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

D H Josephs, M Nakamura, H J Bax, T S Dodev, G Muirhead, L Saul, P Karagiannis, K M Ilieva, S Crescioli, P Gazinska, N Woodman, C Lombardelli, S Kareemaghay, C Selkirk, H Lentfer, C Barton, S Canevari, M Figini, N Downes, D Dombrowicz & 8 others C J Corrigan, F O Nestle, P S Jones, H J Gould, P J Blower, S Tsoka, J F Spicer, S N Karagiannis

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)2328-2341
Number of pages14
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume73
Issue number12
DOIs
Publication statusPublished - Dec 2018

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Immunoglobulin E
Rodentia
Safety
Neoplasms
Therapeutics
Antibodies
Folate Receptor 1
Antiparasitic Agents
Antigen Receptors
Fc Receptors
Neoplasm Antigens
Immunotherapy
Cytokines
Lung
Growth
Serum

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Josephs, D. H., Nakamura, M., Bax, H. J., Dodev, T. S., Muirhead, G., Saul, L., ... Karagiannis, S. N. (2018). An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE. Allergy: European Journal of Allergy and Clinical Immunology, 73(12), 2328-2341. https://doi.org/10.1111/all.13455

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

In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 73, No. 12, 12.2018, p. 2328-2341.

Research output: Contribution to journalArticle

Josephs, DH, Nakamura, M, Bax, HJ, Dodev, TS, Muirhead, G, Saul, L, Karagiannis, P, Ilieva, KM, 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, CJ, Nestle, FO, Jones, PS, Gould, HJ, Blower, PJ, Tsoka, S, Spicer, JF & Karagiannis, SN 2018, 'An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE', Allergy: European Journal of Allergy and Clinical Immunology, vol. 73, no. 12, pp. 2328-2341. https://doi.org/10.1111/all.13455
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. / An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE. In: Allergy: European Journal of Allergy and Clinical Immunology. 2018 ; Vol. 73, No. 12. pp. 2328-2341.
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TY - JOUR

T1 - An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE

AU - Josephs, D H

AU - Nakamura, M

AU - Bax, H J

AU - Dodev, T S

AU - Muirhead, G

AU - Saul, L

AU - Karagiannis, P

AU - Ilieva, K M

AU - Crescioli, S

AU - Gazinska, P

AU - Woodman, N

AU - Lombardelli, C

AU - Kareemaghay, S

AU - Selkirk, C

AU - Lentfer, H

AU - Barton, C

AU - Canevari, S

AU - Figini, M

AU - Downes, N

AU - Dombrowicz, D

AU - Corrigan, C J

AU - Nestle, F O

AU - Jones, P S

AU - Gould, H J

AU - Blower, P J

AU - Tsoka, S

AU - Spicer, J F

AU - Karagiannis, S N

N1 - © 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.

PY - 2018/12

Y1 - 2018/12

N2 - 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.

AB - 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.

U2 - 10.1111/all.13455

DO - 10.1111/all.13455

M3 - Article

VL - 73

SP - 2328

EP - 2341

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

SN - 0105-4538

IS - 12

ER -