CASE REPORT published: 30 September 2020 doi: 10.3389/fphar.2020.587621 Dual Monoclonal Antibody Therapy for a Severe Asthma Patient Christian Domingo 1,2*, Xavier Pomares 1,2, Anisi Morón 3 and Ana Sogo 1,2 1 Pulmonary Service, Corporació Sanitària Parc Taulı´, Barcelona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3 Pharmacy Department, Corporació Sanitària Parc Tauli, Barcelona, Spain Introduction: Omalizumab, the first biological treatment for severe allergic bronchial asthma, has been on the market for more than a decade. Omalizumab was initially considered to be an IgE-blocking agent, and therefore, an inhibitor of the Th2 (allergic or adaptive) cascade. More recently, other monoclonal antibodies for severe eosinophilic asthma have become available, which exert an anti-eosinophilic effect basically by Edited by: blocking IL5 or its receptor. These agents exert this effect regardless of the origin of the Mauro Maniscalco, eosinophils (i.e., the adaptive or the innate immune system). Fondazione Salvatore Maugeri (IRCCS), Italy Case study: An oral corticosteroid-dependent allergic asthma patient was treated with Reviewed by: omalizumab. After a year of treatment, the improvement remained very limited and the Corrado Pelaia, medical team proposed discontinuation. However, the patient felt that her asthma had University of Catanzaro, Italy Claudia Crimi, improved and she refused to give up the therapy, which continued for ten years. The mean Gaspare Rodolico Hospital, Italy accumulated oral corticosteroid dose per month during the last year was around 200 mg; *Correspondence: despite this, the FEV1 was low, Since the patient had a high number of eosinophils in Christian Domingo cdomingo@tauli.cat peripheral blood, she accepted a switch to mepolizumab when this agent became available. One year later, the clinical improvement was limited and severe symptoms of Specialty section: allergy reappeared, and a combination of monoclonal antiobodies (omalizumab and This article was submitted mepolizumab) was proposed. Respiratory Pharmacology, a section of the journal Results: After 24 months of dual therapy, a marked improvement in the FEV1 was Frontiers in Pharmacology observed, reaching the normal range, and the OC dose was reduced to 2.5 mg per day of Received: 28 July 2020 Accepted: 14 September 2020 prednisolone. No side effects were observed. Published: 30 September 2020 Conclusions: In some severe allergic asthma patients with persistently high eosinophil Citation: counts in peripheral blood and who are considered non- or mild responders to anti-IgE Domingo C, Pomares X, Morón A and Sogo A (2020) Dual Monoclonal and anti-IL5 administered individually, a combination of the two antibodies covering the Antibody Therapy for a entire T2 spectrum may be effective. Severe Asthma Patient. Front. Pharmacol. 11:587621. Keywords: severe asthma, Th2 (type-2) immune responses, T2 immune responses, omalizumab, mepolizumab, doi: 10.3389/fphar.2020.587621 combined therapy Frontiers in Pharmacology | www.frontiersin.org 1 September 2020 | Volume 11 | Article 587621 Domingo et al. Omalizumab and Mepolizumab Combination Therapy INTRODUCTION was 132 IU/ml. The peripheral blood eosinophil count was 400 (6.4%) and the FENO (Niox, Phadia®) score was 232 ppb. Until omalizumab was first marketed in 2006, the international The following anthropometric data were recorded: height guidelines considered oral corticosteroids (OCs) to be the final 155 cm; weight: 72 Kg; body mass index (BMI): 29.9 kg/m2. step in the treatment of severe asthma patients (Domingo et al., Spirometry showed a severe lung obstruction with an FEV1 of 2007). The use of certain immunosuppressive drugs was also 1.03 L (38% of the predicted figure) despite administration of 15– proposed (Domingo et al., 2009; Domingo et al., 2011a) although 20 mg/day of prednisolone as add-on therapy. A computerized they were not included in the guidelines. With the advent of tomography of the paranasal sinuses ruled out nasal polyposis biological treatments linked to the concept of precision medicine but confirmed some inflammation, and a chest CT scan showed (Jameson and Longo, 2015), it became necessary to phenotype air trapping and ruled out other lung diseases. Before starting the patients (Wenzel, 2012), and more recently to endotype them biological treatment, the adherence to inhalation therapy was (Lötvall et al., 2011). As a result, the latest GINA update advises confirmed by checking the electronic drug delivery of inhalers in the use of monoclonal antibodies (mAbs) before chronic OCs pharmacies, while the inhalation technique was systematically and recommends mAbs as add-on therapy: omalizumab in checked at each visit by respiratory nurses. allergic patients (IgE-mediated asthma), and anti-IL5 in The patient was administered sub-cutaneous (sc) eosinophilic patients (including anti-IL5r). Recently, omalizumab at a dose of 300 mg/month, in accordance with dupilumab (an anti-IL4 and anti-IL13) was added to this the dosing table (Domingo et al., 2007). After 16 weeks of group. Although these drugs have been shown to be highly treatment, she reported a mild improvement and the treatment efficacious (Humbert et al., 2005; Ortega et al., 2014) and real-life was maintained. After a year of omalizumab, the improvement studies report an even greater effectiveness than randomized remained very limited (GETE: mild responder; asthma control studies (Domingo et al., 2011b; Lugogo et al., 2016), not all test (ACT):12) and the medical team proposed discontinuation patients respond favorably. Little is known about the of the treatment. However, the patient felt that her asthma had consequences of switching from one family of mAbs to improved and she refused to give up the treatment, which another, and there is no experience with mAb combinations. continued for ten years. During this period she did not suffer Here, we report the improvement in a patient with severe allergic severe asthma exacerbations requiring hospital admission, her asthma with a high eosinophil count treated with two ACT ranged between 10–14, and she was unable to discontinue concomitant mAbs. OCs. When mepolizumab became available, the medical team proposed a switch from omalizumab to this agent since the blood eosinophil count had remained repeatedly high (always above 400, and up to 1600 in one measurement). The patient CASE STUDY agreed to the change, and a mild improvement was observed A 55-year-old female was referred to our unit 14 years ago for (ACT= 15) with reduction of the mean OC dose to 7.5-10 mg/ management of her severe asthma. She had never smoked, had day without significant changes in FEV1. After 14 months of a not worked for the last 10 years due to her disease (previously monthly sc mepolizumab dose of 100 mg, the clinical signs of she had worked in a photography and printing shop), had no allergy re-appeared. At that point, the medical team suggested regular contact with animals, and her past clinical history did that a combination of two mAbs administered concomitantly not reveal any relevant disease. Her asthma started at the age of on the same day (omalizumab 300 mg/month plus 23 and was initially classified as allergic. She had been a patient mepolizumab 100 mg per month, both sc) might offer a at our hospital throughout her adult life, and the skin prick test synergistic benefit. using standardized products (ALK-Abelló ) found in her hospital records showed allergy to house dust mites, cupressus, banana tree and dog epithelium. The patient was RESULTS monitored by her general physician until she started to deteriorate. She was treated with a fixed dose combination of After 24 months of dual biological therapy, the patient presented salmeterol 50 µg and fluticasone 500 µg bid, montelukast 10 a notable improvement. At month 6, her ACT was 17 and ranged mg per day and salbutamol on request. Since she had needed between 17 and 20 during the following six months. At the end of repeated bursts of OCs during the three years previous to her the first year, the FEV1 was normal (83% of the predicted value - hospital visit, these drugs had been chronically prescribed. The Figure 1A) and although it showed some variability during the year prior to starting treatment with omalizumab she had had second year, airway obstructions (when they occurred) were five exacerbations requiring OCs. On referral to our unit, she always mild. At the end of the second year, the FEV1 value was reported dyspnea on mild exertion, frequent wheezing, and 96%. Meantime, daily OC dose was reduced to and maintained at high consumption of rescue medication. She also reported 2.5 mgr/day due to the risk of adrenal insufficiency (Figure 1B); some allergic comorbidities such as eye lachrymation and no exacerbations occurred; GETE: good/excellent; ACT: itching, rhinorrhea, and coryza. The new skin prick test maintained ≥20). The concomitant treatment with two mAbs using standardized antigens from the same company (ALK- was well tolerated. Figure 1B shows the evolution of OC Abelló ) showed the same sensitization results. Total IgE value consumption during the last three years of treatment. Frontiers in Pharmacology | www.frontiersin.org 2 September 2020 | Volume 11 | Article 587621 Domingo et al. Omalizumab and Mepolizumab Combination Therapy A B FIGURE 1 | (A) The figure shows the changes in the FEV1 during three different periods. In the first period, the patient was receiving omalizumab, in the second mepolizumab, and in the third, mepolizumab and omalizumab. Note the marked improvement in the FEV1 during the dual mAb therapy. (B) The values of oral corticosteroid are the mean monthly accumulated intake during the treatment period of the last year of omalizumab alone, the 14 months on mepolizumab and the 24 months on omalizumab plus mepolizumab. A clear trend towards a decrease in oral corticosteroid consumption was observed. During the last three months, the daily OC dose was 2.5 mg/day. DISCUSSION was made from one mAb family to another. Mepolizumab has been found to be effective in sensitized patients (Pelaia et al., 2020). Omalizumab was initially considered to be an IgE blocker, but it was However, in our case, the improvement with mepolizumab was very soon observed that many immunological changes occurred after its limited, and the re-appearance of allergic symptoms in the absence administration; it was then redefined as an immunoregulatory drug of the anti-IgE suggested that the Th2 cascade remained active. acting mainly in the adaptive immune system (Domingo, 2014). Eosinophils are effector cells which can be recruited from the The drug has been shown to be effective in allergic patients adaptive immune system (Th2 profile) or from the innate regardless of the eosinophil count (Hanania et al., 2013; Busse, immune system (a concept termed the “T2 profile”, which 2018; Humbert et al., 2018), and achieves a significant reduction in encompasses both adaptive and innate activity) (Israel and tissue eosinophils (Djukanović et al., 2004). In the view of many Reddel, 2017). Although in allergic patients the origin of the authors (including our own group) patients with positive allergic eosinophils is the activity of the allergic cascade itself (mast cells tests are considered to have an allergic phenotype despite having are the cells that release the highest amounts of IL5), the toxic effect high eosinophil counts, and are therefore placed on omalizumab of activated eosinophils can damage the bronchial epithelium and (Blaiss et al., 2017; Bousquet et al., 2017; Domingo, 2017; Israel and favor the release of alarmins (TSLP and IL33) that will activate type Reddel, 2017). On occasions the improvement is very limited 2 innate lymphoid cells (ILC2) and natural killer T cells (NKT), (Braunstahl et al., 2013) and the blood eosinophil count remains which in turn will release IL5 and thus raise the eosinophil high. In these cases, when mepolizumab became available, a switch count (Israel and Reddel, 2017). This synergistic effect of the two Frontiers in Pharmacology | www.frontiersin.org 3 September 2020 | Volume 11 | Article 587621 Domingo et al. Omalizumab and Mepolizumab Combination Therapy arms of immunity included under the umbrella of the T2 profile DATA AVAILABILITY STATEMENT can explain why the clinical response to one mAb (either omalizumab or mepolizumab) was limited and why the The original contributions presented in the study are included in concomitant administration of the two drugs achieved a marked the article; further inquiries can be directed to the clinical improvement. corresponding author. In 2017, a patient with allergic bronchopulmonary aspergillosis was treated with omalizumab and mepolizumab (Altman et al., 2017). This patient was receiving high doses of ETHICS STATEMENT OCs (1-2 mg/Kg) due to the aspergillosis, but did not present improvement. Her allergic status was not well documented when Ethical review and approval was not required for the study on omalizumab was started; the dose of this drug was changed human participants in accordance with the local legislation and during the follow-up and anti-fungal drugs were also institutional requirements. The patient provided their written concomitantly administered. The follow-up period was short informed consent to participate in this study. Written informed and so no evidence of long-term benefit can be ascertained. To consent was obtained from the individual(s) for the publication our knowledge, the report we present here is the first of a severe of any potentially identifiable images or data included in asthma patient correctly phenotyped as allergic, who had this article. peripheral blood eosinophilia and was successfully treated with two concomitant mAbs without any other potentially confusing treatment and with a long follow-up period (two years) that demonstrated the persistent benefits of the combination. AUTHOR CONTRIBUTIONS CD, XP, and AS were the pulmonologists involved in the ambulatory care of the patient in her monthly visits at the CONCLUSIONS hospital day unit of the severe asthma unit of the Hospital during these fourteen years. CD is the head of the severe asthma unit who In cases in which some biological overlap occurs (Tran et al., made the diagnosis of severe asthma and indicated the biologic 2016), the first step should be to prescribe the adequate drug for treatment. He is also the author who wrote the manuscript. AM was the corresponding phenotype; if this approach fails, a switch to the responsible of accepting the combination of both drugs and was another mAb should be made. In some selected patients who the responsible of the delivering and control the correct treatment partially respond to either mAb individually, dual concomitant with omalizumab and mepolizumab. All authors contributed to the mAb administration should be considered. article and approved the submitted version. REFERENCES Domingo, C., Moreno, A., Amengual, M. J., Comet, R., and Lujá n, M. (2009). Twelve years’ experience with methotrexate for GINA treatment step 5 asthma Altman, M. C., Lenington, J., Bronson, S., and Ayars, A. G. (2017). Combination patients. Curr. Med. Res. Opin. 25, 367–394. doi: 10.1185/03007990802643466 omalizumab and mepolizumab therapy for refractory allergic bronchopulmonary Domingo, C., Moreno, A., and Mirapeix, R. M. (2011a). 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D., Brusselle, G. G., FitzGerald, J. M., Chetta, A., et al. (2014). Mepolizumab treatment in patients with severe eosinophilic Copyright © 2020 Domingo, Pomares, Morón and Sogo. This is an open-access article asthma. N Engl. J. Med. 371 (13), 1198–1207. doi: 10.1056/NEJMoa1403290 distributed under the terms of the Creative Commons Attribution License (CC BY). Pelaia, C., Crimi, C., Pelaia, G., Nolasco, S., Campisi, R., Heffle, E., et al. (2020). The use, distribution or reproduction in other forums is permitted, provided the Real-life evaluation of mepolizumab efficacy in patients with severe original author(s) and the copyright owner(s) are credited and that the original eosinophilic asthma, according to atopic trait and allergic phenotype. Clin. publication in this journal is cited, in accordance with accepted academic practice. No Exp. Allergy 50 (7), 780–788. doi: 10.1111/cea.13613 use, distribution or reproduction is permitted which does not comply with these terms. 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