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.
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
Submitter: Sujoy Khan | firstname.lastname@example.org
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 , 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 .
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 . 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.