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Antithrombin (AT) concentrates derived from pooled human plasma have been used for the management of hereditary and acquired AT deficiencies since the early 1980s. The development of a recombinant version of AT would alleviate supply and safety concerns associated with the use of the plasma-derived biotherapeutic. However, the complex structure of the AT molecule, and the large doses usually required in supplementation treatments, have precluded the use of traditional bacterial and cell culture bioreactors for commercial production. GTC Biotherapeutics has applied the transgenic animal expression system to the production of recombinant AT (tradename ATryn). A herd of transgenic dairy goats expressing high levels of human AT in their milk was characterized and expanded, providing a homogeneous, well-defined and abundant supply of AT. This chapter describes the clinical development of ATryn (including eight clinical studies), and the production of this modern biopharmaceutical in transgenic goats. Abbreviations ACT activated clotting time ARDS adult respiratory distress syndrome AT antithrombin BSE bovine spongiform encephalopathy CD circular dichroism CJD Creutzfeld–Jakob disease CPB cardiopulmonary bypass DIC disseminated intravascular coagulation DVT deep-vein thrombosis FFP fresh-frozen plasma FISH fluorescence in-situ hybridization HD hereditary-deficient HSPG heparan sulfate proteoglycans HUVEC human umbilical vein endothelial cells IL interleukin LC/MS liquid chromatography/mass spectrophotometry LPS lipopolysaccharide nvCJD new-variant Creutzfeld-Jakob disease PCR polymerase chain reaction TAT thrombin–antihrombin (complex) TSE transmissible spongiform encephalopathy 1 11 The First Biopharmaceutical from Transgenic Animals: ATryn Yann Echelard, Harry M. Meade, and Carol A. Ziomek Modern Biopharmaceuticals. Edited by J. Knablein, R.H. Muller Copyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31184-X WILEY-VCH Knablein, Kap. 4-11 1. UK Schmitt K+V Fotosatz GmbH Beerfelden 11.4.2005 |
