OC 37.4 - A humanized mouse model to assess the therapeutic potential of IdeS in hemophilia A with inhibitors

Background: The development of inhibitory anti-factor VIII (FVIII) antibodies (inhibitors) is the major drawback of replacement therapy in patients with hemophilia A (HA). IdeS is a proteinase from Streptococcus pyogenes that specifically degrades human IgG. We previously showed that IdeS efficiently hydrolyzes polyclonal anti-FVIII IgG in patients’ plasma as well as recombinant monoclonal anti-FVIII IgG in vitro.

Aims: To develop a humanized inhibitor-positive HA mouse model and test the clinical relevance of IdeS in eliminating human anti-FVIII IgG.

Methods: FVIII-deficient mice were passively immunized with a human monoclonal anti-FVIII IgG1 (BO2C11, 1200 Bethesda units (BU)/kg). On day-1 (d1), passively immunized mice were treated with IdeS (0.6 mg/kg) or with PBS. BO2C11 levels were monitored for 4 days. On d4, all mice were injected with 200 UI/kg of human recombinant FVIII. FVIII recovery and blood loss in a tail-clip bleeding model were assessed two hours later.

Results: Passively immunized mice had steady BO2C11 levels around 10 BU/mL between d1 and d4. Injection of IdeS induced a drop in BO2C11 levels: 8.3±1.4 versus 0.7±0.4 BU/mL in PBS-treated and IdeS-treated mice. The recovery of injected FVIII was higher in IdeS-treated mice than in PBS-treated mice (0.47±0.51 vs 0.02±0.02 IU/mL, p=0.0004). Likewise, following FVIII injection, IdeS-treated mice demonstrated lower blood loss than PBS-treated mice (16±26 vs 74±65 µl, p=0.0289) in a tail-clip model, that did not differ from naïve FVIII-treated mice (24±21 µl, p=0.3).

Conclusion(s): We validated a reproducible humanized inhibitor-positive mouse model of HA. Using this model, we present proof of concept for the removal of FVIII inhibitors by IdeS, opening a time window for the efficient use of FVIII replacement therapy. Aside from the use of by-passing agents and/or emicizumab, IdeS-mediated transient removal of FVIII inhibitors may be a new therapeutic option to improve the management of inhibitor-positive patients.