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 Blood, 12 November 2009, Vol. 114, No. 20, pp. 4562-4565.
Prepublished online as a Blood First Edition Paper on September 21, 2009; DOI 10.1182/blood-2009-05-220327.

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THROMBOSIS AND HEMOSTASIS

Brief report

Recombinant canine B-domain–deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model

Denise E. Sabatino1,*, Christian Furlan Freguia2,*, Raffaella Toso2, Andrey Santos2, Elizabeth P. Merricks3, Haig H. Kazazian, Jr1, Timothy C. Nichols3, Rodney M. Camire2,4, and Valder R. Arruda2,4

1 Department of Genetics, University of Pennsylvania, Philadelphia; 2 Children's Hospital of Philadelphia, PA; 3 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill; and 4 Department of Pediatrics, University of Pennsylvania, Philadelphia

Production of recombinant B-domain–deleted canine factor VIII (cFVIII-BDD) unexpectedly revealed superior protein yields with 3-fold increased specific activity relative to human FVIII-BDD (hFVIII-BDD). We also determined that activated cFVIII-BDD is more stable than activated hFVIII-BDD. Furthermore, cFVIII-BDD is efficient at inducing hemostasis in human plasma containing FVIII inhibitors. Infusion of cFVIII-BDD in hemophilia A dogs resulted in correction of the disease phenotype with a pharmacokinetic profile similar to clinical experience with hFVIII-BDD. Notably, immune tolerance challenges with cFVIII-BDD in young and adult hemophilia A dogs did not induce the formation of neutralizing or nonneutralizing antibodies to cFVIII. These data establish the framework to quantitatively investigate the efficacy and safety in preclinical studies of novel therapies for hemophilia A.


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