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Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity

Authors

  • S. M. Rudman,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
    2. Division of Cancer Studies, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • D. H. Josephs,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
    2. Division of Cancer Studies, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • H. Cambrook,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • P. Karagiannis,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • A. E. Gilbert,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • T. Dodev,

    1. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK
    2. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, UK
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  • J. Hunt,

    1. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK
    2. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, UK
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  • A. Koers,

    1. Division of Imaging Sciences, King's College London, Rayne Institute, St Thomas' Hospital, London, UK
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  • A. Montes,

    1. Guy's and St Thomas' NHS Foundation Trust, London, UK
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  • L. Taams,

    1. Centre for Molecular & Cellular Biology of Inflammation, Division of Immunology, Infection and Inflammatory Diseases, King's College London, London, UK
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  • S. Canevari,

    1. Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumouri, Milan, Italy
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  • M. Figini,

    1. Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumouri, Milan, Italy
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  • P. J. Blower,

    1. Division of Imaging Sciences, King's College London, Rayne Institute, St Thomas' Hospital, London, UK
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  • A. J. Beavil,

    1. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK
    2. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, UK
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  • C. F. Nicodemus,

    1. Advanced Immune Therapeutics Inc., Charlestown, MA, USA
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  • C. Corrigan,

    1. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, UK
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  • S. B. Kaye,

    1. Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
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  • F. O. Nestle,

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • H. J. Gould,

    1. Randall Division of Cell and Molecular Biophysics, King's College London, London, UK
    2. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, UK
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  • J. F. Spicer,

    1. Division of Cancer Studies, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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  • S. N. Karagiannis

    1. NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK
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Dr Sophia N. Karagiannis, Division of Genetics and Molecular Medicine, St. John's Institute of Dermatology, King's College London, Guy's Hospital, Tower Wing 9th Floor, London SE1 9RT, UK.
E-mail: sophia.karagiannis@kcl.ac.uk

Summary

Background IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-FcɛRI complexes on basophils to cause type I hypersensitivity.

Objective To assess the propensity for MOv18 used in a therapeutic setting to cause FcɛRI-mediated type I hypersensitivity.

Methods As validated readouts of the potential for MOv18 to cause FcɛRI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) FcɛRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo.

Results Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5).

Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, FcɛRI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

Cite this as: S. M. Rudman, D. H. Josephs, H. Cambrook, P. Karagiannis, A. E. Gilbert, T. Dodev, J. Hunt, A. Koers, A. Montes, L. Taams, S. Canevari, M. Figini, P. J. Blower, A. J. Beavil, C. F. Nicodemus, C. Corrigan, S. B. Kaye, F. O. Nestle, H. J. Gould, J. F. Spicer and S. N. Karagiannis, Clinical & Experimental Allergy, 2011 (41) 1400–1413.

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