The Comparative Immunogenicity of Human and Porcine Factor VIII in Hemophilia A Mice

• Type of Material: Article
• Authors: John F Healey, Emory University; Ernest Theodore Parker, Emory University; Rachel T. Barrow, Emory University; T. J. Langley, Emory University; W. R. Church, Green Mountain Antibodies; Pete Lollar, Emory University
• Language: English
• Date: 2009-07
• Publisher: Schattauer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Schattauer GmbH, Stuttgart
• Final Published Version (URL): http://www.schattauer.de/de/magazine/uebersicht/zeitschriften-a-z/thrombosis-and-haemostasis/contents/archive/issue/941/manuscript/11303.html
• Title of Journal or Parent Work: Thrombosis and Haemostasis
• ISSN: 0340-6245
• Volume: 102
• Issue: 1
• Start Page: 35
• End Page: 41
• Grant/Funding Information: Supported by a grants from the National Institutes of Health (HL082609 and HL040921) (P.L.).; National Heart, Lung, and Blood Institute : NHLBI
• Keywords: Factor VIII; coagulation inhibitors; hemophilia therapy
• Research Categories: Health Sciences, Oncology

Abstract

Inhibitory antibodies to factor VIII (fVIII inhibitors) are the most significant complication in the management of hemophilia A. The immunogenicity of fVIII may be driven in part by structural determinants within the fVIII molecule itself. Regions of non-identity between human and porcine fVIII possibly could drive differential immune responses. The goal of this study was to compare the overall antibody response and levels of antibodies to the individual fVIII domains in naïve hemophilia A mice immunized with human or porcine fVIII. Hemophilia A mice were immunized with human or porcine fVIII using a protocol that mimics human clinical use. Inhibitor and total anti-fVIII antibody titers were measured and the domain-specificity of antibodies from 1759 anti-fVIII hybridomas was determined. The overall immunogenicity of human and porcine fVIII was similar but significant differences in domain recognition were discovered. Anti-A2 and anti-C2 antibodies constituted the majority of inhibitors in both the human and porcine fVIII groups, similar to inhibitors that develop in humans. The proportions of anti-A2 or anti-C2 antibodies were not significantly different between the two groups. However, the specific inhibitory activity of anti-A2 antibodies was higher in the human fVIII group. Additionally, proportion of anti-C1 antibodies was significantly higher in the human fVIII group. In contrast, anti-A3 antibodies were more common in the porcine fVIII group. The differential immune response to human and porcine fVIII suggests that it may be possible to reduce the immunogenicity of fVIII by mutagenesis of the A2, A3 and C1 domains.