Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids

Noonan, Michael; Korenblat, Phillip E.; Mosesova, Sofia; Scheerens, Heleen; Arron, Joseph R.; Zheng, Yanan; Putnam, Wendy S.; Parsey, Merdad V.; Bohen, Sean P.; Matthews, John G.

doi:10.1016/j.jaci.2013.03.051

Cited by 155 publications

(96 citation statements)

References 19 publications

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“…IL-13 induces a corticosteroid-insensitive stimulation of TGF-b release from bronchial epithelial cells (2), suggesting that novel therapies directed toward limiting airway remodeling by corticosteroid-independent mechanisms will be necessary. IL-13 antagonist therapy has been shown to be beneficial in patients with high serum periostin (39), but does not improve lung function in patients not taking inhaled corticosteroids (40). Understanding the complex and varied pathophysiology of the disease is vital for the future of research and clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Jaffer¹,

Carter

Sanders³

et al. 2015

Am J Respir Cell Mol Biol

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Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-b promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-b, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-b-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-b activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-b expression and activity. TGF-b from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrialtargeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-b, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-b activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Jaffer¹,

Carter

Sanders³

et al. 2015

Am J Respir Cell Mol Biol

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“…Treatment efficacy was higher in patients with a high serum periostin level. M Noonan et al [36] treated 210 patients with BA using lebrikizumab. Treatment efficacy analysis showed no significant changes in the clinical course and FEV1 of BA patients treated with lebrikizumab as compared to the placebo group.…”

Section: Anti-cytokine Therapymentioning

confidence: 99%

Untitled

2017

JLPRR

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Submit Manuscript | http://medcraveonline.com HT and IHD (comparison group) and 20 were healthy subjects. All patients signed informed consent before the study. The Protocol of the study was passed review and was approved by the local ethics Committee of our University. The presence of IgE was determined to tick and house dust allergens, as well as the combined allergens of grass pollen, trees, weeds and flowers, S. pneumon, H. influenzae, and N. rerflava. The following cytokines were investigated: IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα. All patients were examined during disease exacerbation. The INFP and ATP were determined for each subject. The results of the study of CK levels and CK combinations, the so-called cytokine profile, indicate that they cannot be used for clinical diagnosis, including nosological diagnosis, the assessment of disease severity, and for selecting individual therapy, including anti-cytokine medications.The incredible heterogeneity of bronchial asthma (BA) is becoming more and more clear. More than 30 years ago, in 1977, we pointed out the existence of seven clinical and pathogenetic types of BA in patients, subsequently called the following phenotypes: infection-dependent, atopic, hormonal, neuropsychological, autoimmune, significant adrenergic imbalance, and primary bronchial hyperreactivity [1]. Individual methods of diagnosis and treatment were developed for each of these options, and the results of their testing have been repeatedly published. Subsequently, the phrase "primary bronchial hyperreactivity" was replaced with the idea of exercise-induced BA, peri-menstrual and aspirin-related clinical and pathogenetic types (phenotypes) of BA. The methods of individual diagnosis and treatment continued to improve and their efficacy continued to increase.Inhalation corticosteroids (ICS) are considered to be the most effective in the treatment of BA. However, in 5-10% of patients with BA, comprehensive treatment is ineffective even with the inclusion of ICS [2]. Although the percentage of patients resistant to ICS, is quite low, they make up 50% of the overall cost of treatment for patients with BA [3]. The insufficient treatment efficacy of existing methods for a group of patients with BA is a reason for examining the BA phenotypes and the endotypes that form them. Knowledge of the mechanisms (endotypes) that form the phenotypes creates the prospects for developing new treatment methods, which take into account the individual characteristics of BA in a particular patient. A cluster analysis of two large European cohorts identified two phenotypes. The first refers to patients with early onset allergic BA, while the second comprises mainly women with late onset disease, without atopy, and with a high body mass index [4].Seven parameters were selected to classify the endotypes in patients with BA after the cluster analysis: clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology, and response to treatment. The following BA endotypes were proposed based o...

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“…IL-13 receptor is a complex assembly of both IL-4 and IL-13 receptor subunits, allowing for redundancy. Blocking IL-13 signalling is achievable through direct cytokine binding and many monoclonal antibodies (mAbs) have been developed following various clinical strategies [102][103][104][105]. Notably, periostin is a downstream IL-13-induced protein that offers a chance to assess the IL-13 signature in the serum.…”

Section: Interleukin-13mentioning

confidence: 99%

Future treatment for asthma

et al. 2016

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The landscape of asthma has considerably changed after 40 years of inhaled corticosteroid development and nearly 20 years since the first monoclonal antibodies (mAbs) were approved. New members of pharmacological families and more effective drug-delivery devices have been designed but the proportion of uncontrolled patients, unfortunately, remains stable. The most promising treatments now rely on targeted therapies that encourage the improvement of the characterisation of our patients. These clinical ( phenotype) or new biological (endotype) tools lead to palpable personalised medicine. This review examines not only the future of mAbs and other new ways of treating asthma but also describes futuristic views based on the paradigm shifts that are ready to occur. @ERSpublications Future treatment for asthma: easier, safer, personalised http://ow.ly/V7b4h

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Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids

Cited by 155 publications

References 19 publications

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model

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Future treatment for asthma

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