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Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application

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Abstract

Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor α (FRα). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fcε receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.

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Abbreviations

FBP/FRα:

Folate-binding protein/folate receptor alpha

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ADCP:

Antibody-dependent cell-mediated phagocytosis

FcεRI:

Fc epsilon Receptor I

HER2/neu :

Human epidermal growth factor receptor 2

FcεRIα:

FcεRI alpha

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Acknowledgments

The authors acknowledge support from Cancer Research UK (C30122/A11527); This work was supported by the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust; CR UK/EPSRC/MRC/NIHR KCL/UCL Comprehensive Cancer Imaging Centre (C1519/A10331); KCL Experimental Cancer Medicine Centre, jointly funded by Cancer Research UK, the National Institute for Health Research, Welsh Assembly Government, HSC R&D Office for Northern Ireland and Chief Scientist Office, Scotland.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. NIHR Biomedical Research Centre at Guy’s and St. Thomas’s Hospitals and King’s College London, London, UK

    Sophia N. Karagiannis, Debra H. Josephs, Panagiotis Karagiannis, Amy E. Gilbert, Louise Saul & Frank O. Nestle

  2. Cutaneous Medicine and Immunotherapy Unit, St. John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Tower, Guy’s Hospital, London, SE1 9RT, UK

    Sophia N. Karagiannis, Debra H. Josephs, Panagiotis Karagiannis, Amy E. Gilbert, Louise Saul & Frank O. Nestle

  3. Randall Division of Cell and Molecular Biophysics, New Hunt’s House, King’s College London, Guy’s Campus, London, SE1 1UL, UK

    Tihomir Dodev, Andrew J. Beavil & Hannah J. Gould

  4. Section of Research Oncology, Division of Cancer Studies, King’s College London School of Medicine, Guy’s Hospital, 3rd Floor, Bermondsey Wing, London, SE1 9RT, UK

    Sarah M. Rudman & James F. Spicer

  5. Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King’s College London School of Medicine, Guy’s Hospital, London, SE1 9RT, UK

    Tihomir Dodev, Christopher Corrigan & Andrew J. Beavil

  6. Department of Imaging Chemistry & Biology, Division of Imaging Sciences and Biomedical Engineering, King’s College London, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UK

    Alexander Koers & Philip J. Blower

Authors
  1. Sophia N. Karagiannis
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  2. Debra H. Josephs
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  3. Panagiotis Karagiannis
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  4. Amy E. Gilbert
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  5. Louise Saul
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  6. Sarah M. Rudman
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  7. Tihomir Dodev
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  8. Alexander Koers
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  9. Philip J. Blower
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  10. Christopher Corrigan
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  11. Andrew J. Beavil
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  12. James F. Spicer
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  13. Frank O. Nestle
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  14. Hannah J. Gould
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Corresponding author

Correspondence to Sophia N. Karagiannis.

Additional information

This paper is part of the Symposium in Writing: AllergoOncology: The Role of Th2 responses in cancer.

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Karagiannis, S.N., Josephs, D.H., Karagiannis, P. et al. Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application. Cancer Immunol Immunother 61, 1547–1564 (2012). https://doi.org/10.1007/s00262-011-1162-8

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  • DOI: https://doi.org/10.1007/s00262-011-1162-8

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