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    Oral Communication

    Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies

    Von Willebrand Disease and Thrombotic Thrombocytopenic Purpura (TTP) Novel Treatments

    OC 08.3 - KB-V13A12, a novel nanobody-based therapeutic molecule for the treatment of von Willebrand disease

    Saturday, June 24, 2023
    13:30 – 13:45 ET
    Room: 518
    Session Available As: On-Demand

      Presenting Author(s)

    • Ivan Peyron, PhD (he/him/his)

      Post-doctoral fellow
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Le Kremlin-Bicêtre, Ile-de-France, France

      • Co-Author(s)

    • Caterina Casari, PhD (she/her/hers)

      Principal Investigator
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay
      PARIS, Ile-de-France, France

    • OC

      Olivier D. Christophe

      Principal Investigator, Director of research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • Peter J. Lenting, PhD

      Principal Investigator, Director of research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • Cécile V. Denis, PhD

      Principal investigator, Director of Research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Le Kremlin-Bicêtre, Ile-de-France, France

    Background: Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by quantitative or qualitative defects of von Willebrand factor (VWF). Replacement therapies with VWF-concentrates are limited by the short half-life of VWF (10-15 hours).

    Aims: To develop a novel drug candidate that prolongs the half-life of VWF by bridging circulating VWF with albumin.

    Methods: A bi-functional molecule was generated combining the variable fragments of two single-domain antibodies: one targeting VWF (KB-VWF-013) and one targeting both human and murine albumins (OptiAlb-12). Binding of this molecule (designated KB-V13A12) to both VWF and albumin was tested in vitro. A mouse model for VWD-type 1 was used to evaluate its effect on VWF levels following subcutaneous administration. Blood samples were taken before injection, and at day 1, 3, 7, 10 and 14. In addition, a tail-clip procedure was performed to determine the potency of KB-V13A12 to restore hemostasis.

    Results: Interaction of KB-V13A12 with both albumin and VWF was validated in static binding assays. In vivo, subcutaneous administration of KB-V13A12 increased VWF plasma levels in a sustained fashion between 1.9±0.4 fold (p < 0.0001) at day 1 and 2.1±0.6 fold (p < 0.0001) at day 10 compared to t=0. In a tail-clip assay, blood loss was significantly increased in VWD-type 1 mice compared to wild-type mice (102±123 µl versus 19±37 µl respectively; p=0.0251). However, VWD-type 1 mice receiving KB-V13A12 had similar blood loss compared to that of wild-type mice (47±49 µl; p=0.711).

    Conclusion(s): Our results show that KB-V13A12 efficiently bridges VWF to albumin. In vivo experiments demonstrated that a single subcutaneous injection of KB-V13A12 elevates VWF levels for up to 10 days and restores functional hemostasis in a mouse model of VWD-type 1. KB-V13A12 seems a promising candidate for further development as treatment option for patients with reduced levels of VWF.

    Learning Objectives:

    • Upon completion, participants will understand the urge of developping new therapeutic molecules for the treatment of patients with von Willebrand disease.
    • Upon completion, participants will have a better undstanding of the steps required to develop target-specific nanobodies and their biochemical characterization.
    • Upon completion, participants will be able to appreciate how 3D modelling and docking algorithms can assist the development of drug candidates.