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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

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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 1

Omalizumab/IgE ICs bind FcγRs and activate neutrophils.

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Omalizumab/IgE ICs bind FcγRs and activate neutrophils.
(A) Binding of p...
(A) Binding of preformed IgE/omalizumab ICs to FcγRs in CHO cells stably transfected with each one of the human FcγRs (16). Upper histograms show binding of an anti-FLAG mAb as a control for FcγR expression. Lower histograms show binding of ICs or IgE FITC alone. Data are representative of 3 independent experiments. (B) Binding of omalizumab to human C1q assessed by ELISA. An irrelevant IgG1 mutated in its Fc portion at position 322 (K322A) to preclude binding to C1q was used as a negative control. Results in B show mean ± SD from data pooled from 2 independent experiments (total of n = 4 replicates). Expression of CD66b (C), CD62L (D), and CD32 (E) on purified CD45+CD15+ human neutrophils after 1 hour of incubation with omalizumab/IgE immobilized ICs, IgE, or medium alone. Results in C–E show values from neutrophils from individual donors normalized against cells stimulated with medium alone; bars indicate mean ± SEM of n = 7 total values per group pooled from 3 independent experiments. (F) CD62L expression on CD11b+Ly6G+ neutrophils purified form hFcγRKI or FcγRnull mice after 1 hour of incubation with ICs or medium. Results in F show values from individual mice with bars indicating mean ± SEM pooled from 2 (FcγRnull; total n = 4/group) or 3 (hFcγRKI; total n = 5/group) independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001 using 1-way ANOVA in B, contrast linear model in C–E, and Welch test in F. For further details on the statistical analysis, please refer to Supplemental Table 1.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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