Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma

Bacharier, Leonard B.; Máspero, Jorge; Katelaris, Constance H.; Fiocchi, Alessandro; Gagnon, Rémi; Mir, I. de; Jain, Neal; Sher, Lawrence; Mao, Xuezhou; Liu, Dongfang; Zhang, Yi; Khan, Asif; Kapoor, Upender; Khokhar, Faisal A; Rowe, Paul; Deniz, Yamo; Ruddy, Marcella; Laws, Elizabeth; Patel, Naimish; Weinreich, David M.; Yancopouloš, George D.; Amin, Nikhil; Mannent, Leda; Lederer, David J.; Hardin, Megan

doi:10.1056/nejmoa2106567

Cited by 155 publications

(163 citation statements)

References 21 publications

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“…Indeed, ILC2s are a well-recognized component of a network of immune cells that contribute to allergy and asthma and, as such, are targets of multiple biologics currently approved or in advanced clinical trials for adults and, in some cases, adolescents, including those targeting IgE, IL-4, IL-13, IL-5, IL-33 and thymic stromal lymphopoietin 104 . Of note, recent data show effects of the anti-IL-4/anti-IL-13 drug dupilumab in ameliorating uncontrolled moderate-to-severe asthma in 6–11-year-old children 105 . By contrast, the pro-inflammatory functions of ILC2s are beneficial in certain cancers, where ILC2s can be targets for anti-PD1 therapy to improve tumour rejection, at least in mouse models 61 .…”

Section: Conclusion and Therapeutic Prospectsmentioning

confidence: 99%

Heterogeneity of type 2 innate lymphoid cells

Spits

Mjösberg

2022

Nat Rev Immunol

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More than a decade ago, type 2 innate lymphoid cells (ILC2s) were discovered to be members of a family of innate immune cells consisting of five subsets that form a first line of defence against infections before the recruitment of adaptive immune cells. Initially, ILC2s were implicated in the early immune response to parasitic infections, but it is now clear that ILC2s are highly diverse and have crucial roles in the regulation of tissue homeostasis and repair. ILC2s can also regulate the functions of other type 2 immune cells, including T helper 2 cells, type 2 macrophages and eosinophils. Dysregulation of ILC2s contributes to type 2-mediated pathology in a wide variety of diseases, potentially making ILC2s attractive targets for therapeutic interventions. In this Review, we focus on the spectrum of ILC2 phenotypes that have been described across different tissues and disease states with an emphasis on human ILC2s. We discuss recent insights in ILC2 biology and suggest how this knowledge might be used for novel disease treatments and improved human health.

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Section: Conclusion and Therapeutic Prospectsmentioning

confidence: 99%

Heterogeneity of type 2 innate lymphoid cells

Spits

Mjösberg

2022

Nat Rev Immunol

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“…The Liberty Asthma Voyage trial was a phase 3, double-blind, randomized, and placebo-controlled study which lasted 52 weeks and evaluated the therapeutic effects of dupilumab in children (age: 6–11 years) with moderate-to-severe asthma ( Bacharier et al, 2021 ). Dupilumab was administered every 2 weeks as add-on biological therapy at doses of either 100 mg (body weight ≤30 kg) or 200 mg (body weight >30 kg).…”

Section: Therapeutic Effects Of Dupilumab In Severe Asthmamentioning

confidence: 99%

Interleukins 4 and 13 in Asthma: Key Pathophysiologic Cytokines and Druggable Molecular Targets

et al. 2022

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Interleukins (IL)-4 and -13 play a pivotal role in the pathobiology of type-2 asthma. Indeed, IL-4 is crucially involved in Th2 cell differentiation, immunoglobulin (Ig) class switching and eosinophil trafficking. IL-13 cooperates with IL-4 in promoting IgE synthesis, and also induces nitric oxide (NO) production, goblet cell metaplasia and fibroblast proliferation, as well as elicits contractile responses and hyperplasia of airway smooth muscle cells.IL-4 and IL-13 share common signaling pathways, activated by the binding of both cytokines to receptor complexes including the α-subunit of the IL-4 receptor (IL-4Rα). Therefore, the subsequent receptor dimerization is responsible for the pathophysiologic effects of IL-4 and IL-13. By selectively blocking IL-4Rα, the fully human IgG4 monoclonal antibody dupilumab behaves as a dual receptor antagonist of both IL-4 and IL-13. Through this mechanism of action, dupilumab exerts effective therapeutic actions in type-2 inflammation, thus decreasing asthma exacerbations, FeNO (fractional exhaled NO) levels, and the intake of oral corticosteroids (OCS). In addition to being approved for the add-on biological therapy of severe asthma, dupilumab has also been licensed for the treatment of nasal polyposis and atopic dermatitis.

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“…Dupilumab is also effective in cases with elevated FeNo in the absence of eosinophilia, suggesting an IL-13 role in this kind of patient ( 27 ). A recent trial reported the efficacy and safety of dupilumab in moderate to severe asthma patients aged 6–11 years ( 28 ).…”

Section: T2-high Treatmentsmentioning

confidence: 99%

Biological Treatments and Target Therapies for Pediatric Respiratory Medicine: Not Only Asthma

et al. 2022

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We present a description of pediatric pneumology biological medications and other target therapies. The article aims at introducing the importance of a molecular approach to improve treatments. The first item treated was T2-High asthma and its current biological treatment and prescribing indications to propose a flow-chart to guide the clinical choice. Molecular rationales of such treatments are used to introduce a more general description of the biological and molecular approach to target therapies application. We introduce a general interpretation approach to neutrophilic asthma using the molecular plausibility one in order to propose possible future treatments mainly targeting interleukin-1 (IL-1), IL-17, IL-12, and IL-23. Indeed, cytokines can be excellent targets for several biological treatments. Downregulation of specific cytokines can be crucial in treating autoinflammatory and rheumatological diseases with a pulmonary involvement. Such conditions, although rare, should be early recognized as they can involve significant improvement with a properly targeted therapy. We face these conditions in a cherry-picking fashion picturing SAVI (STING-associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), and COPA (coat proteins alpha syndrome) syndrome pulmonary involvement. Such examples are functional to introduce molecular-based approach for patients with rare conditions. Molecular plausibility can be highly valuable in treating patients with not-approved but possibly highly effective therapies. Due to the rarity of these conditions, we stress the concept of basket trials using the example of cytokinin-directed immunosuppressive treatment. Lastly, we provide an example of augmentative therapy using the alpha1 antitrypsin deficiency as a model. In summary, the article presents a collection of the most recent achievements and some possible future developments of target therapies for pediatric pulmonary conditions.

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Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma

Cited by 155 publications

References 21 publications

Heterogeneity of type 2 innate lymphoid cells

Heterogeneity of type 2 innate lymphoid cells

Interleukins 4 and 13 in Asthma: Key Pathophysiologic Cytokines and Druggable Molecular Targets

Biological Treatments and Target Therapies for Pediatric Respiratory Medicine: Not Only Asthma

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