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

Roland Kolbeck, Alexander Kozhich, Masamichi Koike, Li Peng, Cecilia K Andersson, Melissa M Damschroder, Jennifer L Reed, Robert Woods, William W Dall'Acqua, Geoffrey L Stephens, Jonas S Erjefalt, Leif Bjermer, Alison A Humbles, David Gossage, Herren Wu, Peter A Kiener, George L Spitalny, Charles Mackay, Nestor A Molfino, Anthony J Coyle

    Research output: Contribution to journalArticleResearchpeer-review

    254 Citations (Scopus)

    Abstract

    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-5Ralpha) 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 FcgammaRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Ralpha 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-5Ralpha 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.
    Original languageEnglish
    Pages (from-to)1344 - 1353.e2
    Number of pages10
    JournalJournal of Allergy and Clinical Immunology
    Volume125
    Issue number6
    DOIs
    Publication statusPublished - 2010

    Cite this

    Kolbeck, R., Kozhich, A., Koike, M., Peng, L., Andersson, C. K., Damschroder, M. M., ... Coyle, A. J. (2010). MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. Journal of Allergy and Clinical Immunology, 125(6), 1344 - 1353.e2. https://doi.org/10.1016/j.jaci.2010.04.004
    Kolbeck, Roland ; Kozhich, Alexander ; Koike, Masamichi ; Peng, Li ; Andersson, Cecilia K ; Damschroder, Melissa M ; Reed, Jennifer L ; Woods, Robert ; Dall'Acqua, William W ; Stephens, Geoffrey L ; Erjefalt, Jonas S ; Bjermer, Leif ; Humbles, Alison A ; Gossage, David ; Wu, Herren ; Kiener, Peter A ; Spitalny, George L ; Mackay, Charles ; Molfino, Nestor A ; Coyle, Anthony J. / MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. In: Journal of Allergy and Clinical Immunology. 2010 ; Vol. 125, No. 6. pp. 1344 - 1353.e2.
    @article{ad84695a691d4177948f5ead47fcfdc7,
    title = "MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function",
    abstract = "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-5Ralpha) 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 FcgammaRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Ralpha 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-5Ralpha 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.",
    author = "Roland Kolbeck and Alexander Kozhich and Masamichi Koike and Li Peng and Andersson, {Cecilia K} and Damschroder, {Melissa M} and Reed, {Jennifer L} and Robert Woods and Dall'Acqua, {William W} and Stephens, {Geoffrey L} and Erjefalt, {Jonas S} and Leif Bjermer and Humbles, {Alison A} and David Gossage and Herren Wu and Kiener, {Peter A} and Spitalny, {George L} and Charles Mackay and Molfino, {Nestor A} and Coyle, {Anthony J}",
    year = "2010",
    doi = "10.1016/j.jaci.2010.04.004",
    language = "English",
    volume = "125",
    pages = "1344 -- 1353.e2",
    journal = "Journal of Allergy and Clinical Immunology",
    issn = "0091-6749",
    publisher = "Elsevier",
    number = "6",

    }

    Kolbeck, R, Kozhich, A, Koike, M, Peng, L, Andersson, CK, Damschroder, MM, Reed, JL, Woods, R, Dall'Acqua, WW, Stephens, GL, Erjefalt, JS, Bjermer, L, Humbles, AA, Gossage, D, Wu, H, Kiener, PA, Spitalny, GL, Mackay, C, Molfino, NA & Coyle, AJ 2010, 'MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function', Journal of Allergy and Clinical Immunology, vol. 125, no. 6, pp. 1344 - 1353.e2. https://doi.org/10.1016/j.jaci.2010.04.004

    MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. / Kolbeck, Roland; Kozhich, Alexander; Koike, Masamichi; Peng, Li; Andersson, Cecilia K; Damschroder, Melissa M; Reed, Jennifer L; Woods, Robert; Dall'Acqua, William W; Stephens, Geoffrey L; Erjefalt, Jonas S; Bjermer, Leif; Humbles, Alison A; Gossage, David; Wu, Herren; Kiener, Peter A; Spitalny, George L; Mackay, Charles; Molfino, Nestor A; Coyle, Anthony J.

    In: Journal of Allergy and Clinical Immunology, Vol. 125, No. 6, 2010, p. 1344 - 1353.e2.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function

    AU - Kolbeck, Roland

    AU - Kozhich, Alexander

    AU - Koike, Masamichi

    AU - Peng, Li

    AU - Andersson, Cecilia K

    AU - Damschroder, Melissa M

    AU - Reed, Jennifer L

    AU - Woods, Robert

    AU - Dall'Acqua, William W

    AU - Stephens, Geoffrey L

    AU - Erjefalt, Jonas S

    AU - Bjermer, Leif

    AU - Humbles, Alison A

    AU - Gossage, David

    AU - Wu, Herren

    AU - Kiener, Peter A

    AU - Spitalny, George L

    AU - Mackay, Charles

    AU - Molfino, Nestor A

    AU - Coyle, Anthony J

    PY - 2010

    Y1 - 2010

    N2 - 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-5Ralpha) 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 FcgammaRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Ralpha 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-5Ralpha 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.

    AB - 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-5Ralpha) 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 FcgammaRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Ralpha 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-5Ralpha 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.

    UR - http://www.sciencedirect.com/science/article/pii/S0091674910005907

    U2 - 10.1016/j.jaci.2010.04.004

    DO - 10.1016/j.jaci.2010.04.004

    M3 - Article

    VL - 125

    SP - 1344 - 1353.e2

    JO - Journal of Allergy and Clinical Immunology

    JF - Journal of Allergy and Clinical Immunology

    SN - 0091-6749

    IS - 6

    ER -