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Structure and use of 5'phosphate oligonucleotides

a technology of phosphate oligonucleotides and oligonucleotides, which is applied in the field of structure and use of 5'phosphate oligonucleotides, can solve the problems of reduced bone marrow function, high production cost, and broad side effects

Inactive Publication Date: 2010-07-15
KLINISCHE PHARMAKOLOGIE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

IFN-α products that are currently in clinical use include the recombinant protein and the highly purified natural protein, both of which have high production costs.
Furthermore, IFN-α is currently administrated systematically and causes a broad spectrum of side effects (e.g. fatigue, flu-like symptoms, diarrhea).
Most alarmingly, IFN-α causes a decrease in bone marrow function which leads to increased susceptibility to life-threatening infections, anemia and bleeding problems.
In the cytoplasm, abundant self RNA complicates our understanding of the recognition of

Method used

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  • Structure and use of 5'phosphate oligonucleotides
  • Structure and use of 5'phosphate oligonucleotides
  • Structure and use of 5'phosphate oligonucleotides

Examples

Experimental program
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examples

Material and Methods

examples 1-10

Cell Culture

[0412]Human PBMC were prepared from whole blood donated by young healthy donors by Ficoll-Hypaque density gradient centrifugation (Biochrom, Berlin, Germany). PDC were isolated by MACS using the blood dendritic cell Ag (BCDA)-4 dendritic cell isolation kit from Miltenyi Biotec (Bergisch-Gladbach, Germany). Briefly, PDC were labelled with anti-BDCA-4 Ab coupled to colloidal paramagnetic microbeads and passed through a magnetic separation column twice (LS column, then MS column; Miltenyi Biotec). The purity of isolated PDC (lineage-negative, MHC-II-positive and CD123-positive cells) was above 95%. Before isolation of monocytes, PDC were depleted by MACS (LD column; Miltenyi Biotec) and then monocytes were isolated using the monocyte isolation kit II (Miltenyi Biotec). Murine bone marrow-derived conventional dendritic cells were generated by incubating pooled bone marrow cells in the presence of murine GM-CSF (10 ng / ml; R&D Systems, Minneapolis, Minn.). After 7 days, these ...

examples 11-16

Media and Reagents

[0424]RPMI 1640 (Biochrom) supplemented with 10% (v / v) heat-inactivated FCS (Invitrogen Life Technologies), 3 mM L-glutamine, 0.01 M HEPES, 100 U / ml penicillin, and 100 μg / ml streptomycin (all from Sigma-Aldrich) and Dulbecco's modified Eagle's medium (PAN, Aidenbach, Germany) supplemented with 10% fetal calf serum (FCS), 3 mM L-glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin was used. CpG ODNs (Coley Pharmaceutical Group) show small letters, phosphorothioate (PT) linkage and capital letters, phosphodiester (PD) linkage 3′ of the base; CpG-A-ODN 2216 (5′-ggGGGACGATCGTCgggggG-3′), CpG-B ODN 1826 (5′-TCCATGACGTTCCTGACGTT-3′). Polyinosinic:polycytidylic acid (poly(I:C)) was purchased from Sigma-Aldrich. For depletion of NK cells and CD8 T cells, the IL-2 receptor-β chain-specific mAb TMβ1 and mAb RmCD8-2 were used as described (kind gift of Ralph Mocikat, GSF-Institut für Molekulare Immunologie, Munich, Germany). Recombinant murine IFNβ was purchased at Euro...

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Abstract

Oligonucleotides bearing free, uncapped 5′ phosphate group(s) are recognized by RIG-I, leading to the induction of type I IFN, IL-18 and IL-1β production. Bacterial RNA also induces type I IFN production. 5′ phosphate oligonucleotides and bacterial RNA can be used for inducing an anti-viral response or an anti-bacterial response, in particular, type I IFN and/or IL-18 and/or IL-1β production, in vitro and in vivo and for treating various disorders and diseases such as viral infections, bacterial infections, parasitic infections, tumors, allergies, autoimmune diseases, immunodeficiencies and immunosuppression. Single-stranded 5′ triphosphate RNA can be used for inducing an anti-viral response, an anti-bacterial response, or an anti-tumor response, in particular, type I IFN and/or IL-18 and/or IL-1β production, in a target cell-specific manner.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the field of immunotherapy and drug discovery. The present invention provides oligonucleotides which are capable of inducing an anti-viral or an anti-bacterial response, in particular, the production of type I IFN, IL-18 and / or IL-1β, and their in vitro as well as therapeutic uses.BACKGROUND OF THE INVENTION[0002]The vertebrate immune system established different ways to detect invading pathogens based on certain characteristics of their microbial nucleic acids. Detection of microbial nucleic acids alerts the immune system to mount the appropriate type of immune response that is required for the defense against the respective type of pathogen detected. Detection of viral nucleic acids leads to the production of type I interferon (IFN) including IFN-α and IFN-β, the key cytokines for anti-viral defense.[0003]IFN-α was the first type of interferon to be identified and commercialized; it is widely used clinically in the treat...

Claims

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Application Information

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IPC IPC(8): A61K38/21C07H21/02A61K31/7105C12N5/071C07H21/04A61K31/7088A61P31/12A61P31/04A61P33/00A61P35/00A61P37/02C12N15/117
CPCA61K31/7105C07H21/00A61K31/7115A61P25/00A61P31/00A61P31/04A61P31/12A61P33/00A61P35/00A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00Y02A50/30A61K45/06C12N15/117C12N2310/17C12N2310/31C12N2310/32C12N2310/335C12N2310/346C12N2310/351C12N2320/30
Inventor HARTMANNHORNUNG, VEIT
Owner KLINISCHE PHARMAKOLOGIE
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