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Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice
dc.contributor.author | Pisal, Dipak S. | |
dc.contributor.author | Kosloski, Matthew P. | |
dc.contributor.author | Middaugh, C. Russell | |
dc.contributor.author | Bankert, Richard B. | |
dc.contributor.author | Balu-lyer, Sathy V. | |
dc.date.accessioned | 2017-04-26T15:30:20Z | |
dc.date.available | 2017-04-26T15:30:20Z | |
dc.date.issued | 2012-06 | |
dc.identifier.citation | Pisal, D. S., Kosloski, M. P., Middaugh, C. R., Bankert, R. B., & Balu-Iyer, S. V. (2012). Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice. Journal of Pharmaceutical Sciences, 101(6), 2055–2065. http://doi.org/10.1002/jps.23091 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23781 | |
dc.description.abstract | The administration of recombinant Factor VIII (FVIII) is the first line therapy for Hemophilia A (HA), but 25–35% of patients develop an inhibitory antibody response. In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native-like and non-native aggregates. Previously, we showed that non-native aggregates of FVIII are less immunogenic compared to the native protein. Here we investigated the effect of native-like aggregates of FVIII on immunogenicity in HA and von Willebrand Factor knockout (vWF−/−) mice. Mice immunized with native-like aggregates showed significantly higher inhibitory antibody titers compared to animals that received native FVIII. Following re-stimulation in vitro with native FVIII, the activation of CD4+ T cells isolated from mice immunized with native-like aggregates is ~4 fold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of pro-inflammatory cytokines IL-6 and IL-17 in the native-like aggregate treatment group. The results indicate that the native-like aggregates of FVIII are more immunogenic than native FVIII for both the B cell and T cell responses. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Factor VIII | en_US |
dc.subject | Protein Aggregation | en_US |
dc.subject | Immunogenicity | en_US |
dc.subject | Native-like aggregates | en_US |
dc.subject | Von Willebrand Factor | en_US |
dc.subject | Immunogenicty | en_US |
dc.title | Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Middaugh, C. Russell | |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1002/jps.23091 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC3774159 | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.