title: Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura.
abstract: ALX-0681 is a therapeutic Nanobody targeting the A1-domain of VWF. It inhibits the interaction between ultra-large VWF and platelet GpIb-IX-V, which plays a crucial role in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). In the present study, we report the efficacy and safety profile of ALX-0681 in a baboon model of acquired TTP. In this model, acute episodes of TTP are induced by administration of an ADAMTS13-inhibiting mAb. ALX-0681 completely prevented the rapid onset of severe thrombocytopenia and schistocytic hemolytic anemia. After induction of TTP, platelet counts also rapidly recovered on administration of ALX-0681. This effect was corroborated by the full neutralization of VWF activity. The schistocytic hemolytic anemia was also halted and partially reversed by ALX-0681 treatment. Brain CT scans and post mortem analysis did not reveal any sign of bleeding, suggesting that complete neutralization of VWF by ALX-0681 under conditions of thrombocytopenia was not linked with an excessive bleeding risk. The results obtained in this study demonstrate that ALX-0681 can successfully treat and prevent the most important hallmarks of acquired TTP without evidence of a severe bleeding risk. Therefore, ALX-0681 offers an attractive new therapeutic option for acquired TTP in the clinical setting.
authors.affiliation: Pharmacology Department, Ablynx NV, Zwijnaarde, Belgium. filip.callewaert@ablynx.com
authors.forename: Filip
authors.initials: F
authors.lastname: Callewaert
authors.forename: Jan
authors.initials: J
authors.lastname: Roodt
authors.forename: Hans
authors.initials: H
authors.lastname: Ulrichts
authors.forename: Thomas
authors.initials: T
authors.lastname: Stohr
authors.forename: Walter Janse
authors.initials: WJ
authors.lastname: van Rensburg
authors.forename: Seb
authors.initials: S
authors.lastname: Lamprecht
authors.forename: Stefaan
authors.initials: S
authors.lastname: Rossenu
authors.forename: Sofie
authors.initials: S
authors.lastname: Priem
authors.forename: Wouter
authors.initials: W
authors.lastname: Willems
authors.forename: Josefin-Beate
authors.initials: JB
authors.lastname: Holz
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000743:Anemia, Hemolytic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D064847:Multimodal Imaging; D010215:Papio; D010976:Platelet Count; D049268:Positron-Emission Tomography; D011697:Purpura, Thrombotic Thrombocytopenic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D014841:von Willebrand Factor; D051722:ADAM Proteins