An immunologically relevant rodent model demonstrates safety of therapy using a tumour‐specific IgE

Background Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially wi...

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Published in:	Allergy (Copenhagen) Vol. 73; no. 12; pp. 2328 - 2341
Main Authors:	Josephs, D. H., Nakamura, M., Bax, H. J., Dodev, T. S., Muirhead, G., Saul, L., Karagiannis, P., Ilieva, K. M., Crescioli, S., Gazinska, P., Woodman, N., Lombardelli, C., Kareemaghay, S., Selkirk, C., Lentfer, H., Barton, C., Canevari, S., Figini, M., Downes, N., Dombrowicz, D., Corrigan, C. J., Nestle, F. O., Jones, P. S., Gould, H. J., Blower, P. J., Tsoka, S., Spicer, J. F., Karagiannis, S. N.
Format:	Journal Article
Language:	English
Published:	Denmark Blackwell Publishing Ltd 01-12-2018 Wiley John Wiley and Sons Inc
Subjects:	Activation AllergoOncology Animal models Animals Antibodies, Monoclonal, Murine-Derived - administration & dosage Antibodies, Monoclonal, Murine-Derived - adverse effects Antibodies, Monoclonal, Murine-Derived - metabolism Antibodies, Monoclonal, Murine-Derived - therapeutic use Cancer Cancer immunotherapy Cell Line, Tumor Folate Receptor 1 - immunology Folic acid Humans Hypersensitivity IgE Immune response Immunoglobulin E Immunoglobulin E - administration & dosage Immunoglobulin E - adverse effects Immunoglobulin E - immunology Immunoglobulin E - therapeutic use Immunoglobulin G - immunology Immunoglobulin G - metabolism Immunology Immunotherapy Immunotherapy - methods Life Sciences Metastases Mice Models, Animal Neoplasms - pathology Neoplasms - therapy Original ORIGINAL ARTICLES Protein Binding rat Rats Receptors, IgE - metabolism Rodents Safety Statistics, Nonparametric Toxicity Translation Treatment Outcome Tumor Necrosis Factor-alpha - blood Tumor necrosis factor-α Tumors cancer AllergoOncology rat IgE immunotherapy AllergoOncology cancer IgE immunotherapy rat
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Summary:	Background Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class‐specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. Methods We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour‐associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE‐FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. Results In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a “cytokine storm” or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE‐mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour‐bearing lungs. Conclusion Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena. To study IgE class‐specific functions and safety, we designed a surrogate rat tumour model and rat equivalent antibodies of a human/chimeric IgE therapeutic candidate recognising a tumour associated antigen. IgE restricted tumour growth, elevated intratumoural immune cell infiltration and enhanced immune pathway activation, without clinical, histopathological or metabolic toxicity signs, nor immunological evidence of allergic response or cytokine storm. This model may inform translation of anti‐tumour IgE antibodies to clinical study, and help to dissect IgE functions in AllergoOncology, allergic inflammation, allergen immunotherapy and anti‐parasitic responses.
Bibliography:	Funding information The authors acknowledge support by Cancer Research UK (C30122/A11527; C30122/A15774; C33043/A12065); The Academy of Medical Sciences; the Medical Research Council (MR/L023091/1); Breast Cancer Now (147) working in partnership with Walk the Walk; CRUK/EPSRC/MRC/NIHR KCL/UCL Comprehensive Cancer Imaging Centre (C1519/A10331); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy's and St Thomas’ NHS Foundation Trust and King's College London (IS‐BRC‐1215‐20006). The authors are solely responsible for study design, data collection, analysis, decision to publish and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Josephs and Nakamura equally contributed to this work.
ISSN:	0105-4538 1398-9995
DOI:	10.1111/all.13455