WO2021210070A1 - Composition pharmaceutique pour conjonctivite adénovirale - Google Patents

Composition pharmaceutique pour conjonctivite adénovirale Download PDF

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Publication number
WO2021210070A1
WO2021210070A1 PCT/JP2020/016447 JP2020016447W WO2021210070A1 WO 2021210070 A1 WO2021210070 A1 WO 2021210070A1 JP 2020016447 W JP2020016447 W JP 2020016447W WO 2021210070 A1 WO2021210070 A1 WO 2021210070A1
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Prior art keywords
adenovirus
pharmaceutical composition
conjunctivitis
serum
antibody
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PCT/JP2020/016447
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English (en)
Japanese (ja)
Inventor
奥田　研爾
島田　勝
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奥田　研爾
水木 信久
島田　勝
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Application filed by 奥田　研爾, 水木 信久, 島田　勝 filed Critical 奥田　研爾
Priority to PCT/JP2020/016447 priority Critical patent/WO2021210070A1/fr
Priority to JP2020538878A priority patent/JP6816332B1/ja
Publication of WO2021210070A1 publication Critical patent/WO2021210070A1/fr

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a pharmaceutical composition for adenovirus conjunctivitis.
  • Non-Patent Document 1 describes epidemic keratoconjunctivitis. "There is no effective drug for treatment / prevention of adenovirus in general. Anti-inflammatory agents are instilled as a symptomatic treatment, and if the cornea is inflamed and opaque, steroids are instilled. For the possibility, apply antibacterial agents. Pay attention to the handling and disposal of secretions of patients with eye diseases, wash hands and disinfect properly. Be careful not to contaminate eye drops with virus, and contaminate them.
  • the equipment in the hospital is sterilized with an autoclave or disinfected with alcohol, iodine, etc.
  • the basis of prevention is thorough prevention of contact infection. Items that come into contact with the eyes such as towels and eye drops are for personal use. do.” Is explained.
  • An object of the present invention is to provide a highly effective pharmaceutical composition for adenovirus conjunctivitis.
  • the pharmaceutical composition of the present invention is for adenovirus conjunctivitis, which is characterized by containing an anti-adenovirus polyclonal antibody.
  • the pharmaceutical composition is an eye drop, it can be commercialized without being restricted by strict regulations as much as an internal medicine, and is highly practical.
  • the pharmaceutical composition is for the treatment of adenovirus conjunctivitis, it can contribute to the treatment of adenovirus conjunctivitis.
  • the pharmaceutical composition is for the prevention of eyes on the side not infected with adenovirus conjunctivitis, it can contribute to the prevention of adenovirus conjunctivitis.
  • the preventive and therapeutic effects on adenovirus conjunctivitis infection can be confirmed by intraventrally administering adenovirus antibody to mice and measuring the luciferase activity of adenovirus expressing a reporter gene (luciferase) against eye infection. rice field.
  • E1 E3-deficient adenovirus type 5 vectors expressing reporter genes such as green fluorescent protein (GFP) (Ad5-GFP) and luciferase (Ad5-Luci) were constructed. These adenovirus vectors were grown in HEK293 cells and purified by cesium chloride equilibrium density gradient centrifugation. A solution containing 10 mM Tris (pH 7.5), 1 mM MgCl2, and 10% glycerol was dialyzed using a Float-A-Lyzer G2 dialysis machine (MWCO: 20 kD, Spectrum Laboratories Inc.).
  • MWCO Float-A-Lyzer G2 dialysis machine
  • OD 260 1 ⁇ 10 12 virus particles (VP) / mL (formula 1) was calculated from the optical density at 260 nm (OD 260).
  • Anti-adenovirus immune sera were prepared using 8-week-old female ICR mice (Nippon SLC Co., Ltd.). On days 0 and 14, mice were intramuscularly immunized with 10 10 VPs of Ad5, Ad7, Ad8, Ad19 and Ad37, and blood was drawn 3 months after the initial immunization.
  • mice eyes containing the conjunctiva were isolated, washed with PBS to remove blood, and 1.5 mL tube (Eppendorf AG) containing 300 ⁇ L of 1 ⁇ Cell Culture Lysis reagent (Promega Co., Ltd.). Soaked in.
  • Tissues were homogenized with a 1.5 mL microtube pestle for a microcentrifuge tube (Scientific Specialties, Inc.), centrifuged at 8,000 g for 10 minutes, and the supernatant was used for luciferase assay. 4 ⁇ L of cytolysis was mixed with 20 ⁇ L of luciferase assay substrate and luciferase activity was measured with a luminometer.
  • FIG. 1 shows the results for Ad5.
  • the "normal serum” on the horizontal axis is the control group, which is the group of non-immunized serum, the "immunized serum” is the group of the above-mentioned immune serum, and the “1/10 serum” is a 10-fold dilution of the immune serum. It is a group of immune sera, and "1/100 serum” is a group of 100-fold diluted sera.
  • Neutralizing Antibodies It was investigated whether immune sera have a similar ability to inhibit Ad virus infection against other types of adenoviruses such as Ad5, Ad7, Ad8, Ad19 and Ad37 that cause conjunctivitis. A neutralization test was performed.
  • CTL results are shown in FIG. “CTL” on the horizontal axis is a control group (control) of non-immunized normal serum, and “Ad5” to “Ad37” are a group of each adenovirus.
  • the vertical axis shows the neutralizing antibody titer on a logarithmic scale (log2).
  • FIG. 2 shows that immunization of each adenovirus induced a neutralizing antibody titer similar to Ad5 (2 13.4).
  • the results show that the immune sera of Ad7 (2 12.8 ), Ad8 (2 12.5 ), Ad19 (2 11.6 ) and Ad37 (2 13.5 ) have similar capacity for corresponding adenovirus infections. Shown.
  • the pharmaceutical composition containing the anti-adenovirus polyclonal antibody of the present invention has a strong effect on the prevention of adenovirus conjunctivitis.
  • Ad5-specific mouse immune serum Ad5 type vector 10 10 vg three times intramuscularly into mice, and then about 10 days later. Serum obtained by collecting blood, titer: 1: 1,000 was instilled at 50 ⁇ L / eye, 3 times / day.
  • Control Normal serum group
  • the Ad5 titer was determined on A549 cells (human lung cancer cell line) by a standard plaque assay for TCID50 (http://www.virapur.com/protocols/TCID50%20Protocol.pdf).
  • the cotton swab cultures frozen and stored above are serially diluted with DMEM medium supplemented with 2% FBS (fetal bovine serum) and antibiotics and placed in 96-well plates, followed by 3 ⁇ 10 4 A549. Cells / wells were added and the plates were incubated at 37 ° C., 5% CO2 for 10 days. Then the virus titer was calculated.
  • the pharmaceutical composition containing the anti-adenovirus polyclonal antibody of the present invention is effective for the treatment of adenovirus conjunctivitis.
  • serotypes There are more than 51 serotypes and more than 100 genotypes of adenovirus, and there are many types. Respiratory infections are types Ad3 and 7. Pharyngoconjunctivitis, which is called pool fever, mainly develops in types 4, 5, 7, 8, 19, and 37, mainly in type 3. Epidemic keratoconjunctivitis that occurs in summer is also common in types 3, 8, 19, 37, and 54. Types 19 and 37 are infected by sexual activity and cause urethritis and cervicitis.
  • Adenovirus-derived conjunctivitis is the most common conjunctivitis and is the second largest expression after influenza in children and the like, and in that respect, there is a great need as a therapeutic agent and a preventive agent.
  • the above adenoviruses 3,4,8,19 / 64,37,53,54,56 can prevent more than 85% of human adenovirus infections.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'objet de la présente invention est de fournir une composition pharmaceutique efficace contre une conjonctivite adénovirale.　L'invention concerne une composition pharmaceutique contre une conjonctivite adénovirale, contenant un anticorps polyclonal anti-adénovirus. La composition pharmaceutique est une solution ophtalmique. La composition pharmaceutique peut être utilisée dans le traitement d'une conjonctivite adénovirale. La composition pharmaceutique peut être utilisée dans la prévention d'une conjonctivite adénovirale dans un œil non infecté.
PCT/JP2020/016447 2020-04-14 2020-04-14 Composition pharmaceutique pour conjonctivite adénovirale WO2021210070A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP2020/016447 WO2021210070A1 (fr) 2020-04-14 2020-04-14 Composition pharmaceutique pour conjonctivite adénovirale
JP2020538878A JP6816332B1 (ja) 2020-04-14 2020-04-14 アデノウイルス結膜炎に対する医薬組成物

Applications Claiming Priority (1)

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PCT/JP2020/016447 WO2021210070A1 (fr) 2020-04-14 2020-04-14 Composition pharmaceutique pour conjonctivite adénovirale

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012526075A (ja) * 2009-05-04 2012-10-25 リボバックス バイオテクノロジーズ ソシエテ アノニム 眼疾患を処置または診断する際に使用するための抗体の抗原結合フラグメント

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012526075A (ja) * 2009-05-04 2012-10-25 リボバックス バイオテクノロジーズ ソシエテ アノニム 眼疾患を処置または診断する際に使用するための抗体の抗原結合フラグメント

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KITAICHI, NOBUYOSHI ET AL.: "The evaluation of a newly developed rapid diagnosis kit of human adenovirus by immunochromatography labeled platinum-gold colloids", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 237, no. 2, 2011, pages 210 - 214 *
YOKOTA, TOMOYUKI: "An Immunoepidemiological Study of Neutralizing Antibody against Adenovirus Type-3 in Children of Primary Schools Which had Experienced Outbreaks of Pharyngoconjunctival Fever", JOURNAL OF JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES, vol. 41, 1968, pages 245 - 251 *

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JPWO2021210070A1 (fr) 2021-10-21
JP6816332B1 (ja) 2021-01-20

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