WO1992000098A1 - Methodes destinees a provoquer une reponse immunitaire au virus du sida - Google Patents

Methodes destinees a provoquer une reponse immunitaire au virus du sida Download PDF

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Publication number
WO1992000098A1
WO1992000098A1 PCT/EP1991/001225 EP9101225W WO9200098A1 WO 1992000098 A1 WO1992000098 A1 WO 1992000098A1 EP 9101225 W EP9101225 W EP 9101225W WO 9200098 A1 WO9200098 A1 WO 9200098A1
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Prior art keywords
composition
hiv
epitopes
peptides
recombinant
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PCT/EP1991/001225
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English (en)
Inventor
Daniel Zagury
Jean-Claude Imbert
Jean-Jacques Salaun
Lurhuma Zirimwamba
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Daniel Zagury
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Publication of WO1992000098A1 publication Critical patent/WO1992000098A1/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
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4612—B-cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • 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
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
    • C12N2710/24141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16071—Demonstrated in vivo effect
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention provides means of inducing an immune response to viral antigens as a means to protect against infection.
  • the methods of the invention also induce immune response against viral antigens in infected individuals, thereby slowing the progress of the disease.
  • HIV human immuno-deficiency virus
  • AIDS acquired immune deficiency syndrome
  • immunization against the HIV retrovirus is exemplified, such exemplification should not be considered as a limitation on the invention.
  • T 4 lymphocytes is required for viral release. These cells act as the source for expansion, and dissemination of virions in the organisms leading to AIDS.
  • the viral release which leads to death of infected cells is preceded by a stage where HIV signals are present in the cell membrane. This immunogenic stage is important as a trigger for the cellular reaction against HIV. The reaction leads to the destruction of the infected cells.
  • HIV HIV
  • rapid progress in the isolation, cloning, and sequencing of the entire genome has shown the remarkable propensity of the HIV strains to mutate, particularly within the viral envelope gene.
  • viral envelope proteins are often the target for neutralizing antibodies, this extensive variation may play an important role in the interaction between the virus and the host's immune system.
  • rapid mutation is an important means of escape from neutralizing antibodies.
  • Such mutation results in successive waves of influenza epidemics among previously infected populations.
  • For visna virus, a sheep retrovirus, the mutation rate is believed to be so rapid as to allow antibody escape during the course of a single chronic infection.
  • the CD4 binding site of HIV has been mapped to three relatively conserved regions of gpl20. Divergent isolates bind soluble CD4 and are inactivated by it, suggesting conservation of the CD4 binding site. Presumably, if neutralizing anti.bodies were directed against this site or another site responsible for a critical viral function, such antibodies would be active against numerous clinical isolates of the virus. A vaccine capable of eliciting antibodies against a broad spectrum of HIV strains is needed.
  • recombinant virus carrying HIV segments (envelope, gag, or pol).
  • HIV recombinant virus
  • An example of such a recombinant virus is the virus of Moss. Mackett, et al., J. Virol. 49, 857-864.
  • Another method of developing immune response to HIV may be accomplished by incubating autologous cells with synthetic peptides to allow peptides to form complexes with HLA antigens on the cell surface, then fixing the cells by usual methods known in the art, e.g., fixation with paraformaldehyde or glutaraldehyde (Zagury, et al, Nature. 332, pp. 728-731 (1988)).
  • compositions containing only the cell-free membranes from autologous cells that have been incubated with the appropriate peptides or have been infected with virus containing recombinant HIV nucleic acid sequences.
  • sequences to which the autologous cells are exposed are usually from the envelope, gag, or pol proteins.
  • compositions containing "cocktails" of several free peptides representing sequences found in HIV proteins can be added to oils to form an emulsion.
  • These compositions have immunogenic properties and can be administered to individuals either in conjunction with administration of preparations containing treated autologous cells or cell free membranes.
  • the peptidecontaining emulsions can also be administered alone as a means of raising an immune response in the individual
  • the emulsions are administered parenterally, intramuscularly or subcutaneously.
  • compositions of the present invention either alone or in c ⁇ njunction with a protocol that includes use of autologous cells that have been exposed in vitro to HIV antigens, or cell membranes obtained therefrom.
  • the "peptide cocktail" approach allows the use of selected amino acid sequences. These sequences may be chosen from regions of the protein that are conserved across the various strains of the organism. Additionally, peptide sequences from several stra.ins may be chosen so that a broad range of viral strains may be used to give broad group protection against HIV Vairus.
  • the peptides may be prepared by any means known in the art, such as by recombinant means or by the Merrifield process.
  • the process of preparing the peptides by synthetic means provides not only reliability, but also provides certain economic advantages.
  • Peptides should be of about 8 to 40 amino acids, with peptides of 12 to 30 amino acids preferred.
  • protein fragments having molecular weights of over 10,000 can be added to the emulsion or can be given separately from the peptides to stimulate increased antibody response.
  • adjuvants and other additives known in the art may also be added to the peptide-containing emulsions.
  • Some of the larger segments that can be used include gp160, gp41, gp 566 , gp24, reverse trans ⁇ riptase (RT), Tat protein, and protease.
  • peptides from several strains and differing locations in the HIV proteins can be used, particularly preferred sites are listed below:
  • AIDS or ARC aids-related complex patients with 150 - 400 T4 cells per mm 3 were immunized with fixed autologous B cells transformed with EBV (Epstein-Barr Virus) and infected with recombinant vaccinia expressing
  • HIV proteins env, gag, and pol on the surface of infected cells.
  • the fixed cells were given by intravenous slow drip infusion (5-7 ⁇ 10] cells), intramuscularly (10
  • the vaccinia vector used is the non-neurotropio strain Lister and the recombinant is produced by the method of Moss (sea Mackett, supra.)
  • the patients underwent biweekly physical examination. Blood samples were drawn for preparation of serum and cells for biological investigations including virus neutralizing antibody, T4 cell count, cell mediated immunity, and cell mediated cytotoxicity.
  • AIDS or ARC patients with 150 - 400 T4 cells per mm 3 received the preparation described in example 1 in conjunction with AZT (600 mg per day Other conditions were similar to those described in example 1.
  • AIDS or ARC patients with 150 - 400 T4 cells per mm 3 received treatment as described in example 1 along with discontinuous AZT at low doses (600 mg per day for 30 days every 90 days). Other conditions were similar to those described in example 1.
  • AIDS or ARC patients with 150 - 400 T4 cells per mm 3 received a mixture of synthetic HIV peptides comprising peptides which constituted immunodominant sites of env, gag, pol (peptide 342-350 according to Ratner). Immunisation protocols and patient follow up were as described in example 1.
  • Seronegativepatients were treated as described in example 5 except that the synthetic peptides administered ware protectively encapsulated as a water-in-oil emulsion. All other conditions were as described in example 5.
  • Seronegativepatients wore given synthetic peptides as In example 5 except that the peptides were administered as free peptides.
  • Seronegativepatients were given synthetic peptides representing HIV epitopes wherein the peptides were covalently linked to an immuno-enhancing moiety. All other conditions were as described in example 5.
  • Peptide derivatives having hydrophobic groups consisting of tripalmitoyl cysteine, dipalmitoyl lysine, or a non-viral peptide of alpha helix configuration were administered in accord with the protocol used to administer the peptides in example 5.
  • Peptides were administered in accord with example 5. However, the patients were also given recombinant vectors containing HIV nucleic acid sequences at separate sites in conjunction with the peptides.
  • Peptides were given in a composition containing recombinant live vectors containing HIV nucleic acid sequences mixed with the synthetic peptides which represented HIV immunodominant epitopes protectively encapsulated as a water in oil emulsion.
  • the composition was given in the manner described in example 5.
  • Montanide is a product of SEPPIC, a division of Cosmetique-Pharmacie, 70, Champs-Elysees, 75008 Paris, France, and is obtainable therefrom.

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  • Life Sciences & Earth Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Genetics & Genomics (AREA)
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Abstract

Un vaccin sûr et efficace provoque la production d'anticorps agissant contre plusieurs parties du génome du virus de l'immunodéficience humaine (VIH). Un protocole pour l'administration du vaccin permet d'obtenir une réponse immunitaire de façon à protéger la personne contre plusieurs souches du virus VIH. Le protocole d'immunothérapie provoque chez la personne le développement d'une immunité protectrice et bloque la prolifération et la propagation virale du virus VIH chez les personnes contaminées. On décrit également des nouvelles compositions immunogéniques améliorées.
PCT/EP1991/001225 1990-06-29 1991-07-01 Methodes destinees a provoquer une reponse immunitaire au virus du sida WO1992000098A1 (fr)

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US54506490A 1990-06-29 1990-06-29
US545,064 1990-06-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022577A1 (fr) * 1991-06-17 1992-12-23 Neovacs Composes immunogenes a effet notamment anti-cytokine, procede de preparation, compositions pharmaceutiques et kits les renfermant
US7311921B2 (en) * 1995-08-25 2007-12-25 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4384995A (en) * 1980-01-16 1983-05-24 The Ohio State University Antigenic modification of polypeptides
EP0339504A2 (fr) * 1988-04-26 1989-11-02 The Du Pont Merck Pharmaceutical Company Virus d'immunodéficience humaine (HIV) peptide env-codé capable de provoquer les anticorps inhibiteurs du HIV dans les mammifères
EP0346022A1 (fr) * 1988-06-10 1989-12-13 United Biomedical, Inc. Fragments peptidiques du VIH

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4384995A (en) * 1980-01-16 1983-05-24 The Ohio State University Antigenic modification of polypeptides
EP0339504A2 (fr) * 1988-04-26 1989-11-02 The Du Pont Merck Pharmaceutical Company Virus d'immunodéficience humaine (HIV) peptide env-codé capable de provoquer les anticorps inhibiteurs du HIV dans les mammifères
EP0346022A1 (fr) * 1988-06-10 1989-12-13 United Biomedical, Inc. Fragments peptidiques du VIH

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Advances in Veterinary Science and Comparative Medicine, volume 33, Academic Press, Inc., A. Altman et al.: "Immunomodifiers in vaccines", pages 301-343 *
Chemical Abstracts, volume 114, no. 3, 21 January 1991 (Columbus, Ohio, US), M. Loleit et al.: "Conjugates of synthetic lymphocyte-activating lipopeptides with segments from HIV proteins induce protein-specific antibody formation", see page 527, abstract 22025m, & Biol. Chem. Hoppe-Seyler 1990, 371(10), 967-75 *
Nature, volume 326, 19 March 1987, D. Zagury et al.: "Immunization aganst AIDS in humans", pages 249-250, see page 249, third column, last paragraph *
Nature, volume 332, 21 April 1988, D. Zagury et al.: "A group specific anamnestic immune reaction against HIV-1 induced by a candidate vaccine against AIDS", pages 728-731, see page 728, right-hand column *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022577A1 (fr) * 1991-06-17 1992-12-23 Neovacs Composes immunogenes a effet notamment anti-cytokine, procede de preparation, compositions pharmaceutiques et kits les renfermant
US7311921B2 (en) * 1995-08-25 2007-12-25 University Of Florida Research Foundation, Inc. Multi-subtype FIV vaccines

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