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 4

Fc-engineered anti-IgE antibodies block IgE-mediated anaphylaxis but do not induce FcγR-dependent inflammation.

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Fc-engineered anti-IgE antibodies block IgE-mediated anaphylaxis but do ...
(A) Changes in body temperature (Δ°C [mean ± SEM]) after i.v. challenge with 500 μg nitrophenyl-coupled BSA (NP-BSA) in hFcεRITg mice pretreated i.v. with 700 μg omalizumab, NA anti-IgE, or PBS 30 minutes before sensitization with anti-NP IgE (10 μg). Data in A are pooled from 2 independent experiments (total n = 4–6/group). hFcεRI–mice were used as a control. Representative bioluminescent images (B) and quantification (C) of MPO activity 2 hours after subcutaneous injection of IgE/omalizumab or IgE/NA anti-IgE ICs in nude hFcγRKI or nude FcγRnull mice. Regions of interest outlined in red surround the site of injection. Bars in C indicate mean ± SEM pooled from 5 (nude hFcγRKI, total n = 18) or 4 (nude FcγRnull, total n = 11) independent experiments. The color bar represents bioluminescent signal in radiance (p/sec/cm2/sr). (D) Changes in body temperature (Δ°C [mean ± SEM]) after i.v. injection of IgE/omalizumab (n = 10) or IgE/NA anti-IgE (n = 11) into hFcγRKI mice. Data in D are pooled from 2 independent experiments. *P < 0.05; ***P < 0.001 by contrast test linear model (A and C) or 2-way repeated-measures (ANOVA) (D). For additional details on the statistical analysis, please refer to Supplemental Table 1.