CA2288222A1 - Oligonucleotide mediated specific cytokine induction and in vivo protection from infection - Google Patents

Oligonucleotide mediated specific cytokine induction and in vivo protection from infection Download PDF

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Publication number
CA2288222A1
CA2288222A1 CA002288222A CA2288222A CA2288222A1 CA 2288222 A1 CA2288222 A1 CA 2288222A1 CA 002288222 A CA002288222 A CA 002288222A CA 2288222 A CA2288222 A CA 2288222A CA 2288222 A1 CA2288222 A1 CA 2288222A1
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Prior art keywords
mammal
phosphodiester
phosphorothioate
oligonucleotide
region
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Granted
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CA002288222A
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French (fr)
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CA2288222C (en
Inventor
Sudhir Agrawal
Qiuyan Zhao
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Aceragen Inc
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    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/15—Nucleic acids forming more than 2 strands, e.g. TFOs
    • C12N2310/151—Nucleic acids forming more than 2 strands, e.g. TFOs more than 3 strands, e.g. tetrads, H-DNA
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/18—Type of nucleic acid acting by a non-sequence specific mechanism
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/345—Spatial arrangement of the modifications having at least two different backbone modifications

Abstract

The invention provides methods for modulating specific CMI-inducing cytokines in vivo. Such methods result in stimulation of the cytokines IL-6, IL-12 MIP-1.beta. and MCP without substantially inducing undesired cytokines. The methods according to the invention are based upon administration of oligonucleotides containing particular structural motifs which lead to specific cytokine induction.

Claims (9)

1. A method for elevating serum levels of IL-12 in a mammal, including a human, the method comprising measuring a baseline level of IL-12 in the mammal, administering to the mammal an oligonucleotide having a structural motif which induces IL-12 expression in vivo, and measuring the level of IL-12 in the mammal after such administration, wherein the level of IL-12 measured after such administration is higher than the level of IL-12 measured before such administration.
2. The method according to claim 1, wherein the oligonucleotide has the nucleotide sequence N n1,-Nn2-CpG-Nn3-N n4, wherein N represents any nucleoside, n1 and n4 each independently represent a number from 0 to 50, n2 represents a number from 0 to 50 and n3 represents a number from 0 to 50 such that n2 + n3 equals from about 6 to about 100, wherein the underlined region represents a nucleoside phosphodiester or phosphorothioate region or a mixed backbone region having phosphodiester and phosphorothioate nucleosides, wherein CpG represents a cytosine-guanosine dinucleoside phosphorothioate or phosphodiester dinucleoside, wherein the cytosine has a cytidine base having an unmethylated 5-position, and wherein at least one of n1, n2, n3 and n4 comprises four contiguous guanosine nucleosides.
3. A method for elevating expression of IL-12 mRNA in a mammal, the method comprising measuring a baseline level of IL-12 mRNA in cells from the mammal, administering to the mammal an oligonucleotide having a structural motif which induces IL-12 expression in vivo, and measuring the level of IL-12 mRNA in cells from the mammal after such administration, wherein the level of IL-12 mRNA measured after such administration is higher than the level of IL-mRNA measured before such administration.
4. A method for prophylactically protecting a mammal from infection by a pathogen, the method comprising administering to a mammal which is not expressing symptoms of infection by the pathogen an oligonucleotide having a structural motif which induces IL-12 expression in vivo in an amount and for a time sufficient to prevent successful infection by the pathogen.
5. The method according to claim 4, wherein the oligonucleotide has the nucleotide sequence N n1-Nn2-CpG-Nn3-N n4, wherein N represents any nucleoside, n1 and n4 each independently represent a number from 0 to 50, n2 represents a number from 0 to 50 and n3 represents a number from 0 to 50 such that n2 + n3 equals from about 6 to about 100, wherein the underlined region represents a nucleoside phosphodiester or phosphorothioate region or a mixed backbone region having phosphodiester and phosphorothioate nucleosides, wherein CpG represents a cytosine-guanosine dinucleoside phosphorothioate or phosphodiester dinucleoside, wherein the cytosine has a cytidine base having an unmethylated 5-position, and wherein at least one of n1, n2, n3 and n4 comprises four contiguous guanosine nucleosides.
6. A method for therapeutically treating a mammal which is infected by a pathogen, the method comprising administering to the infected animal an oligonucleotide having a structural motif which induces IL-12 expression in vivo in an amount and for a time sufficient to eliminate or reduce symptoms of infection by the pathogen.
7. The method according to claim 6, wherein the oligonucleotide has the nucleotide sequence N n1-Nn2-CpG-Nn3-N n4, wherein N represents any nucleoside, n1 and n4 each independently represent a number from 0 to 50, n2 represents a number from 0 to 50 and n3 represents a number from 0 to 50 such that n2 + n3 equals from about 6 to about 100, wherein the underlined region represents a nucleoside phosphodiester or phosphorothioate region or a mixed backbone region having phosphodiester and phosphorothioate nucleosides, wherein CpG represents a cytosine-guanosine dinucleoside phosphorothioate or phosphodiester dinucleoside, wherein the cytosine has a cytidine base having an unmethylated 5-position, and wherein at least one of n1, n2, n3 and n4 comprises four contiguous guanosine nucleosides.
8. A method for reducing tumor growth in a mammal which has a tumor, the method comprising administering to a mammal having a tumor an oligonucleotide having a structural motif which induces IL-12 expression in vivo in an amount and for a time sufficient to eliminate or reduce tumor growth.
9. The method according to claim 8, wherein the oligonucleotide has the nucleotide sequence N n1,-Nn2-CpG-Nn3-N n4, wherein N represents any nucleoside, n1 and n4 each independently represent a number from 0 to 50, n2 represents a number from 0 to 50 and n3 represents a number from 0 to 50 such that n2 + n3 equals from about 6 to about 100, wherein the underlined region represents a nucleoside phosphodiester or phosphorothioate region or a mixed backbone region having phosphodiester and phosphorothioate nucleosides, wherein CpG represents a cytosine-guanosine dinucleoside phosphorothioate or phosphodiester dinucleoside, wherein the cytosine has a cytidine base having an unmethylated 5-position, and wherein at least one of n1, n2, n3 and n4 comprises four contiguous guanosine nucleosides.
CA2288222A 1997-04-30 1998-04-30 Oligonucleotide mediated specific cytokine induction and in vivo protection from infection Expired - Fee Related CA2288222C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/848,229 US6426334B1 (en) 1997-04-30 1997-04-30 Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal
US08/848,229 1997-04-30
PCT/US1998/008751 WO1998049288A1 (en) 1997-04-30 1998-04-30 Oligonucleotide mediated specific cytokine induction and in vivo protection from infection

Publications (2)

Publication Number Publication Date
CA2288222A1 true CA2288222A1 (en) 1998-11-05
CA2288222C CA2288222C (en) 2011-06-21

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CA2288222A Expired - Fee Related CA2288222C (en) 1997-04-30 1998-04-30 Oligonucleotide mediated specific cytokine induction and in vivo protection from infection

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US (2) US6426334B1 (en)
EP (2) EP1408110B1 (en)
JP (1) JP2002505666A (en)
AT (1) ATE512221T1 (en)
AU (1) AU7171298A (en)
CA (1) CA2288222C (en)
WO (1) WO1998049288A1 (en)

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