research Foundation Immunomodulatorische Oligonukleotide
US5866699A (en) * 1994-07-18 1999-02-02 Hybridon, Inc. Oligonucleotides with anti-MDR-1 gene activity
US5908777A (en) * 1995-06-23 1999-06-01 University Of Pittsburgh Lipidic vector for nucleic acid delivery
DK1005368T3 (da) * 1997-03-10 2010-01-04 Ottawa Hospital Res Inst Anvendelse af nukleinsyrer, der indeholder ikke-metyleret CpG dinukleotid i kombination med alun som hjælpestoffer

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Also Published As

Publication number Publication date
FR2783170A1 (fr) 2000-03-17
NZ510419A (en) 2003-01-31
CA2342313A1 (en) 2000-03-23
US6610308B1 (en) 2003-08-26
FR2783170B1 (fr) 2004-07-16
AU5627899A (en) 2000-04-03
WO2000015256A3 (fr) 2000-07-13
WO2000015256A2 (fr) 2000-03-23
AU749282B2 (en) 2002-06-20

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