**Quilizumab**

Quilizumab (MEMP1972A, Genentech/Roche), another mAb anti-IgE, is being studied now in a phase IIb, randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the efficacy and safety of three different doses (150, 300, and 450 mg, subcutaneously) in adults with allergic asthma not controlled with ICS and a second controller (NCT01582503). Quili‐ zumab already has been proven effective in decreasing total and specific IgE in patients with allergic rhinitis (NCT01160861) and mild allergic asthma (NCT01196039), with a good safety profile [48].

#### **3.2. Eosinophilic and Th2 high asthma**

#### *3.2.1. Anti IL-5 monoclonal antibodies: mepolizumab, reslizumab, and benralizumab*

Interleukin-5 (IL-5) is a hematopoietic cytokine produced by various cells such as Th2 lymphocytes, eosinophils, basophils, mast cells, and natural killer T-cells, and it is the main eosinophil modulator cytokine [49] because it enhances eosinophil chemotaxis, activation, and degranulation, while reducing apoptosis and prolonging eosinophils' survival. The IL-5 receptor (IL-5R), expressed on both basophils and eosinophils, is made up of two subunits: an α-subunit (IL-5Rα) that is IL-5-specific and a βc-subunit (IL-5Rβc) that is responsible for signal transduction and is shared with the specific α-receptor subunits of IL-3 receptors and granu‐ locyte–macrophage colony–stimulating factor (GM-CSF).

Two mAbs (mepolizumab and relizumab) that neutralize IL-5 and another mAb (benralizu‐ mab) that blocks the IL-5Rα have been developed and are currently being evaluated in clinical trials [50].

#### *3.2.1.1 Mepolizumab*

Mepolizumab in a fully humanized anti-IL-5 IgG1 mAb that binds to the free IL-5 with high affinity and specificity, thus preventing its binding to the α chain of the IL-5R on the eosinophil cell surface. It was the first IL-5 antagonist used in randomized, controlled trials in patients with mild asthma [51, 52] and with moderate uncontrolled persistent asthma [53]. A reduced eosinophil count was observed in both sputum and peripheral blood asthma in biopsies of bronchia and bone marrow, but with no effect on bronchial hyperresponsiveness (BHR), late asthmatic response, lung function, symptoms, or use of rescue medication whatsoever [51– 53]. The reduction in the percentage of exacerbations [53] did not reach statistical significance though.

In these studies, patients were not selected according to the presence of eosinophilic airway inflammation, and the number of exacerbations, a parameter directly and causally related with eosinophilic airway inflammation, was not evaluated as a principal variable of the response to treatment [49]. Two new trials were subsequently performed in patients with refractory severe persistent asthma with recurrent exacerbations, who had bronchial eosinophilic inflammation [54, 55]. Both trials reported a very significant reduction in the number of exacerbations and in the dose of oral corticosteroids in the active group when compared to those in the placebo group, as well as a major improvement in asthma control questionnaire (ACQ) scores. This response was accompanied by a significant reduction in eosinophil numbers in blood and sputum.

A phase IIb multicenter study (GlaxoSmithKline) has also been performed in order to deter‐ mine the optimal dose of mepolizumab and to confirm its efficacy and safety in patients with severe eosinophilic asthma (the DREAM study) [56]. A total of 621 patients were randomized to placebo or one of three mepolizumab doses (75, 250, or 750 mg respectively) in parallel groups for 1 year. Mepolizumab reduced the number of severe exacerbations by 50% approx‐ imately in all the mepolizumab groups when compared with placebo, irrespective of the dose. Also, no dose–response effect was reported. The blood and sputum eosinophil counts were also reduced, and a dose–response effect was observed for eosinophil counts in sputum. On the other hand, no changes in asthma symptoms, quality of life, FeNO or lung function were observed. The drug was safe and effective. A multivariant analysis established that blood eosinophilia and the number of exacerbations in the 12 months prior to the study only were associated with a good response to mepolizumab. A meta-analysis performed on published clinical trials with mepolizumab, including a total of 1131 patients, confirmed that in cases of eosinophilic asthma, mepolizumab reduced the number of exacerbations and improved asthma-related quality of life [57].

#### *3.2.1.2 Reslizumab*

symptoms. QGE031B's effectiveness is currently being evaluated in patients with allergic asthma (GINA step 4/5) in a phase IIa clinical trial, with omalizumab as an active comparator.

Quilizumab (MEMP1972A, Genentech/Roche), another mAb anti-IgE, is being studied now in a phase IIb, randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the efficacy and safety of three different doses (150, 300, and 450 mg, subcutaneously) in adults with allergic asthma not controlled with ICS and a second controller (NCT01582503). Quili‐ zumab already has been proven effective in decreasing total and specific IgE in patients with allergic rhinitis (NCT01160861) and mild allergic asthma (NCT01196039), with a good safety

Interleukin-5 (IL-5) is a hematopoietic cytokine produced by various cells such as Th2 lymphocytes, eosinophils, basophils, mast cells, and natural killer T-cells, and it is the main eosinophil modulator cytokine [49] because it enhances eosinophil chemotaxis, activation, and degranulation, while reducing apoptosis and prolonging eosinophils' survival. The IL-5 receptor (IL-5R), expressed on both basophils and eosinophils, is made up of two subunits: an α-subunit (IL-5Rα) that is IL-5-specific and a βc-subunit (IL-5Rβc) that is responsible for signal transduction and is shared with the specific α-receptor subunits of IL-3 receptors and granu‐

Two mAbs (mepolizumab and relizumab) that neutralize IL-5 and another mAb (benralizu‐ mab) that blocks the IL-5Rα have been developed and are currently being evaluated in clinical

Mepolizumab in a fully humanized anti-IL-5 IgG1 mAb that binds to the free IL-5 with high affinity and specificity, thus preventing its binding to the α chain of the IL-5R on the eosinophil cell surface. It was the first IL-5 antagonist used in randomized, controlled trials in patients with mild asthma [51, 52] and with moderate uncontrolled persistent asthma [53]. A reduced eosinophil count was observed in both sputum and peripheral blood asthma in biopsies of bronchia and bone marrow, but with no effect on bronchial hyperresponsiveness (BHR), late asthmatic response, lung function, symptoms, or use of rescue medication whatsoever [51– 53]. The reduction in the percentage of exacerbations [53] did not reach statistical significance

In these studies, patients were not selected according to the presence of eosinophilic airway inflammation, and the number of exacerbations, a parameter directly and causally related with

*3.2.1. Anti IL-5 monoclonal antibodies: mepolizumab, reslizumab, and benralizumab*

locyte–macrophage colony–stimulating factor (GM-CSF).

**Quilizumab**

profile [48].

trials [50].

though.

*3.2.1.1 Mepolizumab*

**3.2. Eosinophilic and Th2 high asthma**

124 Asthma - From Childhood Asthma to ACOS Phenotypes

Reslizumab, a humanized IgG2, is another IL-5 inhibitor that is administered intravenously, although it has not been studied at such extent as mepolizumab. The only published clinical trial in patients with poorly controlled eosinophilic asthma proved that patients treated with reslizumab showed a significant improvement in FEV1 and, interestingly, patients with concomitant polyposis showed better asthma control compared to the placebo group [58].

#### *3.2.1.3 Benralizumab*

Benralizumab is a humanized IgG1 mAb targeting IL-5Rα, which reduces eosinophilia by antibody-dependent cell-mediated cytotoxicity. Intravenous benralizumab has shown acceptable safety and tolerability in a phase I, dose-escalating study, with a marked reduction in circulating eosinophils [59].

In a phase I, multicenter, double-blind, placebo-controlled study, 13 patients were randomized to receive a single intravenous dose of placebo or 1 mg/kg benralizumab, and other 14 patients were randomized to receive a monthly subcutaneous dose of placebo, or either 100 or 200 mg benralizumab, for 3 months. The study concluded that both the single intravenous dose and the multiple subcutaneous doses of benralizumab reduced the percentage of eosinophils in the bronchial biopsies and in induced sputum and suppressed eosinophil counts in the bone marrow and peripheral blood [60]. Additional studies are further required.

#### *3.2.2. Anti IL-13 monoclonal antibodies: Lebrikizumab*

IL-4 and IL-13 are key therapeutic targets in Th2 high asthma, due to their significant role in Th2 lymphocyte responses and in B lymphocyte isotype switching for IgE synthesis and also for their intervention in mast cell selection (see Figure 1). The strong evidence existing upon the involvement of this pathogenic pathway in asthma, initially ranging from genetic studies up to convincing data from animal studies, leads to the development of a wide range of biological agents aimed at these targets, including anti-IL-13, anti-IL-4Rα and anti-IL-13Rα1 mAbs, IL-4Rα/IL-13Rα1 fusion protein, IL-4/IL-13 vaccines, anti-IL-4Rα antisense oligonu‐ cleotides, and double mutein IL-4 [61]. However, although many of these drugs are under development, to date only a few have been evaluated in patients with asthma [62] (see also Table 3).

**Figure 1.** The IL-4/ IL-13 receptor.


Current and Future Asthma Treatments: Phenotypical Approach on the Path to Personalized Medicine in Asthma http://dx.doi.org/10.5772/62411 127


*ASO = "anti-sense" oligonucleotide; CCR3 = cysteine–cysteine chemokine receptor-3; IL = interleukin; mAb = monoclonal antibodies; sIL-4 R = recombinant soluble IL-4 receptor.*

**Table 3.** Monoclonal antibodies for the treatment of asthma.

#### *3.2.2.1 Lebrikizumab*

the bronchial biopsies and in induced sputum and suppressed eosinophil counts in the bone

IL-4 and IL-13 are key therapeutic targets in Th2 high asthma, due to their significant role in Th2 lymphocyte responses and in B lymphocyte isotype switching for IgE synthesis and also for their intervention in mast cell selection (see Figure 1). The strong evidence existing upon the involvement of this pathogenic pathway in asthma, initially ranging from genetic studies up to convincing data from animal studies, leads to the development of a wide range of biological agents aimed at these targets, including anti-IL-13, anti-IL-4Rα and anti-IL-13Rα1 mAbs, IL-4Rα/IL-13Rα1 fusion protein, IL-4/IL-13 vaccines, anti-IL-4Rα antisense oligonu‐ cleotides, and double mutein IL-4 [61]. However, although many of these drugs are under development, to date only a few have been evaluated in patients with asthma [62] (see also

**Drug Pharmaceutical company**

8D6 United BioPharma

Ligelizumab (QGE031B) Novartis

TPI-ASM8 BioCentury

mAb anti IgE Quilizumab (MEMP1972A) Genentech/Roche

mAb anti IL-5 IgG1 Mepolizumab GlaxoSmithKline IgG2 Reslizumab TEVA

marrow and peripheral blood [60]. Additional studies are further required.

*3.2.2. Anti IL-13 monoclonal antibodies: Lebrikizumab*

126 Asthma - From Childhood Asthma to ACOS Phenotypes

Table 3).

**Figure 1.** The IL-4/ IL-13 receptor.

mAb anti IL-5 ASO anti-IL-5Rβc

and anti-CCR3

Corren et al. [30] first studied the effects of lebrikizumab in 219 adults with moderate-to-severe persistent uncontrolled asthma. Lebrikizumab was administered subcutaneously every month for 6 months. A significant improvement in prebronchodilator FEV1 was recorded at 12 weeks in patients treated with lebrikizumab when compared to the placebo group. The study drug was significantly more effective in patients with pretreatment circulating periostin levels above the median and also in those with Th2-high phenotype (total IgE > 100 IU/ml and eosinophilia > 140/mm<sup>3</sup> ), when compared to those with Th2-low phenotype. Exacerbations were not significantly reduced in the active group compared to placebo, but when sub analyzed in the Th2-high subgroup, the rate of exacerbations was 60% lower in patients receiving lebrikizumab compared to placebo. These data suggest that therapy with anti-IL-13 antibodies may be more effective when directed to a selected subgroup of patients (i.e. Th2-high –phenotype).

#### *3.2.3. Anti IL4R monoclonal antibodies: Dupilumab*

Dupilumab (Sanofi) is a humanized mAb that targets the α-subunit of the IL-4–IL-13 shared receptor. The efficacy and safety of dupilumab in the treatment of patients with persistent eosinophilic asthma were evaluated in a phase IIa, randomized, double-blind, placebocontrolled study [63]. One hundred and five patients with moderate-to-severe persistent asthma and eosinophilia ≥300/mm<sup>3</sup> in blood or ≥3% in sputum were included. All patients were on moderate-to-high doses of ICS and LABA. They were randomized to receive either dupilumab 300 mg (*n* = 52) or placebo (*n* = 52), subcutaneously, once a week for 12 weeks, or until the development of a moderate or severe exacerbation (primary endpoint).

Asthma exacerbations were reduced by 87% in the active group (6% exacerbations in the patients receiving dupilumab versus 44% in the placebo group), being this difference statisti‐ cally significant. Significant differences in favor of dupilumab in the time until the first exacerbation and in the risk of exacerbations were also recorded. In the dupilumab patient group, both the morning peak expiratory flow (PEF) and the asthma symptoms evaluated by the ACQ5 improved significantly. Nocturnal awakenings and the use of short-acting beta-2 agonists were also reduced.

Regarding adverse effects, more local reactions at the injection site, nasopharyngitis, nausea, and headache were reported in patients on active treatment, and there was one case of angioedema. The authors of this study emphasize the effect of dupilumab on the reduced frequency of exacerbations, even after withdrawal of ICS and LABA. Nevertheless, they admit that the definition of "exacerbation" used in their protocol does not coincide with that usually employed in clinical practice and, accordingly, recommend that larger studies should be further performed [63].

As we have seen, most new mAbs under development are directed against different targets of the Th2 pathway [62]. A summary of all these drugs is found in Table 3. Figure 2 briefly sketches the allergic inflammatory cascade, so that we might easily visualize these therapeutic targets.

**Figure 2.** Therapeutic targets within the allergic cascade.
