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WO1992004909A1 - Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation - Google Patents

Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation Download PDF

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Publication number
WO1992004909A1
WO1992004909A1 PCT/GB1991/001627 GB9101627W WO9204909A1 WO 1992004909 A1 WO1992004909 A1 WO 1992004909A1 GB 9101627 W GB9101627 W GB 9101627W WO 9204909 A1 WO9204909 A1 WO 9204909A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
hiv
polyanionic
virus
effective dose
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.)
Ceased
Application number
PCT/GB1991/001627
Other languages
English (en)
Inventor
Donald Selwyn Davies
Jonathan Norden Weber
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.)
Innovata Ltd
Original Assignee
ML Laboratories PLC
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 ML Laboratories PLC filed Critical ML Laboratories PLC
Priority to JP3515281A priority Critical patent/JPH06502846A/ja
Priority to AU86127/91A priority patent/AU653962B2/en
Publication of WO1992004909A1 publication Critical patent/WO1992004909A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This invention relates to pharmaceutically active compositi and to their use as agents against human immunodeficiency vi and related viruses.
  • the HIV infection cycle includes a number of steps, each of th steps being a possible target for the use of chemotherapy hinder the infection.
  • the first step in the infection cycle the attachment of the HIV virus to the host cell.
  • the m receptor for the virus is believed to be the cell surf glycoprotein, designated CD4, which is present in some lymphocytes and in some macrophages. Much attention therefore been given to identifying agents which are capable blocking attachment of the virus to CD4.
  • statin CD4 made by genetic engineering, can block attachment of H virus to cellular CD4, thereby inhibiting HIV infection in vitr
  • CD4-li materials capable of binding to gpl20, such as CD4-Ig immunoadhesins, CD4 V1-V2 domains, and CD4-derived peptides, ha also been proposed as anti-HIV agents.
  • CD4-Ig immunoadhesins CD4 V1-V2 domains
  • CD4-derived peptides ha also been proposed as anti-HIV agents.
  • the performan of CD4 and CD4-like materials in preventing the HIV virus fr binding to cells has until now been disappointing, a much high concentration of the agent being necessary than had been hoped.
  • anti-HIV agents which block attachment of the virus cells are a number of polyanionic compounds which include Eva Blue, aurintricarboxylic acid (ATA), suramin, and certai sulphated polysaccharides. It might have been thought that i CD4 and such polyanionic anti-HIV agents were use simultaneously, the total anti-HIV activity would at best be th sum of their separate activities.
  • CD4 which is used here an below, except where otherwise indicated, to include both CD4 an CD4-like materials
  • a polyanionic anti-HIV agent such as a sulphated polysaccharide
  • the invention provides an agent against HIV an related viruses, in dosage unit form, comprising CD4 or a CD4 like material and a polyanionic anti-HIV agent the content of CD and CD4-like material in the agent being less than the anti virally effective dose of the CD4 or CD4-like material alone.
  • the agent according to the invention may contain substantiall less CD4 than the anti-virally effective dosage of CD4 alo i.e. in the absence of a polyanionic anti-HIV agent.
  • reduction in the amount of CD4 required to achieve the same an viral effect as for CD4 alone may be such that less than o tenth (or, in favourable cases, less than one-hundredth) of amount of CD4 is needed.
  • the invention offers possibility of using CD4 as a component of an anti-HIV agent i reduced and therefore safer and more economical amount than previously been feasible.
  • the agent according to the invention may also contain less t the normally effective dose of the polyanionic compound. This advantageous because many of the known polyanionic anti- agents are significantly toxic. For example, sulphat polysaccharides have anti-coagulant activity. When t polyanionic anti-HIV agent is a sulphated polysaccharide, it m be present in the compositions of the invention in an amou which is less than that which would be required in an anti-H agent containing only the sulphated polysaccharide.
  • compositions of the invention which conta sulphated polysaccharides may have a lower level of ant coagulant activity attributable to the sulphated polysacchari content than those previously known.
  • the polyanionic anti-HIV agents used in the present invention a preferably sulphated polysaccharides. They include, for exampl dextran sulphate, pentosan polysulphate, fucoidan, and dextr sulphate. Other sulphated polysaccharides having anti-H activity (see, for example, EP specifications No's 240,098 a 293,826) may also be used.
  • the sulphat polysaccharide contains at least one sulphate group p saccharide unit.
  • the anti-HIV agent of the invention may administered enterally (including orally) or parenteral (including intravenously).
  • administration via t peritoneum may be more effective in that it results in entry at least some of the anti-HIV agent directly into the lymphat system, within which system viral replication may be extensive.
  • the invention also provides the use of the agent described abo against HIV-1 and relates viruses, the agent preferably bei administered peritoneally.
  • the invention provides a pharmaceutical compositi containing the anti-HIV agent of the invention together with inert carrier or diluent and the agent of the invention for u in the manufacture of a pharmaceutical composition against HIV and related viruses.
  • the invention additionally provides a method of treatment of human or animal subject carrying the HIV-1 virus or a rela virus, comprising administering to the subject a pharmaceutica effective amount of the agent of the invention.
  • the CD4 or CD4-like material and the polyanionic anti-HIV ag may be administered to a subject one after the other, in order although preferably with the CD4 or CD4-like mater being administered before the polyanionic agent, when u against HIV-1 or a related virus.
  • the invention thus provides CD4 or a CD4-like material, of amount less than its usual anti-virally effective dose, and polyanionic anti-HIV agent, for use in a method of treatment of human or animal subject carrying the HIV-1 virus or a relat virus in whic the CD4 or CD4-like material are administered the subject one after the other.
  • T dextrin sulphate was produced by sulphation of a dextrin weight average molecular weight of about 20,000 daltons, using sulphur trioxide/trimethylamine complex, the degree substitution being approximately one sulphate group per gluco unit.
  • the srCD4 was produced in a baculo virus system and w purchased from American Biotechnology Inc.
  • Example 1
  • T srCD4/HIV-l was then added to the dextrin sulphate pre-treat M8166 cells, and the plates read at 48 - 72 hours for t presence of syncytia, shown in the table below by +.
  • srCD4 inhibited HIV infection of M8166 cells at 6 ug/ml (final concentration).
  • dextrin sulphate inhibited HIV-1 infecti of M8166 cells at 5-10 ug/ml.
  • 2 - 5.0 ug/ml of dextrin sulphate inhibited HIV-1 infection in t presence of srCD4 at a concentration of 0.05 - 0.09 ug/ml.
  • Th represents a 10 ⁇ reduction in the quantity of srCD4 required prevent HIV-1 infection, and shows that the effect of the t drugs together is synergistic rather than simply additive.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention se rapporte à un agent anti-VIH et virus apparentés, sous forme pharmaceutique unitaire, comprenant la glycoprotéine de surface cellulaire CD4 ou une substance similaire à CD4 et un agent polyanionique anti-VIH, la quantité de CD4 ou de substance similaire à CD4 dans l'agent étant inférieure à la dose anti-virale efficace de CD4 ou de substance similaire seule. On a découvert que, quand on utilise CD4 ou la substance similaire avec un agent polyanionique anti-VIH, la combinaison est plus efficace contre l'infection par VIH que ce ne serait le cas si l'effet anti-viral était uniquement additif.
PCT/GB1991/001627 1990-09-25 1991-09-23 Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation Ceased WO1992004909A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP3515281A JPH06502846A (ja) 1990-09-25 1991-09-23 Ｃｄ４及び抗ｈｉｖポリアニオン剤からなる薬剤組成体及びその利用方法
AU86127/91A AU653962B2 (en) 1990-09-25 1991-09-23 Pharmaceutical composition comprising CD4 and a polyanionic anti-HIV agent and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909020872A GB9020872D0 (en) 1990-09-25 1990-09-25 Pharmaceutical compositions and use thereof
GB9020872.9 1990-09-25

Publications (1)

Publication Number Publication Date
WO1992004909A1 true WO1992004909A1 (fr) 1992-04-02

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PCT/GB1991/001627 Ceased WO1992004909A1 (fr) 1990-09-25 1991-09-23 Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation

Country Status (10)

Country Link
EP (1) EP0550529A1 (fr)
JP (1) JPH06502846A (fr)
AU (1) AU653962B2 (fr)
CA (1) CA2092093A1 (fr)
GB (1) GB9020872D0 (fr)
IE (1) IE913341A1 (fr)
NZ (1) NZ239909A (fr)
PT (1) PT99058B (fr)
WO (1) WO1992004909A1 (fr)
ZA (1) ZA917596B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021943A1 (fr) * 1992-05-07 1993-11-11 M.L. Laboratories Plc Agent antiviral comprenant la proteine cd4 et une histone h2
US5272261A (en) * 1989-01-11 1993-12-21 Merrell Dow Pharmaceuticals Inc. Preparation of sulfated polysaccharide fractions
FR2838649A1 (fr) * 2002-04-19 2003-10-24 Commissariat Energie Atomique Composition anti-vih, procede de fabrication et medicament

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293826A2 (fr) * 1987-06-02 1988-12-07 Stichting REGA V.Z.W. Application thérapeutique et prophylactique des polysaccharides sulfatés contre le SIDA
EP0332952A2 (fr) * 1988-03-12 1989-09-20 BASF Aktiengesellschaft Combinaisons d'héparines polysulfatées pour combattre les infections rétrovirales
WO1989011860A1 (fr) * 1988-06-10 1989-12-14 Biogen, Inc. Combinaisons de proteines t4 solubles et d'agents anti-retroviraux, ainsi que procedes pour traiter ou prevenir l'infection par le sida, l'arc et le vih
WO1990000596A1 (fr) * 1988-07-07 1990-01-25 The Trustees Of The University Of Pennsylvania Procede de modulation d'interactions entre des cellules hotes et un virus par l'utilisation d'hydrates de carbone et de derives d'hydrates de carbone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293826A2 (fr) * 1987-06-02 1988-12-07 Stichting REGA V.Z.W. Application thérapeutique et prophylactique des polysaccharides sulfatés contre le SIDA
EP0332952A2 (fr) * 1988-03-12 1989-09-20 BASF Aktiengesellschaft Combinaisons d'héparines polysulfatées pour combattre les infections rétrovirales
WO1989011860A1 (fr) * 1988-06-10 1989-12-14 Biogen, Inc. Combinaisons de proteines t4 solubles et d'agents anti-retroviraux, ainsi que procedes pour traiter ou prevenir l'infection par le sida, l'arc et le vih
WO1990000596A1 (fr) * 1988-07-07 1990-01-25 The Trustees Of The University Of Pennsylvania Procede de modulation d'interactions entre des cellules hotes et un virus par l'utilisation d'hydrates de carbone et de derives d'hydrates de carbone

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5272261A (en) * 1989-01-11 1993-12-21 Merrell Dow Pharmaceuticals Inc. Preparation of sulfated polysaccharide fractions
US5861383A (en) * 1989-01-11 1999-01-19 Merrell Pharmaceuticals Inc. Sulfated polysaccharide fractions having anti-HIV activity
WO1993021943A1 (fr) * 1992-05-07 1993-11-11 M.L. Laboratories Plc Agent antiviral comprenant la proteine cd4 et une histone h2
FR2838649A1 (fr) * 2002-04-19 2003-10-24 Commissariat Energie Atomique Composition anti-vih, procede de fabrication et medicament
WO2003089000A3 (fr) * 2002-04-19 2004-04-08 Commissariat Energie Atomique Composition anti-vih, comprenant un polyanion et un agent agissant sur gp120 de acon equivalent au cd4
US7494975B2 (en) 2002-04-19 2009-02-24 Commissariat A L'energie Atomique Anti-HIV composition, production method thereof and medicament

Also Published As

Publication number Publication date
IE913341A1 (en) 1992-02-25
AU653962B2 (en) 1994-10-20
PT99058A (pt) 1992-08-31
NZ239909A (en) 1993-02-25
PT99058B (pt) 1999-02-26
ZA917596B (en) 1992-05-27
AU8612791A (en) 1992-04-15
EP0550529A1 (fr) 1993-07-14
JPH06502846A (ja) 1994-03-31
CA2092093A1 (fr) 1992-03-26
GB9020872D0 (en) 1990-11-07

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