The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors
Bianca Balbino, … , Pierre Bruhns, Laurent L. Reber
Bianca Balbino, … , Pierre Bruhns, Laurent L. Reber
Published November 26, 2019
Citation Information: J Clin Invest. 2020;130(3):1330-1335. https://doi.org/10.1172/JCI129697.
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Concise Communication Immunology Inflammation

The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors

Abstract

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.

Authors

Bianca Balbino, Pauline Herviou, Ophélie Godon, Julien Stackowicz, Odile Richard-Le Goff, Bruno Iannascoli, Delphine Sterlin, Sébastien Brûlé, Gael A. Millot, Faith M. Harris, Vera A. Voronina, Kari C. Nadeau, Lynn E. Macdonald, Andrew J. Murphy, Pierre Bruhns, Laurent L. Reber

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Figure 3

Fc-engineered anti-IgE antibodies display markedly reduced FcγR-binding and neutrophil activation.

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Fc-engineered anti-IgE antibodies display markedly reduced FcγR-binding ...
(A) Binding of ICs made of FITC-IgE and WT anti-IgE or Fc-engineered N297A (NA) anti-IgE. Data are representative of 3 independent experiments. Expression of CD66b (B), CD62L (C), and CD32 (D) on purified CD45+CD15+ human neutrophils after 1 hour of incubation with IgE/WT anti-IgE or IgE/NA anti-IgE ICs or medium alone. Results in B–D show values from neutrophils from individual donors normalized against cells stimulated with medium alone. Bars indicate mean ± SEM pooled from 3 independent experiments (total n = 7/group). (E) 100 μg of WT or NA anti-IgE was injected i.p. into hFcγRKIhFcRnKIhβ2mKI mice, and serum was collected at different time points. Levels of anti-IgE mAbs were measured by ELISA. Data are indicated as mean ± SEM pooled from 2 independent experiments (n = 13/group). ***P < 0.001 by contrast linear model in B–D and ANOVA in E. For additional details on the statistical analysis, please refer to Supplemental Table 1.