Benralizumab--a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma

Abstract

Introduction: Benralizumab is a monoclonal antibody that binds the α subunit of the receptor to IL-5. As IL-5 is implicated in disease states that are mediated by eosinophils, benralizumab is an attractive option for use in the management of asthma. As a result of enhanced antibody-directed cell cytotoxicity, it has enhanced eosinophil-depleting activity as compared with neutralizing monoclonal antibody directed against IL-5.

Areas covered: This review presents the available data on benralizumab, including pharmacodynamics, pharmacokinetics, preclinical data and relevant clinical studies.

Expert opinion: Our review indicates that although further investigation is necessary to demonstrate clinical benefit, benralizumab remains a promising treatment modality.

Figure 1

The α chain specifically binds with IL-5 with low affinity, however, the ligand binding of IL-5 and IL-5Rα is followed by hetero-oligomerization of α and β subunits that leads to further proximity of β subunit intracellular domains producing a high-affinity phenotype.

Figure 2

Benralizumab binds with the α chain of IL-5R, which in turn blocks the ligand binding of IL-5 as well as other putative ligands (such as IL-3, IL-4, IL-13 and GM-CSF), thereby no hetero-oligomerization of α and β subunits takes place and thus no signal transduction occurs.

Figure 3. Summary of non-compartmental pharmacokinetic parameters

Reproduced from [16]. *Parameters are presented as mean ± SD. ^‡Observations for cohot 6 (0.003 mg/kg) and cohort 7 (0.0003 mg/kg) were below the limit of quantitation. AUC∞: Area Area under the curve from time 0 extrapolated to infinite rtime; CL: systemic clearance; C_max maximum concentration; T_1/2: elimination half life; V_ss: volume of distribution at steady state.

Figure 4. Mean (6 SD) MEDI-563 concentration–time profile

Mean MEDI-563 plasma concentration after a single i.v. dose of 0.03, 0.1, 0.3, 1 and 3 mg/kg Reproduced from [16].