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Methods related to immunostimulatory nucleic acid-induced interferon

a nucleic acid-induced interferon and immunostimulatory technology, applied in the direction of antibody medical ingredients, drug compositions, peptide/protein ingredients, etc., can solve the problem of limited therapeutic use of ifn- treatment, and achieve the effect of preventing an ifn- treatment-related side

Inactive Publication Date: 2005-08-04
UNIV OF IOWA RES FOUND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] In addition to the ability to activate γδ T cells, it was also surprisingly discovered according to the invention that type I IFN-inducing CpG ODN, but not CpG ODN that are strong activators of B cells and pDCs without being strong inducers of type I IFN, can enhance proliferation of antigen-activated γδ T cells present within a population of PBMCs. In particular, proliferation is enhanced in connection with the presence of specific nonpeptide antigen, for example, the phosphoantigen isopentenyl pyrophosphate (IPP).
[0019] In another surprising discovery according to the invention, it was found that type I IFN-inducing CpG ODN, but not CpG ODN that are strong activators of B cells and pDCs without being strong inducers of type I IFN, can block CD40-stimulated IL-12 production in PBMC. It was surprisingly found, in addition, that CpG ODN that are strong activators of B cells and pDCs without being strong inducers of type I IFN had the opposite effect, i.e., these ODN actually enhanced CD40-stimulated IL-12 production in PBMC.
[0033] According to another aspect of the invention, a method is provided for preventing an IFN-α treatment-related side effect in a subject receiving or in need of treatment with IFN-α. The method involves administering to a subject in need of the treatment an IFN-α pharmaceutical composition and a pharmaceutical composition comprising an immunostimulatory nucleic acid in an amount which, together with the administered IFN-α, is an effective IFN-α treatment. The IFN-α treatment-related side effect is reduced in comparison to the side effect when IFN-α is administered in the absence of co-administering ISNA. The IFN-α treatment-related side effect may be systemic. The IFN-α treatment-related side effect prevented by the method can include any one of flu-like syndrome, fever, headache, chills, myalgia, fatigue, anorexia, nausea, vomiting, diarrhea, and depression. The pharmaceutical composition including the ISNA can be administered locally. The ISNAs and conditions calling for treatment with IFN-α according to this aspect of the invention are as described above.

Problems solved by technology

Its therapeutic use is limited.

Method used

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  • Methods related to immunostimulatory nucleic acid-induced interferon
  • Methods related to immunostimulatory nucleic acid-induced interferon
  • Methods related to immunostimulatory nucleic acid-induced interferon

Examples

Experimental program
Comparison scheme
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example 1

Isolation and Characterization of IPCs

[0172] Peripheral blood mononuclear cells (PBMCs) contain a total of 0.2 to 0.4 percent IPCs, which are characterized by the lack of lineage markers (CD3, CD14, CD16, CD19, CD20, CD56) and can be distinguished from other lineage-negative cells by the expression of CD4, CD123 (IL-3Rα), and MHC class II.

[0173] IPCs were isolated from peripheral blood by using the VARIOMACS technique (Milteny Biotec, Auburn, Calif.) and the technique previously described. O'Doherty U et al. J Exp Med 178:1067-76 (1993). PBMCs were obtained from buffy coats of healthy blood donors by Ficoll-Paque density gradient centrifugation (Histopaque-1077, Sigma) as previously described. Hartmann G et al. Antisense Nucleic Acid Drug Dev 6:291-9 (1996). Monoclonal antibodies directed to CD3 (UCHT1), CD14 (M5E2), and CD19 (B43) were purchased from PharMingen (San Diego). PBMCs were incubated with anti-CD3, CD14, CD16, CD19, and CD56 antibodies conjugated to colloidal superpara...

example 2

CpG Oligonucleotide Supports the Survival and Activation of IPCs In Vitro

[0177] The majority of freshly isolated IPCs die within 3 days if not incubated in the presence of IL-3 or GM-CSF. Remaining live cells are not activated or are only weakly activated. If CpG oligonucleotide but no other growth factors are added to the cell culture of IPCs, IPCs survive and become highly activated as shown by their increased expression of costimulatory molecules (e.g., CD80, FIG. 2).

[0178] Freshly isolated IPCs (see Example 1) were suspended in RPMI 1640 culture medium supplemented with 10 percent (vol / vol) heat-inactivated (56° C., 1 h) FCS (HyClone), 1.5 mM L-glutamine, 100 units / ml penicillin, and 100 μg / ml streptomycin (all from GIBCO / BRL) (complete medium). All compounds were purchased endotoxin-tested. Freshly prepared IPCs (final concentration 5×105 cells per ml) were cultured for two days in complete medium alone or complete medium supplemented with 6 μg / ml phosphorothioate CpG ODN 200...

example 3

CpG Oligonucleotide, but not Poly IC, Activates IPCs In Vitro

[0180] IL-3 provides excellent survival of IPCs but does not activate IPCs. When IL-3 was combined with CpG oligonucleotide, expression of CD80 increased by 5 to 20-fold (FIG. 3). Poly IC, another polynucleotide with well known immunostimulatory functions on myeloid cells (dendritic cells, macrophages), did not stimulate IPCs.

[0181] Freshly prepared IPCs (see Example 1, final concentration 3×105 cells per ml) were cultured for three days in complete medium (see Example 2) supplemented with 10 ng / ml IL-3. Cultures of IPCs were then continued for a further 24 hours (a) without any additional supplements, (b) following the addition of 6 μg / ml CpG ODN 2006 (SEQ ID NO:147), and (c) following the addition of 10 μg / ml poly IC. Forward scattering (FSC), side scattering (SSC), and expression of CD80 and MHC class II on IPCs were examined by flow cytometry (see Example 1).

[0182] Results. Representative results of three independen...

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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.

Description

RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 156,147, filed Sep. 27, 1999, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION [0002] Human interferon alpha (IFN-α), also known as leukocyte interferon and α interferon, comprises a family of extracellular signaling proteins with antiviral, antiproliferative, and immunomodulatory activities. The first type of interferon to be identified and commercialized, IFN-α remains the most widely used interferon for clinical applications. [0003] IFN-α is a member of the family of Type I interferons, which also includes IFN-β, omega (leukocyte (II)) interferon and tau (trophoblast) interferon. Omega and tau interferons are not clinically used. IFN-β, also known as fibroblast interferon, is well characterized but less utilized than IFN-α in the clinic. Fibroblasts are the predominant cellular producers of IFN-β. IFN-β has been approved in the Un...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/21A61K39/00C12N5/0784C12N15/117
CPCA61K38/21A61K2039/5154A61K2039/5158A61K2039/55561C12N5/0639C12N15/117C12N2501/23C12N2501/056C12N2501/22A61K2300/00A61P31/14A61P31/18A61P31/20A61P31/22A61P35/00A61K39/464463A61K39/464419A61K39/461A61K39/464411
Inventor HARTMANNBRATZLER, ROBERTKRIEG, ARTHUR
Owner UNIV OF IOWA RES FOUND
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