Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 6; pp. 1237 - 1244.e2
• Main Authors: Busse, William W., Katial, Rohit, Gossage, David, Sari, Suha, Wang, Bing, Kolbeck, Roland, Coyle, Anthony J., Koike, Masamichi, Spitalny, George L., Kiener, Peter A., Geba, Gregory P., Molfino, Nestor A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2010; Elsevier
• Subjects: Adolescent; Adult; Allergy and Immunology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; antibody-dependent cell-mediated cytotoxicity; Apoptosis - drug effects; Apoptosis - immunology; Asthma; Asthma - immunology; Asthma - pathology; Asthma - physiopathology; Asthma - therapy; Biological and medical sciences; C-Reactive Protein - metabolism; Cell Count; Chronic obstructive pulmonary disease, asthma; Eosinophil Cationic Protein - metabolism; eosinophils; Eosinophils - drug effects; Eosinophils - immunology; Eosinophils - metabolism; Eosinophils - pathology; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; IL-5; IL-5 receptor; Immunopathology; Immunotherapy; Interleukin-5 Receptor alpha Subunit - immunology; Interleukin-6 - metabolism; Lymphopenia - etiology; Male; Medical sciences; Middle Aged; monoclonal antibody; Pneumology; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; Respiratory Function Tests; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; CRP; FENO; IL-5R; AE; CPKMB; antibody-dependent cell-mediated cytotoxicity; eosinophils; IL-5; AHR; Asthma; IL-5 receptor; PB; ECP; WBC; monoclonal antibody; JAK2; ADCC; CPK; C-reactive protein; Fractional exhaled nitric oxide; Creatine phosphokinase; Janus Activating Kinase 2; Peripheral blood; Creatine phosphokinase, muscle and brain; Adverse event; Airway hyperresponsiveness; FE NO; Eosinophil cationic protein; White blood cell; Human; Lung disease; Immunopathology; Respiratory disease; Toxicity; Cytokine; Granulocyte; Monoclonal antibody; Biological activity; Eosinophil; Immunology; Interleukin 5; Treatment; Antibody-dependent cell cytotoxicity; Phase I trial; Bronchus disease; Obstructive pulmonary disease; Pharmacokinetics; Biological receptor
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2010.04.005

Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis. To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor α chain. Single, escalating, intravenous doses (0.0003-3 mg/kg) of MEDI-563 were administered to subjects with mild atopic asthma (n = 44) over ∼3 to 30 minutes in this open-label study. Pulmonary function, symptom scores, adverse events, MEDI-563 pharmacokinetics, and levels of C-reactive protein (CRP), IL-6, eosinophil cationic protein (ECP), and eosinophils were evaluated. Mean peripheral blood (PB) eosinophil levels decreased in a dose-dependent fashion (baseline ± SD, 0.27 ± 0.2 × 103/μL; 24 hours postdose, 0.01 ± 0.0 × 103/μL); 94.0% of subjects receiving ≥0.03 mg/kg exhibited levels between 0.00 × 103/μL and 0.01 × 103/μL. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg, respectively. ECP levels were reduced from 21.4 ± 17.2 μg/L (baseline) to 10.3 ± 7.0 μg/L (24 hours postdose). The most frequently reported adverse events were reduced white blood cell counts (34.1%), nasopharyngitis (27.3%), and increased blood creatine phosphokinase (25.0%). Mean C-reactive protein levels increased ∼5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased ∼3.9-fold to 4.7-fold at 6 to 12 hours postdose, respectively. Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg. Single escalating doses of MEDI-563 had an acceptable safety profile and resulted in marked reduction of PB eosinophil counts within 24 hours after dosing.