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 Dombrowicz; Christopher J Corrigan; Frank O Nestle; Paul S Jones; Hannah J Gould; Philip J Blower; Sophia Tsoka; James F Spicer; Sophia N Karagiannis

doi:10.1111/all.13455

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 language	English
Pages (from-to)	2328-2341
Number of pages	14
Journal	Allergy
Volume	73
Issue number	12
Early online date	13 Apr 2018
DOIs	https://doi.org/10.1111/all.13455
Publication status	Published - 1 Dec 2018

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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., Lomardelli, C., Kareemaghay, S., Selkirk, C., Lentfer, H., Barton, C., Canevari, S., Figini, M., Downes, N., ... Karagiannis, S. N. (2018). An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE. Allergy, 73(12), 2328-2341. https://doi.org/10.1111/all.13455

@article{72ee3c09c8b24a9b92c05b28a2abe51c,

title = "An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE",

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.",

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

year = "2018",

month = dec,

day = "1",

doi = "10.1111/all.13455",

language = "English",

volume = "73",

pages = "2328--2341",

journal = "Allergy",

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Josephs, DH , Nakamura, M , Bax, HJ , Dodev, TS , Muirhead, G , Saul, L , Karagiannis, P , Ilieva, KM , Crescioli, S, Gazinska, P, Woodman, N, Lomardelli, 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, vol. 73, no. 12, pp. 2328-2341. https://doi.org/10.1111/all.13455

TY - JOUR

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

AU - Josephs, Debra H

AU - Nakamura, Mano

AU - Bax, Heather J

AU - Dodev, Tihomir S

AU - Muirhead, Gareth

AU - Saul, Louise

AU - Karagiannis, Panagiotis

AU - Ilieva, Kristina M

AU - Crescioli, Silvia

AU - Gazinska, Patrycja

AU - Woodman, Natalie

AU - Lomardelli, Cristina

AU - Kareemaghay, Sedigeh

AU - Selkirk, Christopher

AU - Lentfer, Heike

AU - Barton, Claire

AU - Canevari, Silvana

AU - Figini, Mariangela

AU - Downes, Noel

AU - Dombrowicz, David

AU - Corrigan, Christopher J

AU - Nestle, Frank O

AU - Jones, Paul S

AU - Gould, Hannah J

AU - Blower, Philip J

AU - Tsoka, Sophia

AU - Spicer, James F

AU - Karagiannis, Sophia N

PY - 2018/12/1

Y1 - 2018/12/1

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 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=85054591933&partnerID=8YFLogxK

U2 - 10.1111/all.13455

DO - 10.1111/all.13455

M3 - Article

C2 - 29654623

SN - 0105-4538

VL - 73

SP - 2328

EP - 2341

JO - Allergy

JF - Allergy

IS - 12

ER -

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

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