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Structure and function of a recombinant von Willebrand factor drug candidate.

Authors
  • Turecek, Peter L
  • Schrenk, Gerald
  • Rottensteiner, Hanspeter
  • Varadi, Katalin
  • Bevers, Edouard
  • Lenting, Peter
  • Ilk, Nicola
  • Sleytr, Uwe B
  • Ehrlich, Hartmut J
  • Schwarz, Hans Peter
Type
Published Article
Journal
Seminars in Thrombosis and Hemostasis
Publisher
Georg Thieme Verlag KG
Publication Date
Jul 01, 2010
Volume
36
Issue
5
Pages
510–521
Identifiers
DOI: 10.1055/s-0030-1255445
PMID: 20635317
Source
Medline
License
Unknown

Abstract

The complex structure, large size, and multiple posttranslational modifications of von Willebrand factor (VWF) presented a technological challenge for the production of recombinant VWF (rVWF). Nonetheless, we developed an rVWF product for treating von Willebrand disease, whereupon rVWF is coexpressed with recombinant factor VIII (rFVIII) in Chinese hamster ovary cells used to produce rFVIII for the treatment of hemophilia A. Here we describe the characterization of the structure and function of the rVWF drug product, with a focus on its in vitro platelet aggregation and matrix protein binding functions. Electron microscopy and multimer analysis revealed a highly organized structure for the rVWF protein, with a homogeneous multimer distribution including ultrahigh molecular weight multimers. The specific activity for binding to collagen and platelets mediated by ristocetin is higher in rVWF than in commercial plasma-derived VWF-FVIII complex products. The affinity and binding capacity of rVWF to FVIII is comparable to VWF in plasma. rVWF effectively binds to platelets and promotes platelet adhesion under shear stress similar to VWF in human plasma.

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