Abstract Number: OC 38.4
Meeting: ISTH 2021 Congress
Background: The administration of exogenous therapeutic factor VIII (FVIII) to correct bleeding in patients with hemophilia A (HA) is complicated by the development of neutralizing anti-FVIII IgG, referred to as ‘FVIII inhibitors’. The development of FVIII inhibitors precludes further use of therapeutic FVIII. Bypassing agents, such as activated factor VII or bispecific antibodies, are however not as efficient as FVIII in correcting major bleeds resulting from injuries or surgery. IdeS is an enzyme derived from Streptococcus pyogenes that hydrolyses human IgG and was used with success in kidney transplants to prevent antibody-mediated allograft rejection.
Aims: To investigate whether IdeS may remove FVIII inhibitors from inhibitor-positive patients.
Methods: IdeS was incubated with i) plasma from 119 patients with severe or mild/moderate HA, with or without FVIII inhibitors or ii) human monoclonal anti-FVIII IgG1k or IgG4k specific for the A2 (BOIIB2), A3 (KM41), C1 (LE2E9), or C2 (BO2C11) domains of FVIII. IgG hydrolysis and release of the Fc fragment were confirmed by SDS-PAGE and Western blot. Residual FVIII recognition was measured in ELISA using a secondary anti-Fc detection antibody.
Results: IdeS readily hydrolysed recombinant monoclonal IgG as well as polyclonal IgG in patients’ plasma. IdeS treatment resulted in a 10-fold reduction of FVIII recognition in ELISA, confirming the release of the Fc from the F(ab’)2 fragments. Because IdeS retains the integrity of the F(ab’)2 fragments, treatment had no major impact on the inhibitory activity towards FVIII in vitro.
Conclusions: IdeS efficiently hydrolyses anti-FVIII IgG in vitro. Work in FVIII-deficient mice reconstituted with exogenous human anti-FVIII IgG will bring the proof of concept for the removal of FVIII inhibitors by IdeS in vivo. Importantly, it will reveal whether IdeS-mediated transient removal of FVIII inhibitors may be applied to all inhibitor-positive HA patients or should be restricted to patients with low inhibitor titres.
To cite this abstract in AMA style:Bou-Jaoudeh M, Delignat S, Daventure V, Mimoun A, Astermark J, Lacroix-Desmazes S. Elimination of Factor VIII Inhibitors by the IgG-degrading Enzyme of Streptococcus pyogenes [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/elimination-of-factor-viii-inhibitors-by-the-igg-degrading-enzyme-of-streptococcus-pyogenes/. Accessed December 6, 2023.
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