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.
Subject(s)
Anemia, Hemolytic/drug therapy , Antibodies, Monoclonal/therapeutic use , Fibrinolytic Agents/therapeutic use , Purpura, Thrombotic Thrombocytopenic/drug therapy , von Willebrand Factor/antagonists & inhibitors , ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Anemia, Hemolytic/complications , Anemia, Hemolytic/metabolism , Anemia, Hemolytic/pathology , Animals , Antibodies, Monoclonal/pharmacology , Blood Platelets/drug effects , Blood Platelets/metabolism , Blood Platelets/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Fibrinolytic Agents/pharmacology , Male , Multimodal Imaging , Papio , Platelet Count , Positron-Emission Tomography , Purpura, Thrombotic Thrombocytopenic/complications , Purpura, Thrombotic Thrombocytopenic/metabolism , Purpura, Thrombotic Thrombocytopenic/pathology , Tomography, X-Ray Computed , Treatment Outcome , von Willebrand Factor/metabolismABSTRACT
Evolution has been continuously honing the design of antibodies to function as specific molecular markers that are able to alert the immune system to the presence of pathogenic antigens, and to recruit complement- and Fc receptor-bearing effector cells. During the past 25 years, the versatility of antibodies has been applied to several therapeutic applications. The development of new technologies, combined with data obtained using a new generation of antibody reagents, have allowed the adaptation of the design of antibodies to better match drug development requirements. Nanobodies are therapeutic proteins derived from the heavy-chain variable (VHH) domains that occur naturally in heavy-chain-only Ig molecules in camelidae. These VHH domains are the smallest known antigen-binding antibody fragments. Nanobodies can be easily produced in prokaryotic or eukaryotic host organisms, and their unique biophysical and pharmacological characteristics render these molecules ideal candidates for drug development. This review describes the structural properties of nanobodies and focuses on their unique features, which distinguishes these molecules from other antibody formats and small-molecule drugs. Possible therapeutic applications of nanobodies are discussed and data from phase I clinical trials of the novel 'first-in-class' anti-thrombotic agent ALX-0081 (Ablynx NV) are presented.