Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab
Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors....
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Veröffentlicht in: | Journal of thrombosis and haemostasis 2023-10, Vol.21 (10), p.2776-2783 |
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Zusammenfassung: | Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII.
To investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab.
IdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab.
IdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab’)2 fragments were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab procoagulant activity, low amounts of single-cleaved intermediate IgG persisted for several days. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG and restoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence of emicizumab and polyclonal human IgG in inhibitor-positive HA mice.
Our results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.
•Acute bleed management is complicated in factor (F) VIII inhibitor-positive patients with hemophilia A receiving emicizumab prophylaxis.•Imlifidase (IdeS) efficacy was tested in hemophilia A mice reconstituted with human anti-FVIII IgG and treated with emicizumab.•Removal of neutralizing anti-FVIII IgG by IdeS was not impaired by the presence of emicizumab.•IdeS should ease hemostatic management in inhibitor-positive patients with hemophilia A receiving emicizumab prophylaxis. |
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ISSN: | 1538-7836 1538-7933 1538-7836 |
DOI: | 10.1016/j.jtha.2023.06.038 |