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Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey

Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebr...

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Autores principales: Rossato, Paolo, Glantschnig, Helmut, Leidenmühler, Peter, Kopic, Alexandra, Ruthsatz, Tanja, Majer, Bernhard, Schuster, Maria, Scheiflinger, Friedrich, Höllriegl, Werner
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728677/
https://www.ncbi.nlm.nih.gov/pubmed/34267062
http://dx.doi.org/10.1097/MBC.0000000000001064
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author Rossato, Paolo
Glantschnig, Helmut
Leidenmühler, Peter
Kopic, Alexandra
Ruthsatz, Tanja
Majer, Bernhard
Schuster, Maria
Scheiflinger, Friedrich
Höllriegl, Werner
author_facet Rossato, Paolo
Glantschnig, Helmut
Leidenmühler, Peter
Kopic, Alexandra
Ruthsatz, Tanja
Majer, Bernhard
Schuster, Maria
Scheiflinger, Friedrich
Höllriegl, Werner
author_sort Rossato, Paolo
collection PubMed
description Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD. Deficiencies of VWF, or concomitant treatment with antithrombotic drugs, could pose risks for increased bleeds in these patient populations. The purpose of the experiments was to evaluate the potential of exaggerated pharmacology and temporary bleeding risks associated with rADAMTS13 administration. We utilized safety studies in monkey and tested the effects of administering maximum-feasible doses of rADAMTS13 on nonclinical safety and spontaneous or aggressive bleeds in the rat model. Evaluation of pharmacokinetics, toxicity profiles, and challenge in a tail-tip bleeding model show that treatment with rADAMTS13 did not increase bleeding tendency, either alone, or in combination with enoxaparin or acetylsalicylic-acid. These novel findings demonstrate absence of rADAMTS13 exaggerated pharmacology without spontaneous or aggravated bleeds even at supra-physiologic (>100-fold) plasma concentrations.
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spelling pubmed-87286772022-01-05 Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey Rossato, Paolo Glantschnig, Helmut Leidenmühler, Peter Kopic, Alexandra Ruthsatz, Tanja Majer, Bernhard Schuster, Maria Scheiflinger, Friedrich Höllriegl, Werner Blood Coagul Fibrinolysis Short Communication Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD. Deficiencies of VWF, or concomitant treatment with antithrombotic drugs, could pose risks for increased bleeds in these patient populations. The purpose of the experiments was to evaluate the potential of exaggerated pharmacology and temporary bleeding risks associated with rADAMTS13 administration. We utilized safety studies in monkey and tested the effects of administering maximum-feasible doses of rADAMTS13 on nonclinical safety and spontaneous or aggressive bleeds in the rat model. Evaluation of pharmacokinetics, toxicity profiles, and challenge in a tail-tip bleeding model show that treatment with rADAMTS13 did not increase bleeding tendency, either alone, or in combination with enoxaparin or acetylsalicylic-acid. These novel findings demonstrate absence of rADAMTS13 exaggerated pharmacology without spontaneous or aggravated bleeds even at supra-physiologic (>100-fold) plasma concentrations. Lippincott Williams & Wilkins 2022-01 2021-07-23 /pmc/articles/PMC8728677/ /pubmed/34267062 http://dx.doi.org/10.1097/MBC.0000000000001064 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
spellingShingle Short Communication
Rossato, Paolo
Glantschnig, Helmut
Leidenmühler, Peter
Kopic, Alexandra
Ruthsatz, Tanja
Majer, Bernhard
Schuster, Maria
Scheiflinger, Friedrich
Höllriegl, Werner
Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title_full Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title_fullStr Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title_full_unstemmed Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title_short Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey
title_sort absence of exaggerated pharmacology by recombinant adamts13 in the rat and monkey
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728677/
https://www.ncbi.nlm.nih.gov/pubmed/34267062
http://dx.doi.org/10.1097/MBC.0000000000001064
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