A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma

Singh, Dave; Kane, Binita; Molfino, Néstor A.; Faggioni, Raffaella; Roskos, Lorin; Woodcock, Ashley

doi:10.1186/1471-2466-10-3

Cited by 77 publications

(35 citation statements)

References 16 publications

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“…YM-341619 administered orally to rats during OVA-induced allergic inflammation decreased eosinophil recruitment to the lungs, and decreased airway reactivity (17). Antibodies that target IL-13, IL-4, or the IL-4Ra chain of the IL-13R decreased the activation of STAT6, and are currently undergoing human clinical trials to reduce asthma symptoms and mucus production (16,(29)(30)(31)(32)(33). Based on our findings, STAT6-targeted and IL-13-targeted therapeutics may not eliminate the symptoms associated with mucous cell metaplasia and mucus production in patients with asthma and increased IL-17A protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we examined IL-17A mucous cell metaplasia in the absence of STAT6. Understanding this mechanism is important, because therapeutics targeting the STAT6 pathway are being developed for the treatment of asthma (16,17,(29)(30)(31)(32)(33)). These patients demonstrate increased levels of mucus production, but with variable expressions of IL-13 or periostin, an IL-13 marker protein (34), calling into question the absolute IL-13 dependence of airway mucus production in asthma.…”

Section: Discussionmentioning

confidence: 99%

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IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Newcomb¹,

Boswell²,

Sherrill³

et al. 2013

Am J Respir Cell Mol Biol

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Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.Keywords: asthma; mucous cell metaplasia; IL-17A; STAT6; Airway mucus is a hallmark of asthma. Airway epithelial cell remodeling in asthma includes mucous cell metaplasia and mucus hypersecretion, which narrows the airway lumen and limits airflow (1). A major component of mucus consists of mucins, which are large glycoproteins that determine the viscoelasticity of mucus (2). Mucin genes are expressed in many tissues, but MUC5AC and MUC5B constitute the primary mucin genes expressed in the airway epithelial cells of the lung (3). Previous studies have shown that IL-13, a Th2 cytokine that is increased during allergic airway inflammation, is required for airway mucous cell metaplasia (4-7).IL-13 is abundant in the sputum of some patients with asthma (8). IL-13 binds to the IL-13 receptor (R), which is comprised of two subunits, IL-4Ra and IL-13Ra1. The binding of IL-13 to the IL-13R results in the phosphorylation and activation of the downstream transcription factor signal transducers and activators of transcription (STAT)-6 and the transcription of IL-13-mediated genes. STAT6 and IL-13 are required for maximal airway mucous cell metaplasia in murine models of allergic airway inflammation (4-6, 9). The airway instillation of recombinant IL-13 or t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Newcomb¹,

Boswell²,

Sherrill³

et al. 2013

Am J Respir Cell Mol Biol

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“…The selected maximum dose (10.0 mg/kg, IV) for FIH study of CNTO 5825 provided predicted systemic exposures that were below observed systemic exposures at NO-AEL in rats and cynomolgus monkeys. In addition, the selected doses (0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg) of CNTO 5825 for FIH study were within the range of doses that have been evaluated in clinical studies of related anti-IL-13 mAbs [33][34][35][36].…”

Section: Discussionmentioning

confidence: 95%

Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

Nnane

Zhou

et al. 2015

Basic Clin Pharma Tox

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CNTO 5825 is a human anti-interleukin-13 (IL-13) monoclonal antibody (mAb) that inhibits binding of human IL-13 to IL-13Ra1 and IL-13Ra2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non-clinical PK data in order to select the right and safe doses for first-in-human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19 ml/day/kg in cynomolgus monkeys. The volume of distribution at steady-state (Vss) in rats was large (151.52-155.64 ml/kg) compared to cynomolgus monkey (49.77-61.10 ml/kg). The terminal half-life (T 1/2 ) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1-10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70 kg) based on time-invariant method with combined PK data from rats and monkeys were 4.84 AE 1.13 ml/day/kg and 68.93 AE 35.55 ml/kg, respectively. The selected doses for the FIH study based on time-invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.Several studies have shown that interleukin-13 (IL-13) in airways plays a central role in allergic asthma, where it regulates IgE production, eosinophilic inflammation, mucus secretion and airway hyper-responsivenes [1][2][3][4][5][6][7][8]. Interleukin-13 interacts with IL-13-positive cells in airway smooth muscles through a receptor complex consisting of IL-13 receptor alpha 1 (IL-13aR1) and interleukin-4 receptor alpha (IL-4Ra) subunits [4,5,8]. Therefore, neutralization of IL-13 represents a potential therapeutic approach for intervention in asthma [9,10].CNTO 5825 is a human anti-IL-13 monoclonal antibody (mAb) that potently and specifically inhibits binding of human IL-13 to both IL-13Ra1 and IL-13Ra2 [11]. Non-clinical studies have demonstrated that CNTO 5825 inhibited IL-13-mediated actions and supported advancing CNTO 5825 to first-in-human (FIH) study as a potential therapeutic agent for treatment of asthma.The importance of choosing the right and safe starting doses in FIH trials to mitigate risks of new molecular entities (NME) has been highlighted in guidelines from European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidance on starting dose selection [12,13]. An approach that is widely applied for FIH starting dose selection involves allometrically scaling the no observed adverse effect level (NOAEL) obtained from toxicologically relevant species [12,13]. The pharmacokinetic/pharmacodynamic (PK/PD)-guided approach based on predicted...

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“…Recently, it was described that a human anti-IL-13 mAb given by intravenous injection or by sub-cutaneous administration displays an acceptable safety profile and can be administered safely in patients with asthma (29,30). Furthermore, lebrikizumab, an anti-IL-13 mAb administered subcutaneously significantly improved lung function in patients with moderatesevere asthma who had elevated serum periostin at baseline (26).…”

Section: Discussionmentioning

confidence: 99%

Nebulized Anti–IL-13 Monoclonal Antibody Fab′ Fragment Reduces Allergen-Induced Asthma

Hacha

Tomlinson

Maertens

et al. 2012

Am J Respir Cell Mol Biol

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JH and MG carried out experiments, participated in the experimental design and in the interpretation of data and write the manuscript. KT and RP provided the monoclonal antibody (CA154_582) and revised the manuscript critically. LM, GP and NR did take part to bench work. JMF initiated the project and revised the manuscript. AN did take part to study design and revised the manuscript critically. DC initiated and supervised the "This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org" whole project, was responsible to find grants, participated in the design of the study, reviewed results and reviewed and finalized the manuscript. Conclusions: These data demonstrate that an inhaled anti-IL-13 significantly reduces airway inflammation, hyperresponsiveness and remodeling. Specific neutralization of IL-13 in the lungs using an inhaled anti-IL-13 could represent a novel and effective therapy for the treatment of asthma. Source of support

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A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma

Cited by 77 publications

References 16 publications

IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

Nebulized Anti–IL-13 Monoclonal Antibody Fab′ Fragment Reduces Allergen-Induced Asthma

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