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


CONCLUSIONS
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.
Cutaneous Medicine and Immunotherapy; St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London; London, UK; Research Oncology, Division of Cancer Studies; King's College London; Guy's Hospital; Great Maze Pond; London, UK.
Louise
L
Saul
Cutaneous Medicine and Immunotherapy; St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London; London, UK; Research Oncology, Division of Cancer Studies; King's College London; Guy's Hospital; Great Maze Pond; London, UK.
Debra H
DH
Josephs
Public Health England; Porton Down; Salisbury, Wiltshire UK.
Keith
K
Cutler
Public Health England; Porton Down; Salisbury, Wiltshire UK.
Andrew
A
Bradwell
Cutaneous Medicine and Immunotherapy; St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London; London, UK.
Panagiotis
P
Karagiannis
Biotherapeutics Development Unit; Cancer Research UK; South Mimms, Hertfordshire UK.
Chris
C
Selkirk
Randall Division of Cell and Molecular Biophysics & Division of Asthma; Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London; London, UK.
Hannah J
HJ
Gould
Drug Development Office; Strategy and Research Funding; Cancer Research UK; London, UK.
Paul
P
Jones
Research Oncology, Division of Cancer Studies; King's College London; Guy's Hospital; Great Maze Pond; London, UK.
James F
JF
Spicer
Cutaneous Medicine and Immunotherapy; St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London; London, UK.
Sophia N
SN
Karagiannis
D000818:Animals; D000915:Antibody Affinity; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism*; D007167:Immunotherapy / Q000379:methods*; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008252:Macaca fascicularis; D023421:Models, Animal; D011485:Protein Binding; D017455:Receptors, IgE / Q000378:metabolism; D013045:Species Specificity
D016207:Cytokines; C475664:FCER1A protein, human; C546930:FCER2 protein, human; D037181:Lectins, C-Type; D017455:Receptors, IgE; D007073:Immunoglobulin E
IgE; IgE Fc receptors; allergooncology; allergy; antibody effector functions; cancer; cross-species reactivity; cynomolgus monkey; non-human primate