Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab
Abstract
Emicizumab is a bispecific chimeric humanized IgG4 that mimics the procoagulant activity of
factor VIII (FVIII). Its long half-life and subcutaneous injection route have been life-changing
in 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 on
emicizumab prophylaxis, wherein exogenous FVIII is inefficient. We have shown recently that
Imlifidase, an IgG-degrading enzyme (IdeS) of bacterial origin, efficiently eliminates human
anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window
for the administration of therapeutic FVIII. Here, we investigated the impact of IdeS treatment
in HA mice injected with emicizumab. IdeS hydrolyzed emicizumab in vitro and in vivo, albeit
at slower rates than another recombinant human monoclonal IgG4. While the F(ab’)2 fragments
were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab
procoagulant activity, low amounts of the 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 PwHA under emicizumab prophylaxis to
improve and ease the management of breakthrough bleeds or programmed major surgeries.
Origin | Files produced by the author(s) |
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