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

Debra H Josephs, Mano Nakamura, Heather J Bax, Tihomir S Dodev, Gareth Muirhead, Louise Saul, Panagiotis Karagiannis, Kristina M Ilieva, Silvia Crescioli, Patrycja Gazinska, Natalie Woodman, Cristina Lomardelli, Sedigeh Kareemaghay, Christopher Selkirk, Heike Lentfer, Claire Barton, Silvana Canevari, Mariangela Figini, Noel Downes, David DombrowiczChristopher J Corrigan, Frank O Nestle, Paul S Jones, Hannah J Gould, Philip J Blower, Sophia Tsoka, James F Spicer, Sophia N Karagiannis

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Abstract

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 mirrors 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 anti-tumour 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 anti-tumour and anti-parasitic 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)2328-2341
Number of pages14
JournalAllergy
Volume73
Issue number12
Early online date13 Apr 2018
DOIs
Publication statusPublished - 1 Dec 2018

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