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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

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

Submitter: Sujoy Khan | sujoykhan@gmail.com

Authors: Sujoy Khan

Hull University Teaching Hospitals NHS Trust, Castle Hill Hospital, Cottingham, England, HU16 5JQ

Published March 13, 2020

The interesting report by Bianca Balbino and colleagues of omalizumab-IgE immune complexes that can activate neutrophils through human Fcγ receptors in humanized mice [1], may also partly explain why few patients report paradoxical worsening of urticaria after starting omalizumab. Neutrophil FcγR interaction may be one of the reasons of ineffectiveness of omalizumab in asthmatic patients with very high IgE levels and in eczema, or the newer version ligelizumab that also shows resistance in about 40% of patients with chronic spontaneous (and inducible) urticaria [2].

 

In this context, it is perhaps worth noting that dimerized histamine releasing factor (HRF)/ translationally controlled tumor protein (TCTP) is able to bind to Fab portions of IgE and IgG [3]. HRF is an evolutionary conserved 172-AA polypeptide and the disulphide-linked dimer interacts with both basophils and mast cells which may augment the effect of omalizumab-immune complexes and perpetuate the inflammation cycle in some patients [4, 5]. The exact mechanism of anti-IgE therapy continues to remain elusive.

 

 

References:

 

  1. Balbino B et al. The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors. J Clin Invest. 2020;130:1330-1335.
  1. Maurer M et al. Ligelizumab for Chronic Spontaneous Urticaria. N Engl J Med. 2019;381:1321-1332.
  1. Kashiwakura JC et al. Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy. J Clin Invest. 2012 Jan;122(1):218-28.
  1. Lee H, Lee K. Dimerized translationally controlled tumor protein increases interleukin-8 expression through MAPK and NF-κB pathways in a human bronchial epithelial cell line. Cell Biosci. 2018;8:13.
  1. White MV, Kaplan AP, Haak-Frendscho M, Kaliner M. Neutrophils and mast cells. Comparison of neutrophil-derived histamine-releasing activity with other histamine-releasing factors. J Immunol. 1988;141:3575-83.

 

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