The IgG-degrading enzyme, Imlifidase, restores the therapeutic activity of FVIII in inhibitor-positive hemophilia A mice

Abstract

Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in nonhemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human IgG; it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive HA mice. IdeS cleaved anti-FVIII plasma IgG from PwHA and AHA patients, and hydrolyzed recombinant human anti-FVIII IgG independently from their subclass or specificity for the A2, A3, C1 or C2 domains of FVIII. In HA mice passively immunized with recombinant human anti-FVIII IgG, IdeS restored the hemostatic efficacy of FVIII, as evidenced by the correction of the bleeding tendency. Our results provide the proof of concept for the transient removal of FVIII inhibitors by IdeS, thereby opening a therapeutic window for efficient FVIII replacement therapy in inhibitor-positive patients.

Imlifidase for hematologists: Creating a therapeutic window in the presence of neutralizing alloantibodies

“…This was investigated by the same group recently in a hemophilia mice model. 7 The levels of emicizumab were reduced by 71% 72 h after administering a set of two injections of equimolar amounts of imlifidase; this decrease was enhanced to 90% when a 10-fold excess of imlifidase was infused. Circulating F(ab՛)2 fragments of emicizumab were undetectable after 18 hours.…”

“…Earlier this year, imlifidase was shown to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive hemophilia A mice. 6 Imlifidase cleaved anti-FVIII plasma IgG from patients with congenital and acquired hemophilia A in vitro. In mice passively immunized with recombinant human anti-FVIII IgG, imlifidase restored the hemostatic efficacy of FVIII.…”

“…Earlier this year, imlifidase was shown to eliminate FVIII inhibitors in vitro and in a model of inhibitor‐positive hemophilia A mice 6 . Imlifidase cleaved anti‐FVIII plasma IgG from patients with congenital and acquired hemophilia A in vitro.…”