Native‐like aggregates of factor VIII are immunogenic in von Willebrand factor deficient and hemophilia a mice
Identifieur interne : 001E11 ( Main/Exploration ); précédent : 001E10; suivant : 001E12Native‐like aggregates of factor VIII are immunogenic in von Willebrand factor deficient and hemophilia a mice
Auteurs : Dipak S. Pisal [États-Unis] ; Matthew P. Kosloski [États-Unis] ; C. Russell Middaugh [États-Unis] ; Richard B. Bankert [États-Unis] ; Sathy V. Balu-Iyer [États-Unis]Source :
- Journal of Pharmaceutical Sciences [ 0022-3549 ] ; 2012-06.
English descriptors
- Teeft :
- Aggregate, Aggregated, Aggregation, Animal models, Antibody responses, Antibody titers, Clone, Conformational, Conformational changes, Cytokine, Cytokine secretion, Epitope, Factor viii, Fviii, Fviii aggregates, Greater response, Haemost, Hemophilia, Human factor viii, Immune, Immune response, Immune responses, Immunogenic, Immunogenicity, Inhibitory, Inhibitory titers, Intermolecular beta strands, June, Less immunogenic, Monomeric, More immunogenic, Mouse, Mouse model, Murine, Native fviii, Native protein, Native state, Nonnative, Nonnative aggregates, Pharm, Pharmaceutical, Pharmaceutical sciences, Pisal, Plasma samples, Protein aggregates, Protein therapeutics, Recombinant, Subvisible particles, Tertiary structure, Therapeutic proteins, Thromb, Thromb haemost, Titer, Total area, Total titers, Tris buffer, Uorescence, Viii, Willebrand, Willebrand factor.
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 nonnative aggregates. Previously, we showed that nonnative aggregates of FVIII are less immunogenic than 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 than animals that received native FVIII. Following restimulation in vitro with native FVIII, the activation of CD4+ T‐cells isolated from mice immunized with native‐like aggregates is approximately fourfold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of proinflammatory 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 the T‐cell responses. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2055–2065, 2012
Url:
DOI: 10.1002/jps.23091
Affiliations:
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Russell Middaugh</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Kansas</region></placeName><wicri:cityArea>Department of Pharmaceutical Chemistry, University of Kansas, Lawrence</wicri:cityArea></affiliation></author><author><name sortKey="Bankert, Richard B" sort="Bankert, Richard B" uniqKey="Bankert R" first="Richard B." last="Bankert">Richard B. Bankert</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Amherst</wicri:cityArea></affiliation></author><author><name sortKey="Balu Yer, Sathy V" sort="Balu Yer, Sathy V" uniqKey="Balu Yer S" first="Sathy V." last="Balu-Iyer">Sathy V. 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In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native‐like and nonnative aggregates. Previously, we showed that nonnative aggregates of FVIII are less immunogenic than 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 than animals that received native FVIII. Following restimulation in vitro with native FVIII, the activation of CD4+ T‐cells isolated from mice immunized with native‐like aggregates is approximately fourfold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of proinflammatory 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 the T‐cell responses. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2055–2065, 2012</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Kansas</li><li>État de New York</li></region><settlement><li>Buffalo (New York)</li></settlement><orgName><li>Université d'État de New York à Buffalo</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Pisal, Dipak S" sort="Pisal, Dipak S" uniqKey="Pisal D" first="Dipak S." last="Pisal">Dipak S. Pisal</name></region><name sortKey="Balu Yer, Sathy V" sort="Balu Yer, Sathy V" uniqKey="Balu Yer S" first="Sathy V." last="Balu-Iyer">Sathy V. Balu-Iyer</name><name sortKey="Balu Yer, Sathy V" sort="Balu Yer, Sathy V" uniqKey="Balu Yer S" first="Sathy V." last="Balu-Iyer">Sathy V. Balu-Iyer</name><name sortKey="Balu Yer, Sathy V" sort="Balu Yer, Sathy V" uniqKey="Balu Yer S" first="Sathy V." last="Balu-Iyer">Sathy V. Balu-Iyer</name><name sortKey="Bankert, Richard B" sort="Bankert, Richard B" uniqKey="Bankert R" first="Richard B." last="Bankert">Richard B. Bankert</name><name sortKey="Kosloski, Matthew P" sort="Kosloski, Matthew P" uniqKey="Kosloski M" first="Matthew P." last="Kosloski">Matthew P. Kosloski</name><name sortKey="Middaugh, C Russell" sort="Middaugh, C Russell" uniqKey="Middaugh C" first="C. Russell" last="Middaugh">C. Russell Middaugh</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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