Methods related to immunostimulatory nucleic acid-induced interferon
AssigneesColey Pharmaceutical Group, Inc., University of Iowa Research Foundation, Coley Pharmaceutical GmbH
InventorsGunther Hartmann, Robert L. Bratzler, Arthur M. Krieg
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Abstract
Methods and compositions are provided for extending the clinical utility of IFN-α in the treatment of a variety of viral and proliferative disorders. Among other aspects, the invention provides methods which increase the efficacy of IFN-α treatment and reduce IFN-α treatment-related side effects. In addition, methods are provided for supporting the survival and for activating natural interferon producing cells (IPCs) in vitro without exogenous IL-3 or GM-CSF. The invention is based on the discovery that certain CpG and non-CpG ISNAs promote survival and stimulation of IPCs.
Claims89
In a method which calls for administration of interferon alpha (IFN-α) to a mammalian subject, the improvement comprising co-administering to the mammalian subject an effective amount of an isolated immunostimulatory nucleic acid, wherein said isolated immunostimulatory nucleic acid is 10 to 100 nucleotides long and comprises a poly-G sequence at each end and a central palindromic sequence comprising an unmethylated CpG dinucleotide.
A method of supplementing interferon alpha (IFN-α) treatment of a subject, comprising
- administering to a mammalian subject in need of IFN-α treatment an effective amount of IFN-α and an isolated immunostimulatory nucleic acid, wherein said isolated immunostimulatory nucleic acid is 10 to 100 nucleotides long and comprises a poly-G sequence at each end and a central palindromic sequence comprising an unmethylated CpG dinucleotide.
A method of increasing efficacy of interferon alpha (IFN-α) treatment of a subject, comprising:
- administering to a mammalian subject in need of treatment with IFN-α a pharmaceutical composition comprising IFN-α, and
- coadministering to the subject in need of such treatment a pharmaceutical composition comprising an immunostimulatory nucleic acid in an amount which, together with the administered IFN-α, is an effective IFN-α treatment, wherein the efficacy of the IFN-α treatment is greater than the efficacy of administering the same amount of IFN-α in the absence of coadministering the immunostimulatory nucleic acid, and wherein said immunostimulatory nucleic acid is 10 to 100 nucleotides long and comprises a poly-G sequence at each end and a central palindromic sequence comprising an unmethylated CpG dinucleotide.
A method of decreasing a dose of interferon alpha (IFN-α) effective for treating a subject, comprising:
- administering to a mammalian subject in need of treatment with IFN-α a pharmaceutical composition comprising IFN-α, and
- coadministering to the subject in need of such treatment a pharmaceutical composition comprising an immunostimulatory nucleic acid in an amount which, together with the administered IFN-α, is an effective IFN-α treatment, wherein the amount of administered IFN-α is less than an amount of IFN-α required in the absence of coadministering the immunostimulatory nucleic acid, and wherein said immunostimulatory nucleic acid is 10 to 100 nucleotides long and comprises a poly-G sequence at each end and a central palindromic sequence comprising an unmethylated CpG dinucleotide.
A method of reducing an interferon alpha (IFN-α) treatment-related side effect in a subject receiving or in need of treatment with IFN-α, comprising
- administering to a mammalian subject in need of treatment with IFN-α a pharmaceutical composition comprising IFN-α, and
- coadministering to the subject in need of such treatment a pharmaceutical composition comprising an immunostimulatory nucleic acid in an amount which, together with the administered IFN-αc, is an effective IFN-α treatment, wherein an IFN-α treatment-related side effect is reduced in comparison to the side effect when IFN-α is administered in the absence of coadministering the immunostimulatory nucleic acid, and wherein said immunostimulatory nucleic acid is 10 to 100 nucleotides long and comprises a poly-G sequence at each end and a central palindromic sequence comprising an unmethylated CpG dinucleotide.
A method of stimulating production of a plurality of type I interferon (IFN) subtypes in a mammalian subject, comprising administering to a mammalian subject in need of IFN-α treatment an amount of immunostimulatory nucleic acid effective to induce IFN-producing cells (IPCs) to secrete at least two type I interferons, wherein said immunostimulatory nucleic acid is selected from the group consisting of
- ggGGGACGATCGTCgggggG
- ODN 2216
- SEQ ID NO:7
- ggGGGACGATATCGTCgggggG
- ODN 2245
- SEQ ID NO:9
- ggGGGACGAGCTCGTCgggggG
- ODN 2247
- SEQ ID NO:11
- ggGGGACGATCGTTGggggG
- ODN 2252
- SEQ ID NO:13
- ggGGTCACCGGTGAgggggG
- ODN 2300
- SEQ ID NO:24
- ggGGTCGACGTACGTCGAgggggG
- ODN 2301
- SEQ ID NO:25
- ggGGACGTCGACGTggggG
- ODN 2306
- SEQ ID NO:30
- ggGTCGTCGACGAggggggG
- ODN 2329
- SEQ ID NO:33
- ggGGTCGACGTCGACGTC9AGgggggG
- ODN 2334
- SEQ ID NO:
- 36, and
- ggGGACGACGTCGTGgggggG
- ODN 2336
- SEQ ID NO:
- 37,
- wherein each lower case letter represents phosphorothioate linkage and each upper case letter indicates phosphodiester linkage.
A pharmaceutical composition, comprising
- an isolated nucleic acid having a sequence selected from the group consisting of:
- ggGGGACGATCGTCgggggG
- ODN 2216
- SEQ ID NO:7
- ggGGGACGATATCGTCgggggG
- ODN 2245
- SEQ ID NO:9
- ggGGGACGAGCTCGTCgggggG
- ODN 2247
- SEQ ID NO:11
- ggGGGACGATCGTTGggggG
- ODN 2252
- SEQ ID NO:13
- ggGGTCACCGGTGAgggggG
- ODN 2300
- SEQ ID NO:24
- ggGGTCGACGTACGTCGAgggggG
- ODN 2301
- SEQ ID NO:25
- ggGGACGTCGACGTggggG
- ODN 2306
- SEQ ID NO:30
- ggGTCGTCGACGAggggggG
- ODN 2329
- SEQ ID NO:33
- ggGGTCGACGTCGACGTCGAGgggggG
- ODN 2334
- SEQ ID NO:
- 36, and
- ggGGACGACGTCGTGgggggG
- ODN 2336
- SEQ ID NO:
- 37,
- wherein each lower case letter represents phosphorothioate linkage and each upper case letter indicates phosphodiester linkage;
- and
- a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.