Eosinophils, IL-5 and their role in severe asthma
Normal protective immune response
Eosinophils are a leukocyte subclass involved in host defence against parasitic infections. They also form part of the inflammatory response, and are important mediators of the allergic response and asthma pathogenesis.1
Eosinophils normally represent a low proportion of the total white blood count.1They are not normally present in healthy lungs, but are thought to play a major role in maintaining airway inflammation in chronic asthma.2-3
The cytokine IL-5 is the main promoter of eosinophil production, maturation and release from bone marrow and is responsible for elevating blood eosinophil levels.1IL-5 also activates eosinophils and prolongs their survival in the circulation, as well as providing an essential signal for their migration into tissue.1 4-5
Pathologic effects of eosinophils
Clinical studies have shown a central role for the eosinophil in asthma pathogenesis, including airway hyperresponsiveness induction, elevated mucus production, airway narrowing and airway remodelling.110-11These are all characteristic features of asthma that result from tissue damage and organ dysfunction, with disease severity correlating with peripheral blood eosinophil levels.1 10-11
T cells respond to specific antigens and, in asthma, play an important role in the inflammatory response process through the release of type 2 cytokines. This can trigger airway remodelling through reticular basement membrane thickening, goblet cell metaplasia/hyperplasia, mucus hyperproduction, airway smooth muscle hyperplasia/hypertrophy and angiogenesis.12It is becoming evident that Th2 inflammation is a characteristic of certain asthma phenotypes.13-14 Th2 cells play a role in both severe asthma and severe allergic asthma. However, emerging evidence suggests that these two asthma phenotypes differ at the level of the effector cell. In severe asthma associated with eosinophilic inflammation the effector cell is the eosinophil, whilst in severe allergic asthma the main effector cells are believed to be mast cells and basophils, both of which express IgE receptors.15
IL-5 as a treatment target
IL-5 is a key player in eosinophilic inflammation
IL-5 is a logical therapeutic target for eosinophilic disorders such as severe refractory eosinophilic asthma, due to its key role in mediating eosinophil maturation and release from bone marrow prior to migration into affected tissues. Its specific effect on eosinophil development and recruitment is an attractive feature as it reduces the likelihood of off-topic or adverse immune effects.16
There are also other additional points in the asthma inflammatory pathway with the potential for specific biologic intervention.
Investigate the pathways towards eosinophilic inflammation
What effect does IL-5 blockade have on blood eosinophil levels?
IL-5 is a logical therapeutic target for eosinophilic disorders such as severe refractory eosinophilic asthma due to its specific role in modulating eosinophil development and recruitment.16
Mepolizumab is a humanised mAb (IgG1, kappa) that targets human IL-5 with high affinity and specificity.22It blocks IL-5 bioactivity by binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. This inhibits IL-5 signalling and reduces eosinophil production and recruitment.1623
Initial in vivo studies with mepolizumab
Mepolizumab’s in vivo activity was first demonstrated in mouse models of allergic airway disease.
Administration of mouse anti-IL-5 antibody to ovalbumin-sensitised mice demonstrated reduced eosinophilic airway inflammation and a reduced response to methacholine challenge.24In addition, IL-5 knockout mice did not show increased blood and airway eosinophils, airway hyperreactivity or pulmonary injury compared with control animals in a mouse asthma model.25
Together, these observations demonstrated a significant role for IL-5 and eosinophils in asthma pathogenesis. Preclinical studies demonstrated that the features of asthma were significantly improved when IL-5 signalling is defective or eosinophils are absent.22
Mepolizumab’s pharmacokinetic properties have been studied in both primates and humans.
Pharmacokinetic properties of mepolizumab
AUC, area under the curve; Cmax, maximal serum concentration; i.v., intravenous; s.c., subcutaneous.
Mepolizumab was tested in preclinical studies in cynomolgus monkeys to inform on its efficacy and safety profiles.27Primate studies were required as they represent the only animal model with cross-reactivity between mepolizumab and IL-5 endogenous to the animal.27The primate studies showed that a single dose of mepolizumab suppressed eosinophils in bronchoalveolar lavage when the animals were challenged with inhalation of the parasitic nematode Ascaris suum. However, mepolizumab had no impact on the acute bronchoconstrictor response typically occurring with these inhalations.27These studies also demonstrated that mepolizumab suppressed peripheral blood eosinophils. The animals received either i.v. or s.c. administered mepolizumab. The drug was well tolerated, with no effect on body temperature or on cardiovascular, respiratory or renal function in male monkeys.27
Mepolizumab’s pharmacodynamic profile was first studied in humans in a trial performed by Leckie, et al. 2000.28
This was designed as double-blind, randomised, placebo-controlled, parallel-group trial of a single i.v. infusion of mepolizumab at doses of 2.5mg/kg (n=8) and 10mg/kg (n=8) in men with mild allergic asthma.28
The patients were assessed for airway hyperresponsiveness and blood and sputum eosinophil counts. The study demonstrated long-lasting reduction in both peripheral blood and sputum eosinophils after treatment. However, mepolizumab did not protect against allergen-induced airway hyperresponsiveness.28
Effect of mepolizumab on blood eosinophil count
Graph is adapted by GSK based on ref. 28.
Immunogenic potential of mepolizumab
Mepolizumab has a low immunogenic potential in humans based on both the low incidence and titre of antidrug antibodies and neutralising antibodies. The data demonstrated a low risk for loss of efficacy and adverse events.29
Six percent of patients (15/260) in the placebo-controlled trials developed anti-mepolizumab antibodies after receiving at least one dose of mepolizumab.31 Neutralising antibodies were detected in one patient.30Anti-mepolizumab antibodies did not noticeably impact mepolizumab’s pharmacokinetics or pharmacodynamics in the majority of patients, and there was no evidence of a correlation between antibody titres and change in blood eosinophil level.30The development of antibodies to protein and peptide therapies is consistent with the potentially immunogenic properties of these agents.30
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- Mepolizumab SmPC; GlaxoSmithKline 2016