Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods
Identifieur interne : 000988 ( Ncbi/Merge ); précédent : 000987; suivant : 000989Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods
Auteurs : Nasir Javaid ; Farzana Yasmeen ; Sangdun ChoiSource :
- Pharmaceutics [ 1999-4923 ] ; 2019.
Abstract
The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site.
Url:
DOI: 10.3390/pharmaceutics11090441
PubMed: 31480568
PubMed Central: 6781272
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</title><author><name sortKey="Javaid, Nasir" sort="Javaid, Nasir" uniqKey="Javaid N" first="Nasir" last="Javaid">Nasir Javaid</name></author><author><name sortKey="Yasmeen, Farzana" sort="Yasmeen, Farzana" uniqKey="Yasmeen F" first="Farzana" last="Yasmeen">Farzana Yasmeen</name></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31480568</idno><idno type="pmc">6781272</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781272</idno><idno type="RBID">PMC:6781272</idno><idno type="doi">10.3390/pharmaceutics11090441</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A96</idno><idno type="wicri:Area/Pmc/Curation">000A96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A96</idno><idno type="wicri:Area/Pmc/Checkpoint">000283</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000283</idno><idno type="wicri:Area/Ncbi/Merge">000988</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</title><author><name sortKey="Javaid, Nasir" sort="Javaid, Nasir" uniqKey="Javaid N" first="Nasir" last="Javaid">Nasir Javaid</name></author><author><name sortKey="Yasmeen, Farzana" sort="Yasmeen, Farzana" uniqKey="Yasmeen F" first="Farzana" last="Yasmeen">Farzana Yasmeen</name></author><author><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name></author></analytic><series><title level="j">Pharmaceutics</title><idno type="eISSN">1999-4923</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmaceutics</journal-id><journal-id journal-id-type="iso-abbrev">Pharmaceutics</journal-id><journal-id journal-id-type="publisher-id">pharmaceutics</journal-id><journal-title-group><journal-title>Pharmaceutics</journal-title></journal-title-group><issn pub-type="epub">1999-4923</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31480568</article-id><article-id pub-id-type="pmc">6781272</article-id><article-id pub-id-type="doi">10.3390/pharmaceutics11090441</article-id><article-id pub-id-type="publisher-id">pharmaceutics-11-00441</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Javaid</surname><given-names>Nasir</given-names></name></contrib><contrib contrib-type="author"><name><surname>Yasmeen</surname><given-names>Farzana</given-names></name></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-5920-7848</contrib-id><name><surname>Choi</surname><given-names>Sangdun</given-names></name><xref rid="c1-pharmaceutics-11-00441" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pharmaceutics-11-00441">Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea</aff><author-notes><corresp id="c1-pharmaceutics-11-00441"><label>*</label>Correspondence: <email>sangdunchoi@ajou.ac.kr</email>; Tel.: +82-31-219-2600</corresp></author-notes><pub-date pub-type="epub"><day>01</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>11</volume><issue>9</issue><elocation-id>441</elocation-id><history><date date-type="received"><day>09</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>28</day><month>8</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site.</p></abstract><kwd-group><kwd>Toll-like receptor</kwd><kwd>immunological disease</kwd><kwd>therapeutic</kwd><kwd>drug delivery method</kwd></kwd-group></article-meta></front><floats-group><fig id="pharmaceutics-11-00441-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>A generalized Toll-like receptor signaling mechanism, adapted from [<xref rid="B30-pharmaceutics-11-00441" ref-type="bibr">30</xref>]. TLRs are subdivided into two main categories based on their location, cell surface or endosomal; they are activated by their respective PAMPs and damage-associated molecular patterns. After recognizing respective ligand(s) via extracellular domains, TLRs form homo- or heterodimers and interact with cytoplasmic adaptor molecules (myeloid differentiation primary response protein 88 (MyD88), TIRAP (MAL), TRIF, or TRAM) through their cytoplasmic TIR domain. Most of TLRs activate downstream signaling in a MyD88-dependent manner with or without recruiting MAL; however, TLR3 (only) and TLR4 (alternatively) use TRIF/TRAM adaptors to activate IRFs. The activation of a TLR signaling pathway leads to the translocation of transcription factors (NF-κB (p50 or p65), AP-1, IRF3, and IRF7) into the nucleus and allows them to bind the target sequence(s) of inflammatory and interferon-responsive genes. Abbreviations: TLR, Toll-like receptor; TIR, Toll/interleukin-1 receptor domain; MAL, MyD88 adaptor like; MyD88, myeloid differentiation primary response 88; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing interferon β; IRAK, interleukin receptor-associated kinase; RIP, receptor-interacting protein; TRAF, tumor necrosis factor receptor (TNFR)-associated factor; TAB, TAK-1–binding protein; TAK1, transforming growth factor β-activated kinase 1; TBK1, TANK-binding kinase 1; NEMO, NF-κB essential modulator; IκB, inhibitor of κB; IKK, inhibitor of κB kinase; MAP, mitogen-activated protein; ERK, extracellular signal–regulated kinase; JNK, c-Jun N-terminal kinase; p38, protein 38; AP-1, activated protein 1; IFN, interferon; IL, interleukin; IRF, interferon response factor; NF-κB, nuclear factor κB; TNF-α, tumor necrosis factor α.</p></caption><graphic xlink:href="pharmaceutics-11-00441-g001"></graphic></fig><fig id="pharmaceutics-11-00441-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Drug delivery vehicles. (<bold>a</bold>) Liposomes are composed of phospholipids or other small-molecule compounds with various sizes, composition, and drug-loading capability. A lipid-soluble drug is attached to the lipid bilayer for safe and reliable transport to a target tissue. (<bold>b</bold>) Dendrimers are abundantly branched macromolecular structures having three major components: the core, branches, and a reactive surface, which has drug-entrapping properties. (<bold>c</bold>) A hydrogel is a three-dimensional structure consisting of a hydrophilic network of polymer chains, where drug molecules are attached to the polymeric chains. After exposure to the specific stimuli in an aqueous environment, the hydrogel swells and releases drug molecules into the surrounding environment. (<bold>d</bold>) Nanoparticles are small particles ranging in size from 1 to 100 nm where drugs are attached to the surface. (<bold>e</bold>) A prodrug is an inactive form of a drug and is activated after enzymatic or chemical metabolism inside the human body by releasing a promoiety. This property makes the drug a suitable candidate for specific targeting and controlled release. (<bold>f</bold>) Cyclodextrin represents a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity.</p></caption><graphic xlink:href="pharmaceutics-11-00441-g002"></graphic></fig><table-wrap id="pharmaceutics-11-00441-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00441-t001_Table 1</object-id><label>Table 1</label><caption><p>Expression, localization, and ligands of Toll-like receptors (TLRs).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Receptor</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Microbial Ligand(s)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Microbial Ligand Source</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Endogenous Ligand(s)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Adaptor</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">TLR Localization</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Expression</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR1/2/6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Triacyl and diacyl lipopeptides, glycolipids, zymosan, lipoteichoic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacterial lipoprotein and peptidoglycan, fungi, mycoplasma, gram-positive bacteria</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HMGB1, HSPs, HDLs, hyaluronan,</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Double-stranded RNA (dsRNA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self dsRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TRIF-TRAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, L, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lipopolysaccharide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Gram-negative bacteria</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSPs, fibrinogen, HA, heparin sulfate, HMGB1, LDLs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL/TRIF-TRAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mon, Mac, N, DCs, M, B, C</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Flagellin, profilin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacteria, <italic>Toxoplasma gondii</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HMGB1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, C, IE</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Single-stranded RNA (ssRNA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mc, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self ssRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, M, IECs</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bacteria, viruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Self DNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DCs, Mon, Mac, Plt, B</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR10</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Triacylated lipopeptides</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MyD88-MAL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell surface</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mon, N, B, LN, S</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: HMGB1, high mobility group box 1; HSPs, heat shock proteins; HDLs, high-density lipoproteins; LDLs, low density lipoproteins; MyD88, myeloid differentiation primary response protein 88; MAL, MyD88-adaptor-like; DCs, dendritic cells; Mon, monocytes; Mac, macrophages; B, B-cell; Plt, platelets; N, neutrophils; M, mast cells; C, cancer cells; IE, intestinal epithelium; IECs, intestinal epithelial cells; LN, lymph node; S, spleen; HA, hyaluronic acid; NA, not available.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pharmaceutics-11-00441-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00441-t002_Table 2</object-id><label>Table 2</label><caption><p>TLR-targeting drugs in clinical trials.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">TLR</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ligand</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Disease</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanism</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Phase</th></tr></thead><tbody><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR2 (with TLR1 or -6)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OPN-305 and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monoclonal antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inflammatory disease, myelodysplastic syndrome, kidney transplant rejection, pancreatic tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CBLB6I2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Synthetic lipopeptide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers (breast)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Blood cell recovery</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ISA-20I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Peptide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Head and neck tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Maturation of DCs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Poly-ICLC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Synthetic dsRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers (e.g., colon, ovarian, breast, prostate)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulation and modulation of tumor microenvironment</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PRV-300</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="10" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NI-0I0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antibody</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rheumatoid arthritis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GLA and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma, sarcoma, viral infection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LPS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inflammation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSKI79509I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Eritoran</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Insulin sensitivity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CX-0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Polysaccharide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Leukemia</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Microenvironment modulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEPA-I0</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PET-lipid A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glycolipid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JKB and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MN-I66</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Brain injury, glioblastoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-inflammatory</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Entolimod</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mobilan</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancers (prostate)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VAX and derivatives</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recombinant protein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Influenza</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Imiquimod</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers, actinic keratosis, and viral infections</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I to Phase IV, approved</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSK2245035</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma and rhinitis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN production</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GS-9620</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">pDC activator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RO702053I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepatitis B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GSK2245035</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN-α production and immune stimulation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TLR8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VTX-2337</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various cancers</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">TLR9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD-I0I</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-C class oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antitumor immune response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CYT003</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TH-I–mediated immune response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MGNI703</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DNA-based molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HIV and melanoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antiviral and antitumor response</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-7909</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphoma, malaria, HIV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I and II</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-I0I04</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hookworm infection</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG-ODN</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nucleotide-based</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lung tumor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune stimulator</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase I</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecule</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sjogren’s syndrome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune suppressor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase III</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AZDI4I9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CpG oligonucleotide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asthma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IFN production</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phase II</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: TLR, Toll-like receptor; DCs, dendritic cells; dsRNA, double-stranded RNA; GLA, glucopyranosyl lipid A; IFN, interferon; HIV, human immunodeficiency virus; ODN, oligodeoxynucleotide.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Choi, Sangdun" sort="Choi, Sangdun" uniqKey="Choi S" first="Sangdun" last="Choi">Sangdun Choi</name><name sortKey="Javaid, Nasir" sort="Javaid, Nasir" uniqKey="Javaid N" first="Nasir" last="Javaid">Nasir Javaid</name><name sortKey="Yasmeen, Farzana" sort="Yasmeen, Farzana" uniqKey="Yasmeen F" first="Farzana" last="Yasmeen">Farzana Yasmeen</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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