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      The use of intravenous versus subcutaneous monoclonal antibodies in the treatment of severe asthma: a review

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          Abstract

          Background

          Monoclonal antibodies (mAbs) approved for use as add-on therapy in patients with severe asthma target the underlying pathogenesis of asthma.

          Main body

          Omalizumab binds immunoglobulin E (IgE), thereby inhibiting its interaction with the high-affinity IgE receptor and reducing the quantity of free IgE available to trigger the allergic cascade. Anti-interleukin (IL)-5 mAbs mepolizumab, benralizumab and reslizumab block the interaction between IL-5 and its receptor on eosinophils, thus targeting the eosinophilic pathway in asthma. Most mAbs are available as intravenous (IV) or subcutaneous (SC) formulations, as their high molecular weight and gastric degradation preclude oral administration. This review compares the pharmacology, efficacy, immunogenicity, injection- and infusion-related adverse drug reactions of subcutaneously administered omalizumab and mepolizumab with the intravenously administered reslizumab. In terms of pharmacokinetics, IV route of administration appears to be superior to the SC route due to quicker absorption, greater bioavailability, shorter time to maximum serum concentration and similar elimination half-life. Route of administration does not appear to translate into striking differences in efficacy and safety of mAbs used for the treatment of severe asthma, as all are generally considered to be effective and well tolerated. Hypersensitivity and administration-related reactions have been described with both IV and SC mAbs.

          Conclusion

          mABs are effective and have low immunogenicity due to their nature as humanised antibodies. Evidence on the use of mAbs in indications other than severe asthma suggest that both the SC and the IV routes of administrations have their respective advantages and disadvantages; but their full utility remains to be elucidated.

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          Most cited references35

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          Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

          Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial

            Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia.
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              Clinical pharmacokinetics of therapeutic monoclonal antibodies.

              Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
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                Author and article information

                Contributors
                00390552751816 , andrea.matucci@unifi.it
                vultaggioalessandra@gmail.com
                romano.danesi@unipi.it
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                16 August 2018
                16 August 2018
                2018
                : 19
                : 154
                Affiliations
                [1 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Immunoallergology Unit, AOU Careggi, , University of Florence, ; Largo Brambilla 3, 50134 Florence, Italy
                [2 ]ISNI 0000 0004 1757 3729, GRID grid.5395.a, Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, , University of Pisa, ; Pisa, Italy
                Article
                859
                10.1186/s12931-018-0859-z
                6097430
                30115042
                be904cad-9387-4401-940d-b8d9f2bdb9e8
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 May 2018
                : 8 August 2018
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Respiratory medicine
                eosinophil,mepolizumab,monoclonal antibodies,omalizumab,reslizumab,severe asthma
                Respiratory medicine
                eosinophil, mepolizumab, monoclonal antibodies, omalizumab, reslizumab, severe asthma

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