Disabling inflammatory pathways with biologics and resulting clinical outcomes in severe asthma

Caruso, Massimo; Crisafulli, Emanuele; Demma, Shirin; Holgate, Stephen T.; Polosa, Riccardo

doi:10.1517/14712598.2013.743989

Cited by 8 publications

(3 citation statements)

References 81 publications

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“…As healthcare costs associated with newer biological precision medicine therapies soar for patients with moderate and particularly severe asthma, improved high-sensitivity noninvasive nonionizing imaging to optimize and minimize the use of these therapies will be welcome. 48-51 Anticipating that repeat imaging studies will be used in pediatric patients as well as adults, the implementation of MRI techniques becomes highly attractive and circumvents potential cumulative X-ray risks.…”

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

et al. 2017

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Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a clinically relevant rodent model.

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Section: Discussionmentioning

confidence: 99%

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

et al. 2017

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“…The IL-5 receptor includes an α and a βc chain; the first one is specific for the IL-5, while the βc subunit is also recognized by IL-3 and GM-CSF [Menzies-Gow et al 2003; Kouro and Takatsu, 2009]. Antagonizing the IL-5 with specific monoclonal antibodies (mAbs) may have beneficial advantage, given that the eosinophil may also serve a pathogenetic role in the mixed Th2/Th1/Th17 endotype of severe asthma [Caruso et al . 2013a].…”

Section: Eosinophilic Inflammation Il-5 and Mepolizumabmentioning

confidence: 99%

Mepolizumab for severe refractory eosinophilic asthma: evidence to date and clinical potential

Menzella

Lusuardi

Galeone

et al. 2016

Therapeutic Advances in Chronic Disease

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Severe asthma is characterized by major impairment of quality of life, poor symptom control and frequent exacerbations. Inflammatory, clinical and causative factors identify different phenotypes and endotypes of asthma. In the last few years, new treatment options have allowed for targeted treatments according to the different phenotypes of the disease. To accurately select a specific treatment for each asthmatic variant, the identification of appropriate biomarkers is required. Eosinophilic asthma is a distinct phenotype characterized by thickening of the basement membrane and corticosteroid responsiveness. This review reports the latest evidence on an anti-IL-5 monoclonal antibody, mepolizumab, a new and promising biological agent recently approved by the FDA specifically for the treatment of severe eosinophilic refractory asthma.

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“…Such considerations highlight the potential importance of biologic treatments directed against proinflammatory cytokines, including monoclonal antibodies and small-molecule inhibitors. In particular, biologics may represent useful adjunctive therapies, especially for patients with more severe asthma which is not fully responsive to conventional treatments alone [18–20]. Variable responses have been observed using experimental cytokine-directed therapies, probably because of the significant differences occurring among distinct asthma phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Update on Anticytokine Treatment for Asthma

Gallelli

Busceti

Vatrella

et al. 2013

BioMed Research International

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Current advances in the knowledge of asthma pathobiology suggest that anticytokine therapies can be potentially useful for the treatment of this complex and heterogeneous airway disease. Recent evidence is accumulating in support of the efficacy of anti-IL-4, anti-IL-5, and anti-IL-13 drugs. Therefore, these new developments are now changing the global scenario of antiasthma therapies, especially with regard to more severe disease. Current findings referring to variability of individual therapeutic responses highlight that the different asthma subtypes need to be well characterized, in order to implement phenotype-targeted treatments which in the near future will hopefully be mainly based on cytokine-directed biologics.

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Disabling inflammatory pathways with biologics and resulting clinical outcomes in severe asthma

Cited by 8 publications

References 81 publications

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

Mepolizumab for severe refractory eosinophilic asthma: evidence to date and clinical potential

Update on Anticytokine Treatment for Asthma

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