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

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

N1 - This article is protected by copyright. All rights reserved.

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.

KW - Journal Article

U2 - 10.1111/all.13455

DO - 10.1111/all.13455

M3 - SCORING: Journal article

C2 - 29654623

VL - 73

SP - 2328

EP - 2341

JO - ALLERGY

JF - ALLERGY

SN - 0105-4538

IS - 12

ER -