<scp>CYT</scp>003, a <scp>TLR</scp>9 agonist, in persistent allergic asthma – a randomized placebo‐controlled Phase 2b study

Casale, Thomas B.; Cole, Jeremy; Beck, Ekkehard; Vogelmeier, Claus; Willers, Jörg; Lassen, Cheryl; Hammann-Haenni, Anya; Trokan, L.; Saudan, Philippe; Wechsler, M.E.

doi:10.1111/all.12663

Cited by 59 publications

(36 citation statements)

References 38 publications

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“…However, the role of TLR9 as a novel therapeutic target for allergic airway disease is still controversial. Synthetic TLR9 ligands (CpG ODNs) are shown to be beneficial in various animal models of asthma and even in a number of early human clinical trials , while CpG ODNs are also reported to activate TLR9 and cause lung inflammation . In fact, consistent with our previous report and the study of Carmen Maldonado‐Berna that high expression of TLR9 is found in asthma , the present study demonstrated that pronounced elevated expression of TLR9 was accompanying with lung inflammation exacerbation in WT mice after OVA challenges.…”

Section: Discussionsupporting

confidence: 91%

“…Therefore, modulators have been developed to target TLRs for the therapeutic potential, with a particular focus on TLR9. CpG oligodeoxynucleotides, which are TLR9 ligands, have been used in the treatment of allergic airway diseases such as asthma in animal models and even in placebo‐controlled phase II study . Nevertheless, achieving inflammation control is still an important goal in the management of allergic airway disease.…”

Section: Introductionmentioning

confidence: 99%

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JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

Shen

Fang

et al. 2016

Journal of Pineal Research

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Toll-like receptors (TLRs) play pivotal role in the pathogenesis of allergic airway diseases such as asthma. TLR9 is one of the most extensively studied TLRs as an approach to treat asthma. In this study, we investigated the role of TLR9 in the allergic airway inflammation and the underlying mechanism. Wild-type (WT) mice and TLR9(-/-) mice were sensitized and challenged with OVA to establish allergic airway disease model. We found that the expression of TLR9 was elevated concomitantly with airway inflammation post-OVA challenge, and TLR9 deficiency effectively inhibited airway inflammation, including serum OVA-specific immunoglobulin E (IgE), pulmonary inflammatory cell recruitment, mucus secretion, and bronchoalveolar lavage fluid (BALF) inflammatory cytokine production. Meanwhile, the protein expression of hydroxyindole-o-methyltransferase (HIOMT) in lung tissues, the level of melatonin in serum, and BALF were reduced in OVA-challenged WT mice, while these reductions were significantly restored by TLR9 deficiency. Additionally, we showed that although TLR9 deficiency had no effect on OVA-induced phosphorylation of JNK, inhibition of JNK by specific inhibitor SP600125 significantly decreased OVA-induced expression of TLR9, suggesting that JNK is the upstream signal molecular of TLR9. Furthermore, SP600125 treatment promoted resolution of allergic airway inflammation in OVA-challenged WT mice, but not further ameliorated allergic airway inflammation in OVA-challenged TLR9(-/-) mice. Similarly, SP600125 significantly restored the protein expression of HIOMT and the level of melatonin in OVA-challenged WT mice, while such effect was not further enhanced by TLR9 deficiency. Collectively, our results indicated that JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

Shen

Fang

et al. 2016

Journal of Pineal Research

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“…However, just recently, there was a report that administration of this same Qβ-derived nanoparticle complex resulted in no therapeutic improvement in patients with persistent moderate-to-severe allergic asthma. 99 Therefore, the efficacy of this particular nanomedicine may only apply to patients with controlled mild-to-moderate persistent allergic asthma undergoing glucocorticosteroid withdrawal.…”

mentioning

confidence: 99%

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

Hanagata

2017

IJN

110

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“…We included the well-known Qβ VLP-based allergy vaccine CYT003-QbG10 that contains an encapsulated CpG sequence, so-called QbG10, in table 2, although it does not carry any attached epitope [217,218,219,220,221]. However, this potentially successful vaccine initially originated from epitope-coupling methodology.…”

Section: Vaccines and Vaccine Candidatesmentioning

confidence: 99%

“…It has been demonstrated that MS2 VLPs can be conjugated to peptides recognizing human hepatocellular carcinoma cells and can be loaded with vastly different types of cargo, including low molecular weight chemotherapeutic drugs, siRNA cocktails, protein toxins and nanoparticles, resulting in the selective killing of target cells [268]. The packaging of Qβ VLPs with immunostimulatory CpG sequences led not only to the development of potential allergy vaccines (see above) but also strongly contributed to the general understanding of the mechanics of oligodeoxynucleotide-induced stimulation [217,218,219,220,221,222,223,224,225,226,227,228,229,269,270]. …”

Section: Nonvaccine Applicationsmentioning

confidence: 99%

The True Story and Advantages of RNA Phage Capsids as Nanotools

et al. 2016

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RNA phages are often used as prototypes for modern recombinant virus-like particle (VLP) technologies. Icosahedral RNA phage VLPs can be formed from coat proteins (CPs) and are efficiently produced in bacteria and yeast. Both genetic fusion and chemical coupling have been successfully used for the production of numerous chimeras based on RNA phage VLPs. In this review, we describe advances in RNA phage VLP technology along with the history of the Leviviridae family, including its taxonomical organization, genomic structure, and important role in the development of molecular biology. Comparative 3D structures of different RNA phage VLPs are used to explain the level of VLP tolerance to foreign elements displayed on VLP surfaces. We also summarize data that demonstrate the ability of CPs to tolerate different organic (peptides, oligonucleotides, and carbohydrates) and inorganic (metal ions) compounds either chemically coupled or noncovalently added to the outer and/or inner surfaces of VLPs. Finally, we present lists of nanotechnological RNA phage VLP applications, such as experimental vaccines constructed by genetic fusion and chemical coupling methodologies, nanocontainers for targeted drug delivery, and bioimaging tools.

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CYT003, a TLR9 agonist, in persistent allergic asthma – a randomized placebo‐controlled Phase 2b study

Abstract: Toll-like receptor-9 agonism with CYT003 showed no additional benefit in patients with insufficiently controlled moderate-to-severe allergic asthma receiving standard inhaled glucocorticosteroid therapy with or without LABAs.

Cited by 59 publications

References 38 publications

JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies

The True Story and Advantages of RNA Phage Capsids as Nanotools

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