INSERM U1176, Hémostase, Inflammation et Thrombose
"Application of classic antibodies and nanobodies in hemorrhagic disorders"
The treatment of hemorrhagic disorders like hemophilia and von Willebrand disease is largely dependent on replacement therapy using the missing protein. Such therapies are expensive, require frequent intravenous injections and are (in case of FVIII-replacement therapy) associated with the development of inhibitory antibodies in up to 30% of the patients. Over the last decades, alternative approaches have been or are being developed, some of which are based on the therapeutic use of antibodies or antibody-based proteins. Also in our laboratory, we have developed antibody-based therapies, some of which being advanced candidates for clinical development.
One example regards antibody LTX-508, a monoclonal antibody that binds to von Willebrand factor (VWF). VWF is a multimeric protein responsible for the recruitment of platelets. In patients that receive mechanical circulatory support (as in LVAD or ECMO), VWF is excessively degraded. Up to 50% of these patients manifest bleeding complications, which are associated with prolonged hospitalization and increased mortality. Antibody LTX-508 aims to reduce degradation of VWF under these conditions. Another example relates to a FVIII-nanobody fusion protein, designated FVIII-KB013bv. In this protein, FVIII is fused with a nanobody directed against its carrier protein VWF. The presence of the nanobody increases its affinity for VWF 25-fold, and this increased affinity is associated with a two-fold prolonged half-life and, more importantly, a 7-fold reduction in the number of mice that develop inhibitory antibodies against FVIII. Finally, we have also developed nanobodies against antithrombin, a main inhibitor of the coagulation cascade. The nanobodies interfere with antithrombin activity, and can be used to restore the hemostatic balance in hemophilia A and B. In vitro and in vivo data confirm that such nanobodies can correct for the absence of FVIII or FIX. The advantage of such nanobody-based therapy is that these antibodies can be given both subcutaneously and intravenously, while their stability may allow storage at room temperature rather than 4?C.