Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency

Louise Saul,Debra H Josephs ,Andrew Bradwell,Paul S Jones ,Hannah J Gould ,Hannah J Gould ,Chris Selkirk,Panagiotis Karagiannis,Panagiotis Karagiannis,Keith Cutler,James Spicer ,James Spicer ,Sophia N Karagiannis ,Sophia N Karagiannis

doi:10.4161/mabs.27828

Louise Saul, Debra H Josephs + Show 12 more

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https://doi.org/10.4161/mabs.27828

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Abstract

Background: Due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. IgE therapeutics in development depend upon engagement with the FcεRI and FcεRII receptors on immune effector cells for their function. Only limited knowledge of the primate IgE immune system is available to inform the choice of models for mechanistic and safety evaluations. Methods: The recognition of human IgE by peripheral blood lymphocytes from cynomolgus monkey and man was compared. We used effector cells from each species in ex vivo affinity, dose-response, antibody-receptor dissociation and potency assays. Results: We report cross-reactivity of human IgE Fc with cynomolgus monkey cells, and comparable binding kinetics to peripheral blood lymphocytes from both species. In competition and dissociation assays, however, human IgE dissociated faster from cynomolgus monkey compared with human effector cells. Differences in association and dissociation kinetics were reflected in effector cell potency assays of IgE-mediated target cell killing, with higher concentrations of human IgE needed to elicit effector response in the cynomolgus monkey system. Additionally, human IgE binding on immune effector cells yielded significantly different cytokine release profiles in each species. Conclusion: These data suggest that human IgE binds with different characteristics to human and cynomolgus monkey IgE effector cells. This is likely to affect the potency of IgE effector functions in these two species, and so has relevance for the selection of biologically-relevant model systems when designing pre-clinical toxicology and functional studies.

Highlights

The cynomolgus monkey is a laboratory primate commonly used as a model for the study of allergic diseases, in particular addressing symptoms, disease mechanisms and treatments for allergic asthma
We aimed to identify the residues of the mature cynomolgus monkey sequence that are different to those of the human sequence and are potentially involved in, or could influence, binding to the Fc-region of human Chimeric hapten 4-hydroxy- 3-nitro-phenacetyl specific NIP IgE (IgE)
Differential residues in the cynomolgus monkey FcεRIα chain sequence were distributed throughout the two extracellular immunoglobulin domains that comprise the outer regions of the receptor recognizing the human IgE-Fc (Fig. 1B)

Summary

Introduction

The cynomolgus monkey is a laboratory primate commonly used as a model for the study of allergic diseases, in particular addressing symptoms, disease mechanisms and treatments for allergic asthma. It has found use in preclinical toxicology studies of therapeutic agents prior to clinical trials. Antibodies of the IgE class are known to contribute to the body’s defense against parasites and toxins, and to play critical roles in the pathogenesis and potentiation of allergic diseases.[1] IgE exerts its biological functions through engagement of its cognate receptors, the low affinity receptor CD23 (Ka ~108–109 M-1), and the high affinity receptor FcεRI (Ka ~1010 M-1). Limited knowledge of the primate IgE immune system is available to inform the choice of models for mechanistic and safety evaluations

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Results

Conclusion