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.
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The authors declare that they have no conflict of interest.
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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