Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS-13 activity levels in inhibitor-treated rats by the use of defined doses of recombinant ADAMTS-13

Journal of Thrombosis and Haemostasis : JTH
Barbara PlaimauerFriedrich Scheiflinger

Abstract

Acquired thrombotic thrombocytopenic purpura (TTP) is caused by an autoantibody-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS-13. Acute episodes of the disease are treated with a combination of immunosuppression and repeated cycles of plasma exchange to remove anti-ADAMTS-13 autoantibodies and, at the same time, replenish functional ADAMTS-13. Although this is often effective, the mortality rate has remained between 10% and 20%, highlighting the need for safer treatment options. We previously showed that, in vitro, human recombinant ADAMTS-13 (rADAMTS-13) is able to override neutralizing antibodies and restore ADAMTS-13 activity in plasma from patients with acquired TTP. In the present study, we assessed the in vivo feasibility of this strategy by using a rat model. Wild-type rats were adjusted to an ADAMTS-13 inhibitor (inhibitor) titer of ~ 10 BU mL(-1) with goat anti-ADAMTS-13 IgG, and treated with increasing doses of rADAMTS-13. Blood samples were drawn and analyzed for ADAMTS-13-specific parameters, including FRETS-VWF73 activity, inhibitor, and ADAMTS-13-specific immune complexes (ICs). The pharmacokinetics of ADAMTS-13 activity and inhibitors were evaluated. Administration of inhibitor titer-a...Continue Reading

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Citations

Jul 27, 2018·Research and Practice in Thrombosis and Haemostasis·Camila Masias, Spero R Cataland
Jul 31, 2019·Expert Opinion on Biological Therapy·Maëlle le BesneraisPaul Coppo
Aug 2, 2017·Current Opinion in Hematology·Yvette C TanhehcoAra Metjian
Sep 3, 2020·Expert Review of Hematology·Inés Gómez-SeguíJavier de la Rubia
Apr 7, 2017·Nature Reviews. Disease Primers·Johanna A Kremer HovingaKaren Vanhoorelbeke
Apr 4, 2020·Expert Review of Hematology·Andrés Gómez-De LeónDavid Gómez-Almaguer
Jul 20, 2021·Expert Review of Hematology·Inés Gómez-SeguíJavier de la Rubia Comos
Sep 1, 2021·Transfusion clinique et biologique : journal de la Société française de transfusion sanguine·P Poullin

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