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Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab
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International audience. Emicizumab is a bispecific chimeric humanized IgG4 that mimics the procoagulant activity offactor VIII (FVIII). Its long half-life and subcutaneous injection route have been life-changingin treating patients with hemophilia A (PwHA) with and 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 onemicizumab prophylaxis, wherein exogenous FVIII is inefficient. We have shown recently thatImlifidase, an IgG-degrading enzyme (IdeS) of bacterial origin, efficiently eliminates humananti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic windowfor the administration of therapeutic FVIII. Here, we investigated the impact of IdeS treatmentin HA mice injected with emicizumab. IdeS hydrolyzed emicizumab in vitro and in vivo, albeitat slower rates than another recombinant human monoclonal IgG4. While the F(ab’)2 fragmentswere rapidly cleared from the circulation, thus leading to a rapid loss of emicizumabprocoagulant activity, low amounts of the single-cleaved intermediate IgG persisted for severaldays. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG andrestoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence ofemicizumab and polyclonal human IgG in inhibitor-positive HA mice. Our results suggest thatIdeS could be administered to inhibitor-positive PwHA under emicizumab prophylaxis toimprove and ease the management of breakthrough bleeds or programmed major surgeries.
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