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 2010-06, Vol.125 (6), p.1237-1244.e2
• Main Authors: Busse, William W., MD, Katial, Rohit, MD, Gossage, David, MD, MBA, Sari, Suha, PhD, Wang, Bing, PhD, Kolbeck, Roland, PhD, Coyle, Anthony J., PhD, Koike, Masamichi, PhD, Spitalny, George L., PhD, Kiener, Peter A., PhD, Geba, Gregory P., MD, MPH, Molfino, Nestor A., MD
• Format: Article
• Language: English
• 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
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2010.04.005

Background 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. Objective To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor α chain. Methods 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. Results 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. Conclusion 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.