Preclinical testing of human recombinant von Willebrand factor: ADAMTS13 cleavage capacity in animals as criterion for species suitability

Seminars in Thrombosis and Hemostasis
Eva-Maria MuchitschHans Peter Schwarz

Abstract

Von Willebrand factor (VWF) is cleaved by the plasma metalloprotease ADAMTS13 ( A Disintegrin and Metalloproteinase with Thrombo Spondin repeats, number 13) that regulates the hemostatic activity of VWF by limiting its multimeric size in the human system. In vitro and ex vivo studies have shown that human recombinant VWF (rVWF) is virtually resistant to the proteolytic activity of murine ADAMTS13. In contrast, rabbit and cynomolgus ADAMTS13 is able to cleave human rVWF. These findings were consistent with in vivo results showing distinct pharmacological behavior of human rVWF depending on the cleaving capacity of ADAMTS13 present in the species tested. Studies were performed using three mouse strains (ADAMTS13 deficient, C57BL/6J [wild type], VWF deficient), rats, rabbits, and cynomolgus monkeys. All animals were infused once with different doses of human rVWF and, in addition, 14 daily doses were given to rats and cynomolgus monkeys. Exaggerated pharmacological effects were observed in mice, with the ADAMTS13 knockout mouse being the most sensitive strain. Similar findings with decreased incidence and severity were seen in normal C57BL/6J mice and also in VWF-deficient mice, where they were least pronounced. In rats, exaggerat...Continue Reading

Citations

Mar 21, 2012·Expert Opinion on Biological Therapy·Emmanuel J FavaloroGiuseppe Lippi
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Jul 19, 2016·Expert Review of Hematology·Massimo Franchini, Pier Mannuccio Mannucci
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