WO1999053947A1 - PROMOTEURS DE LA MIGRATION DE Th2 CONTENANT DES EMULSIONS EAU-DANS-HUILE - Google Patents

PROMOTEURS DE LA MIGRATION DE Th2 CONTENANT DES EMULSIONS EAU-DANS-HUILE Download PDF

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Publication number
WO1999053947A1
WO1999053947A1 PCT/JP1999/002008 JP9902008W WO9953947A1 WO 1999053947 A1 WO1999053947 A1 WO 1999053947A1 JP 9902008 W JP9902008 W JP 9902008W WO 9953947 A1 WO9953947 A1 WO 9953947A1
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WO
WIPO (PCT)
Prior art keywords
emulsion
cells
helper
antigen
oil
Prior art date
Application number
PCT/JP1999/002008
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English (en)
Japanese (ja)
Inventor
Kazuyoshi Masuda
Kazutoshi Horie
Ryuji Suzuki
Original Assignee
Shionogi & Co., Ltd.
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 Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU33442/99A priority Critical patent/AU3344299A/en
Priority to JP2000544350A priority patent/JP4375773B2/ja
Publication of WO1999053947A1 publication Critical patent/WO1999053947A1/fr

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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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2

Definitions

  • Th1 Th1 type
  • Th2 Th2 type
  • Th1 helper T cells
  • Autoimmune diseases eg, organ-specific autoimmune diseases, etc.
  • allergic diseases, organ transplant rejection, etc. are hyperimmune reactions to endogenous or foreign antigens, and these diseases are immune to self or non-self.
  • Medications are mainly used as treatments for these diseases.
  • immunosuppressants cause non-specific immunosuppression, and are accompanied by serious side effects such as concurrent infection and the development of malignant tumors.
  • antiallergic agents and the like are simply used as symptomatic treatments.
  • specific immunotherapy such as desensitization therapy has been attempted, but the mechanism of action is unknown in many parts, and it is hard to say that it is an established treatment method.
  • oral tolerance oral tolerance
  • a method for treating the above-mentioned diseases using oral tolerance induced by orally administering a substance that induces the proliferation of regulatory cells that secrete inhibitory cytokines such as TGF- ⁇ , which is called bystander antigen, W093 / 16724, WO96 / 40232, Tokuhyo Hei 8-504745, etc.
  • TGF- ⁇ regulatory cells that secrete inhibitory cytokines
  • bystander antigen W093 / 16724, WO96 / 40232, Tokuhyo Hei 8-504745, etc.
  • these emulsions do not contain antigens, and no changes in ThlZTh2 balance when administered orally are discussed.
  • Thl-Th2 balance in the immune response, and particularly by promoting the transition to Th2 and preferably reaching a Th2-biased state, various diseases related to the Thl / Th2 balance are considered.
  • Methods for efficiently preventing or treating pneumonia have not been sufficiently studied. Disclosure of the invention
  • the present inventors have conducted intensive studies and found that administration of various antigens in a water-in-oil emulsion (W / 0 emulsion) facilitates the transfer of ThlZTh2 balance of helper T cells to Th2.
  • W / 0 emulsion water-in-oil emulsion
  • An agent for promoting the transfer of helper T cells to Th2, comprising a W / 0 emulsion containing an antigen.
  • the value of the antibody titer ratio represented by "IgGl / IgG2a" at the time of oral administration to mice is about twice or more as compared with the case where the control antigen-containing physiological saline is administered.
  • Fig. 4 is a graph showing the total Ig anti-titer titer against OVA of the serum collected on day 21 after oral administration of ovalbumin (OVA) -containing W / 0 emulsion to mice daily for 5 days and subcutaneous immunization with OVA. See Example 1).
  • OVA ovalbumin
  • FIG. 9 is a graph showing the antibody titer to OVA (IgGl / IgG2a) of serum collected on day 21 after subcutaneous immunization with OVA after oral administration of ovalbumin (OVA) -containing W / 0 emulsion to mice daily for 5 days. (See Example 1).
  • the antibody titer to OVA (IgGl / IgG2a) of the serum collected on day 21 after oral administration of ovalbumin (OVA) -containing W / 0 microemulsion to mice daily for 5 days and subcutaneous immunization with OVA is shown. It is a graph (refer to Example 3).
  • 7 is a graph showing a change in the cumulative number of seconds of behavior: average value of 5 to 6 cases (see Example 4).
  • отки can be used in the present invention.
  • Margillon may be used. Its size is usually about 0.001 to 100 ⁇ .
  • aqueous phase water or any buffer of weakly acidic, neutral, or weakly basic can be used, and gelatin or the like is used for stabilization.
  • the aqueous phase may be solidified.
  • oils or waxes may be used alone or in combination as the oil layer.
  • oils vegetable oils, animal oils, fatty acid esters and the like exemplified below can be used.
  • (Vegetable oil) Hardened castor oil, pine nut oil, castor seed oil, almond oil, jojoba oil, peanut oil, coconut oil, palm oil, safflower oil, kukui oil, malt oil, grape seed oil, rapeseed oil, corn oil Olive oil, cottonseed oil, apogado oil, camellia oil, corn oil, wheat germ oil, rice oil, cocoa butter, sesame oil, evening primrose oil, southern oil, and the like, but preferably sesame oil.
  • waxes examples include vegetable wax and animal wax, preferably carnauba wax, beeswax and whale wax.
  • the emulsion of the present invention may optionally contain pharmaceutically acceptable additives such as surfactants, alcohols, fatty acids, polysaccharides, preservatives, ⁇ regulators, viscosity modifiers, and the like.
  • pharmaceutically acceptable additives such as surfactants, alcohols, fatty acids, polysaccharides, preservatives, ⁇ regulators, viscosity modifiers, and the like.
  • the surfactant ionic or nonionic surfactants can be used alone or in combination.
  • the HLB value is 2 to 20.
  • the surfactant is not a necessary component for promoting the transfer to Th2, but is preferably added in view of the stability of the emulsion and the like.
  • the amount of the surfactant is usually about 1 to 75% by weight, preferably about 1 to 30% by weight, based on the whole oil phase.
  • the antigen contained in the aqueous phase of the W / 0 emulsion according to the present invention may be any substance that has high water solubility and can cause an immune reaction in a living body. Examples of the antigen include proteins, peptides, and glycoproteins. Although it can be used, it is preferably a protein or a peptide.
  • ovalbumin OVA
  • cytokeratin type I collagen
  • type II collagen type IV collagen
  • transgluminase myelin basic protein
  • insulin glucagon
  • S-antigen MHC
  • MHC MHC
  • the antigen content varies depending on the type of antigen, target disease, route and timing of administration, and cannot be unconditionally specified, but is usually about 0.001 to 20% by weight based on the total amount of the aqueous phase, preferably Is about 0.001 to 10% by weight.
  • the method for producing the emulsion is not particularly limited, but is carried out, for example, as follows. That is, a mixture comprising an antigen, an aqueous phase component, and an oil phase component is mixed, if necessary, while heating, subjected to ultrasonic treatment for several minutes to several tens of minutes, and then cooled on ice. Alternatively, a method such as shaking the mixture at room temperature may be used.
  • the ThlZTl ⁇ balance is determined by determining the ratio of each antibody titer of IgG2a, which is an antibody produced by TM activation, and IgGl, produced by Th2 activation, as shown in the following test examples.
  • IgG2a which is an antibody produced by TM activation
  • IgGl produced by Th2 activation
  • the promotion of the transfer to Th2 by this preparation means a change in the Thl / Th2 balance of the immune response system in which the proportion of Thl decreases and the proportion of Th2 increases, and preferably the proportion of Th2 Means the change to the Th2 deflection state.
  • ThlZTh2 balance-related diseases especially for autoimmune diseases thought to be due to a Thl-dominant immune response (eg, multiple sclerosis, rheumatoid arthritis, reactive arthritis, psoriasis, juvenile diabetes, chronic thyroid gland) Inflammation, uveitis, etc.), various allergic diseases mediated by or dependent on T cells (eg, contact dermatitis, etc.), or as a preventive or therapeutic agent for rejection during organ transplantation. is there.
  • Thl-dominant immune response eg, multiple sclerosis, rheumatoid arthritis, reactive arthritis, psoriasis, juvenile diabetes, chronic thyroid gland
  • Inflammation uveitis, etc.
  • various allergic diseases mediated by or dependent on T cells eg, contact dermatitis, etc.
  • preventive or therapeutic agent for rejection during organ transplantation is there.
  • atopic dermatitis may involve a Th2-dominant immune response depending on the disease state, and may activate Th2 cells to inhibit cytokines (IL-4, (IL-10, TGF-3, etc.) is secreted, etc., so that the prophylactic or therapeutic effect of this formulation can be expected.
  • the route of administration of this formulation is not particularly limited.For example, one of the concomitant effects of using this formulation is expected to be the induction of immune tolerance induced through mucosa-associated lymphoid tissue (MALT).
  • transmucosal administration such as oral administration, nasal administration, or pulmonary administration is performed, and oral administration is preferred.
  • Example 1 oral administration of ovalbumin-containing W / 0 emulsion
  • ovalbumin As an antigen protein, 7 volumes of aqueous phase ⁇ OVA-containing aqueous solution (0.269-26.9 mg / ml) ⁇ and 40 volumes of oil phase ⁇ 6.7% (w / w) SO-15 ( Nikko Chemical), 1.7% (w / w) HCO-60 (Nikko Chemical) -containing sesame oil at 50, sonicate (300 W, 26 kHz, 50:, 1 min) and cool on ice. 0VA containing W / 0 emulsion John was prepared. The final OVA concentration in the emulsion was between 0.04 and 4 mg / mi.
  • OVA ovalbumin
  • the particle size distribution of the emulsion was measured by GALAI CIS-1 and had a particle size of 50-60 mm.
  • Oral administration (0-1 mg OVA equivalent / mouse / day, day 0-4) of W / 0 emulsion containing OVA or OVA saline solution to BALB / c mice (6 W, male) for 5 consecutive days and complete OVA Freund Subcutaneous immunization (25 g / mouse, day 8) was performed on hind limbs and feet together with adjuvant (FCA (H37Ra), DIFCO), and serum antibody titers (total IgG, IgGK, IgGK) against OVA 21 days after immunization (day 29) IgG2a) was examined by enzyme-linked immunosorbent assay (ELISA).
  • mice treated with 1 mg / mouse / day the total IgG antibody titers of the W / 0 emulsion and the saline solution were almost the same.
  • the W / 0 emulsion had the same total IgG antibody titer as the 1 mg / mouse / day group, and the W / 0 emulsion was consumed on a live basis. It was confirmed that the serum total IgG antibody titer against OVA was significantly lower than that of the solution (P ⁇ 0.05). That is, this preparation induced immunological tolerance.
  • the ratio of the IgGl antibody titer (average value of 4-5 cases) to the IgG2a antibody titer (average value of 4-5 cases) was higher in the mice administered with the OVA-containing W / 0 emulsion than in the mice administered the 0VA saline solution (IgGl / IgG2a). ) was about twice as high.
  • the ratio of IgGlZIgG2a also increased as the OVA content increased. That is, this preparation promoted the transfer of helper T cells to Th2.
  • Example 2 oral administration of type II collagen-containing W / 0 emulsion
  • CII type II collagen
  • 7 volumes of aqueous phase CII-containing salt
  • An acid (0.001N) solution 0.269-2.69 mg / ml and 40 volumes of oil phase ⁇ 6.7% (w / w) SO-15, 1.73 ⁇ 4 (w / w) sesame oil containing HCO-60) are mixed at 50, C / I containing W / 0 emulsion was prepared by sonication (300 W, 26 kHz, 50:, 1 min) followed by ice-cooling
  • the final concentration of CII in the emulsion was 0.04 to 0.4 mg / ml.
  • the particle size distribution of the emulsion was measured by GALAI CIS-1 and had a particle diameter of 50 to 60 mm.
  • Water / emulsion containing CII or a solution of CII hydrochloric acid (0.001N) was added to BALB / c mice (6W, Male) for 5 days orally (0-0.1 mg CII equivalent / mouse / day, day 0-4) and then subcutaneously immunize CII with FCA (H37Ra) on hind limb foot (100 g / mouse, day 8) Then, the serum antibody titer (total IgG, IgGK IgG2a) against CII on day 21 after immunization was examined by enzyme immunoassay (ELISA).
  • ELISA enzyme immunoassay
  • the total IgG antibody titer decreased by the same degree in both the W / 0 emulsion and the hydrochloric acid (0.001N) solution, but in the mice treated with 0.01 mg / mouse / day in emulsion.
  • the total IgG antibody titer was as low as in the group administered with a 10-fold amount of hydrochloric acid (0.001N) solution. As shown in Fig.
  • mice administered with the CII-containing W / 0 emulsion received a IgGl antibody titer (5 to 6 subjects) relative to the IgG2a antibody titer (average of 5 to 6 animals) compared to the mice administered the CII-containing hydrochloric acid (0.001N) solution.
  • the ratio (IgGl / IgG2a) was about twice as high, indicating a Th2 dominant tendency.
  • the ratio of IgG1 to IgG2a increased as the CII content increased.
  • Example 3 oral administration of W / 0 microemulsion containing ovalbumin
  • Example 2 The same operation as in Example 1 was performed, and a serum antibody titer against 0 VA (total IgG, IgGK IgG2a) on day 21 after immunization of BALB / c mice orally administered with a 0 VA-containing W / 0 microemulsion or a 0 VA saline solution was administered.
  • the enzyme immunoassay (ELISA) Investigated by
  • mice treated with 1 mg / mouse / day both the W / 0 microemulsion and the saline solution reduced the total IgG antibody titer to the same extent.
  • the mice treated with 0.1 ing / mouse / day only the W / 0 microemulsion reduced the total IgG antibody titer to the same extent as in the group treated with 1 mg / mouse / day.
  • the mice administered with the OVA-containing W / 0 microemulsion had a 5-to 10-fold higher IgGl / IgG2a ratio than the mice administered with the OVA saline solution, and showed a tendency to be superior to Th2. This trend increased with increasing OVA content in the W / 0 microemulsion.
  • Example 4 oral administration of cytokeratin-containing W / 0 emulsion
  • Cytokeratin (CK) purified from pig skin by anion exchange chromatography was used as the antigen protein. It was confirmed by immunoblotting that at least the cytokeratins Nos. 4, 5, 7, 8, 17, and 18 were contained in this purified product.
  • the final concentration of CK was 0.04 ing / ml
  • the particle size distribution of the emulsion was measured by GALAI CIS-1 and had a particle size of 50 to 60 mm DS / Nh of this CK-containing W / 0 emulsion
  • Therapeutic effects of spontaneous dermatitis in mice were investigated.Experiment was conducted by rearing 4-week-old DS / Nh mice () in a conventional environment for 12 weeks.
  • This preparation is useful for treating various diseases related to the Tl / Th2 balance of helper T cells, such as autoimmune diseases and allergic diseases, and for suppressing rejection during organ transplantation.

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Transplantation (AREA)
  • Pulmonology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Promoteurs de migration de Th2 pour des lymphocytes T auxiliaires caractérisés par le fait qu'ils contiennent des émulsions eau-dans-huile comprenant différents antigènes développés en fonction d'une recherche ayant déterminé que la migration des lymphocytes T auxiliaires dans Th2 peut être favorisée par l'administration orale ou à travers les muqueuses de différents antigènes sous forme d'émulsions eau-dans-huile. Ces préparations sont utiles pour traiter différentes maladies dans lesquelles l'équilibre Th1/Th2 des lymphocytes T auxiliaires jouent un rôle, par exemple, des maladies autoimmunes et des maladies allergiques.
PCT/JP1999/002008 1998-04-20 1999-04-15 PROMOTEURS DE LA MIGRATION DE Th2 CONTENANT DES EMULSIONS EAU-DANS-HUILE WO1999053947A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU33442/99A AU3344299A (en) 1998-04-20 1999-04-15 Th2-migration promoters containing w/o emulsions
JP2000544350A JP4375773B2 (ja) 1998-04-20 1999-04-15 Ｗ／Ｏエマルジョンを含有するＴｈ２移行促進剤

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JP10/109517 1998-04-20
JP10951798 1998-04-20

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WO1999053947A1 true WO1999053947A1 (fr) 1999-10-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007511493A (ja) * 2003-11-14 2007-05-10 ユーシーエル バイオメディカ ピーエルシー 免疫調節物質
US8178102B2 (en) 2005-01-19 2012-05-15 Dainippon Sumitomo Pharma Co., Ltd. Emulsified composition for dilution and cancer vaccine composition
JP2016501709A (ja) * 2012-10-24 2016-01-21 カーギル インコーポレイテッド リン脂質含有乳化剤組成物
JP2016128514A (ja) * 2009-08-12 2016-07-14 シグモイド・ファーマ・リミテッドＳｉｇｍｏｉｄ Ｐｈａｒｍａ Ｌｉｍｉｔｅｄ ポリマーマトリックスおよび油相を含んで成る免疫調節組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996017863A1 (fr) * 1994-12-07 1996-06-13 Idec Pharmaceuticals Corporation Obtention de reactions lymphocytaires t cytotoxiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996017863A1 (fr) * 1994-12-07 1996-06-13 Idec Pharmaceuticals Corporation Obtention de reactions lymphocytaires t cytotoxiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007511493A (ja) * 2003-11-14 2007-05-10 ユーシーエル バイオメディカ ピーエルシー 免疫調節物質
JP4875494B2 (ja) * 2003-11-14 2012-02-15 ユーシーエル バイオメディカ ピーエルシー 免疫調節物質
US8178102B2 (en) 2005-01-19 2012-05-15 Dainippon Sumitomo Pharma Co., Ltd. Emulsified composition for dilution and cancer vaccine composition
JP2016128514A (ja) * 2009-08-12 2016-07-14 シグモイド・ファーマ・リミテッドＳｉｇｍｏｉｄ Ｐｈａｒｍａ Ｌｉｍｉｔｅｄ ポリマーマトリックスおよび油相を含んで成る免疫調節組成物
JP2016501709A (ja) * 2012-10-24 2016-01-21 カーギル インコーポレイテッド リン脂質含有乳化剤組成物

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JP4375773B2 (ja) 2009-12-02

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