MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function

• Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma. Objective: We sought to develop a novel humanized anti IL-5 receptor alpha (IL-5R alpha) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue. resident eosinophils and basophils for the treatment of asthma. Methods: We used surface plasmon resonance to determine the binding affinity of MEDI-563 to Fc gamma RIII alpha. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5R alpha was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates. Results: MEDI-563 binds to an epitope on IL-5R alpha that is in close proximity to the IL-5 binding site, and it inhibits IL-5 mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow. Conclusions: MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5. (J Allergy Clin Immunol 2010;125:1344-53.)

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)

Keyword

IL-5

IL-5 receptor

monoclonal antibody

basophil

Fc

gamma RIII alpha

antibody-dependent cell-mediated cytotoxicity

Asthma

eosinophil

Publication and Content Type

art (subject category)

ref (subject category)