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

Autor: 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.
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Allergy
ISSN: 1398-9995
0105-4538
Popis: 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.
Databáze: OpenAIRE
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