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Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

Identifieur interne : 002257 ( Istex/Corpus ); précédent : 002256; suivant : 002258

Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

Auteurs : Ekambar R. Kandimalla ; Sudhir Agrawal

Source :

Advances in Polymer Science [ 0065-3195 ]

RBID : ISTEX:0DA4D782E265BF06733BBBC34359C59143CD2079

Abstract

Abstract: Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.

Url:

https://api.istex.fr/ark:/67375/HCB-5PTFH70V-G/fulltext.pdf

DOI: 10.1007/12_2011_138

Links to Exploration step

ISTEX:0DA4D782E265BF06733BBBC34359C59143CD2079

Le document en format XML

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<front><div type="abstract" xml:lang="en">Abstract: Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.</div>
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<value>ODN : Oligodeoxynucleoide</value>
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<value>OME : Otitis-mediated effusion</value>
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<value>ORN : Oligoribonucleotide</value>
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<value>OVA : Ovalbumin</value>
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<profileDesc><abstract xml:lang="en"><head>Abstract</head>
<p>Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.</p>
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<textClass ana="abbreviation"><keywords scheme="abbreviations"><list><head>Abbreviations</head>
<item><term>ADCC</term>
<desc>
                  Antibody-dependent cellular cytotoxicity
                </desc>
</item>
<item><term>AE</term>
<desc>
                  Adverse event
                </desc>
</item>
<item><term>CMI</term>
<desc>
                  Cell-mediated immunity
                </desc>
</item>
<item><term>CpG</term>
<desc>
                  Cytidine-phosphate-guanosine
                </desc>
</item>
<item><term>DC</term>
<desc>
                  Dendritic cell
                </desc>
</item>
<item><term>ds</term>
<desc>
                  Double-stranded
                </desc>
</item>
<item><term>EGFR</term>
<desc>
                  Endothelial growth factor receptor
                </desc>
</item>
<item><term>HEK</term>
<desc>
                  Human embryonic kidney
                </desc>
</item>
<item><term>HIV</term>
<desc>
                  Human immunodeficiency virus
                </desc>
</item>
<item><term>IFN</term>
<desc>
                  Interferon
                </desc>
</item>
<item><term>IL</term>
<desc>
                  Interleukin
                </desc>
</item>
<item><term>IMO</term>
<desc>
                  Immune-modulatory oligonucleotide
                </desc>
</item>
<item><term>IP-10</term>
<desc>
                  IFN-γ-inducible protein 10
                </desc>
</item>
<item><term>IRAK</term>
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                  IL-1-associated kinase
                </desc>
</item>
<item><term>LPS</term>
<desc>
                  Lipopolysaccharide
                </desc>
</item>
<item><term>LTR</term>
<desc>
                  Long terminal repeat
                </desc>
</item>
<item><term>mDCs</term>
<desc>
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</item>
<item><term>MyD8</term>
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                  Myeloid differentiation factor 88
                </desc>
</item>
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                  Nuclear factor-kappa B
                </desc>
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                  Natural killer
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                  Otitis-mediated effusion
                </desc>
</item>
<item><term>ORN</term>
<desc>
                  Oligoribonucleotide
                </desc>
</item>
<item><term>OVA</term>
<desc>
                  Ovalbumin
                </desc>
</item>
<item><term>PAMP</term>
<desc>
                  Pathogen-associated molecular pattern
                </desc>
</item>
<item><term>PBMC</term>
<desc>
                  Peripheral blood mononuclear cell
                </desc>
</item>
<item><term>pDC</term>
<desc>
                  Plasmacytoid dendritic cell
                </desc>
</item>
<item><term>PFS</term>
<desc>
                  Progression-free survival
                </desc>
</item>
<item><term>PO</term>
<desc>
                  Phosphodiester
                </desc>
</item>
<item><term>PRR</term>
<desc>
                  Pattern-recognition receptor
                </desc>
</item>
<item><term>PS</term>
<desc>
                  Phosphorothioate
                </desc>
</item>
<item><term>RA</term>
<desc>
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                </desc>
</item>
<item><term>s.c.</term>
<desc>
                  Subcutaneous
                </desc>
</item>
<item><term>SIMRA</term>
<desc>
                  Stabilized immune modulatory RNA
                </desc>
</item>
<item><term>ss</term>
<desc>
                  Single-stranded
                </desc>
</item>
<item><term>TERT</term>
<desc>
                  Telomerase reverse transcriptase
                </desc>
</item>
<item><term>Th1</term>
<desc>
                  T helper type 1
                </desc>
</item>
<item><term>TIR</term>
<desc>
                  Toll/interleukin-1 receptor
                </desc>
</item>
<item><term>TLR</term>
<desc>
                  Toll-like receptor
                </desc>
</item>
<item><term>TRAF6</term>
<desc>
                  TNF receptor-associated factor 6
                </desc>
</item>
<item><term>TRIF</term>
<desc>
                  TIR domain-containing adaptor-inducing interferon-β
                </desc>
</item>
<item><term>VEGF</term>
<desc>
                  Vascular endothelial growth factor
                </desc>
</item>
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<ChapterTitle Language="En">Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides</ChapterTitle>
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<Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Sudhir</GivenName>
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<Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading>
<Para>Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.</Para>
</Abstract>
<KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading>
<Keyword>Agonist</Keyword>
<Keyword>Antagonist</Keyword>
<Keyword>Immune-modulatory oligonucleotides</Keyword>
<Keyword>Immune stimulation</Keyword>
<Keyword>Oligodeoxynucleotides</Keyword>
<Keyword>Oligonucleotides</Keyword>
<Keyword>Oligoribonucleotides</Keyword>
<Keyword>Toll-like receptor 7</Keyword>
<Keyword>Toll-like receptor 8</Keyword>
<Keyword>Toll-like receptor 9</Keyword>
</KeywordGroup>
<AbbreviationGroup><Heading>Abbreviations</Heading>
<DefinitionList><DefinitionListEntry><Term>ADCC</Term>
<Description><Para>Antibody-dependent cellular cytotoxicity</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>AE</Term>
<Description><Para>Adverse event</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>CMI</Term>
<Description><Para>Cell-mediated immunity</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>CpG</Term>
<Description><Para>Cytidine-phosphate-guanosine</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>DC</Term>
<Description><Para>Dendritic cell</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>ds</Term>
<Description><Para>Double-stranded</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>EGFR</Term>
<Description><Para>Endothelial growth factor receptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>HEK</Term>
<Description><Para>Human embryonic kidney</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>HIV</Term>
<Description><Para>Human immunodeficiency virus</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>IFN</Term>
<Description><Para>Interferon</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>IL</Term>
<Description><Para>Interleukin</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>IMO</Term>
<Description><Para>Immune-modulatory oligonucleotide</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>IP-10</Term>
<Description><Para>IFN-γ-inducible protein 10</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>IRAK</Term>
<Description><Para>IL-1-associated kinase</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>LPS</Term>
<Description><Para>Lipopolysaccharide</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>LTR</Term>
<Description><Para>Long terminal repeat</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>mDCs</Term>
<Description><Para>Myeloid dendritic cells</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>MyD8</Term>
<Description><Para>Myeloid differentiation factor 88</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>NF-κB</Term>
<Description><Para>Nuclear factor-kappa B</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>NK</Term>
<Description><Para>Natural killer</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>NSCLC</Term>
<Description><Para>Nonsmall cell lung carcinoma</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>ODN</Term>
<Description><Para>Oligodeoxynucleoide</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>OME</Term>
<Description><Para>Otitis-mediated effusion</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>ORN</Term>
<Description><Para>Oligoribonucleotide</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>OVA</Term>
<Description><Para>Ovalbumin</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PAMP</Term>
<Description><Para>Pathogen-associated molecular pattern</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PBMC</Term>
<Description><Para>Peripheral blood mononuclear cell</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>pDC</Term>
<Description><Para>Plasmacytoid dendritic cell</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PFS</Term>
<Description><Para>Progression-free survival</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PO</Term>
<Description><Para>Phosphodiester</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PRR</Term>
<Description><Para>Pattern-recognition receptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>PS</Term>
<Description><Para>Phosphorothioate</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>RA</Term>
<Description><Para>Rheumatoid arthritis</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>s.c.</Term>
<Description><Para>Subcutaneous</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>SIMRA</Term>
<Description><Para>Stabilized immune modulatory RNA</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>ss</Term>
<Description><Para>Single-stranded</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>TERT</Term>
<Description><Para>Telomerase reverse transcriptase</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>Th1</Term>
<Description><Para>T helper type 1</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>TIR</Term>
<Description><Para>Toll/interleukin-1 receptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>TLR</Term>
<Description><Para>Toll-like receptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>TRAF6</Term>
<Description><Para>TNF receptor-associated factor 6</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>TRIF</Term>
<Description><Para>TIR domain-containing adaptor-inducing interferon-β</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>VEGF</Term>
<Description><Para>Vascular endothelial growth factor</Para>
</Description>
</DefinitionListEntry>
</DefinitionList>
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<abstract lang="en">Abstract: Toll-like receptors (TLRs) 7, 8, and 9 belong to a family of endosomal receptors that are known to detect pathogen-associated nucleic acid molecular patterns and induce appropriate immune responses. Viral single-stranded RNA is the ligand for TLR7 and TLR8, and bacterial and viral DNA containing unmethylated CpG motifs is the ligand for TLR9. We have extensively studied the structure–activity relationships of synthetic oligonucleotides towards the goal of creating novel agonists of TLRs 7, 8, and 9 to modulate immune responses mediated through targeted receptors. Agonists of TLRs 7, 8, and 9 are being studied as therapeutic agents for various diseases, including cancers, allergies, asthma, and infectious diseases, and also as adjuvants with vaccines. In addition, under certain pathological conditions, TLR7 and TLR9 are shown to recognize immune complexes containing self-nucleic acids and contribute to the progression of autoimmune diseases, including lupus, arthritis, psoriasis, and multiple sclerosis. Using the insights gained by studying the interactions of oligonucleotides with endosomal TLRs, we have created oligonucleotide-based antagonists that inhibit both TLR7- and TLR9-mediated immune responses for the treatment of autoimmune and inflammatory diseases. Out of the large portfolio of oligonucleotide-based TLR agonists and antagonists designed, four candidates are currently being evaluated in clinical trials for a broad range of disease indications.</abstract>
<subject lang="en"><genre>Keywords</genre>
<topic>Agonist</topic>
<topic>Antagonist</topic>
<topic>Immune-modulatory oligonucleotides</topic>
<topic>Immune stimulation</topic>
<topic>Oligodeoxynucleotides</topic>
<topic>Oligonucleotides</topic>
<topic>Oligoribonucleotides</topic>
<topic>Toll-like receptor 7</topic>
<topic>Toll-like receptor 8</topic>
<topic>Toll-like receptor 9</topic>
</subject>
<subject><genre>Abbreviations</genre>
<topic>ADCC : Antibody-dependent cellular cytotoxicity</topic>
<topic>AE : Adverse event</topic>
<topic>CMI : Cell-mediated immunity</topic>
<topic>CpG : Cytidine-phosphate-guanosine</topic>
<topic>DC : Dendritic cell</topic>
<topic>ds : Double-stranded</topic>
<topic>EGFR : Endothelial growth factor receptor</topic>
<topic>HEK : Human embryonic kidney</topic>
<topic>HIV : Human immunodeficiency virus</topic>
<topic>IFN : Interferon</topic>
<topic>IL : Interleukin</topic>
<topic>IMO : Immune-modulatory oligonucleotide</topic>
<topic>IP-10 : IFN-γ-inducible protein 10</topic>
<topic>IRAK : IL-1-associated kinase</topic>
<topic>LPS : Lipopolysaccharide</topic>
<topic>LTR : Long terminal repeat</topic>
<topic>mDCs : Myeloid dendritic cells</topic>
<topic>MyD8 : Myeloid differentiation factor 88</topic>
<topic>NF-κB : Nuclear factor-kappa B</topic>
<topic>NK : Natural killer</topic>
<topic>NSCLC : Nonsmall cell lung carcinoma</topic>
<topic>ODN : Oligodeoxynucleoide</topic>
<topic>OME : Otitis-mediated effusion</topic>
<topic>ORN : Oligoribonucleotide</topic>
<topic>OVA : Ovalbumin</topic>
<topic>PAMP : Pathogen-associated molecular pattern</topic>
<topic>PBMC : Peripheral blood mononuclear cell</topic>
<topic>pDC : Plasmacytoid dendritic cell</topic>
<topic>PFS : Progression-free survival</topic>
<topic>PO : Phosphodiester</topic>
<topic>PRR : Pattern-recognition receptor</topic>
<topic>PS : Phosphorothioate</topic>
<topic>RA : Rheumatoid arthritis</topic>
<topic>s.c. : Subcutaneous</topic>
<topic>SIMRA : Stabilized immune modulatory RNA</topic>
<topic>ss : Single-stranded</topic>
<topic>TERT : Telomerase reverse transcriptase</topic>
<topic>Th1 : T helper type 1</topic>
<topic>TIR : Toll/interleukin-1 receptor</topic>
<topic>TLR : Toll-like receptor</topic>
<topic>TRAF6 : TNF receptor-associated factor 6</topic>
<topic>TRIF : TIR domain-containing adaptor-inducing interferon-β</topic>
<topic>VEGF : Vascular endothelial growth factor</topic>
</subject>
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Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

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