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Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice
Pisal, Dipak S. Kosloski, Matthew P. Middaugh, C. Russell Bankert, Richard B. Balu-lyer, Sathy V.
Pisal, Dipak S.
Kosloski, Matthew P.
Middaugh, C. Russell
Bankert, Richard B.
Balu-lyer, Sathy V.
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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.
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Date
2012-06
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Elsevier
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Keywords
Factor VIII, Protein Aggregation, Immunogenicity, Native-like aggregates, Von Willebrand Factor, Immunogenicty
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