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Detection of Biologically Relevant Low-Titer Neutralizing Antibodies Against Adeno-Associated Virus Require Sensitive In Vitro Assays.
Kruzik, Anita; Koppensteiner, Herwig; Fetahagic, Damir; Hartlieb, Bettina; Dorn, Sebastian; Romeder-Finger, Stefan; Coulibaly, Sogue; Weber, Alfred; Hoellriegl, Werner; Horling, Frank M; Scheiflinger, Friedrich; Reipert, Birgit M; de la Rosa, Maurus.
Afiliação
  • Kruzik A; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Koppensteiner H; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Fetahagic D; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Hartlieb B; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Dorn S; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Romeder-Finger S; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Coulibaly S; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Weber A; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Hoellriegl W; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Horling FM; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Scheiflinger F; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • Reipert BM; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
  • de la Rosa M; Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
Hum Gene Ther Methods ; 30(2): 35-43, 2019 04.
Article em En | MEDLINE | ID: mdl-30734588
ABSTRACT
Patients with preexisting anti-adeno-associated virus serotype 8 (AAV8) neutralizing antibodies (NAbs) are currently excluded from AAV8 gene therapy trials. Therefore, the assessment of biologically relevant AAV8-NAb titers is critical for product development in gene therapy. However, standardized assays have not been routinely used to determine anti-AAV8-NAb titers, contributing to a wide range of reported anti-AAV8 prevalence rates. Using a clinical in vitro NAb assay in a separate study, a higher than expected anti-AAV8-NAb prevalence of about 50% was found in international cohorts. This comparative study has a translational character, confirming the biological relevance of anti-AAV8-antibody titers measured by this assay. The significance of low-titer anti-AAV8 NAbs is shown, along with the relevance of the in vitro assay cutoff (15) compared with other assays. Importantly, internally standardized reagents and purified AAV8 constructs containing 90% full capsids were used to reduce the effect of empty capsids. It was found that even very low anti-AAV8-NAb titers (<15) could efficiently hinder transduction in vivo, demonstrating the importance of sensitive NAb assays for clinical applications. The in vitro NAb assay was found to be more sensitive than an in vivo NAb assay and thus more suitable for patient screening. Additionally, the study showed that anti-AAV8-NAb titers <15 were very rare, further supporting the in vitro assay. However, assays using a lower cutoff may still be useful to explain potential variances in transgene expression. These findings support the relevance of the higher than expected prevalence of anti-AAV8 NAbs, highlighting the need for strategies to circumvent preexisting anti-AAV8 NAbs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dependovirus / Anticorpos Neutralizantes / Anticorpos Antivirais Tipo de estudo: Diagnostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Dependovirus / Anticorpos Neutralizantes / Anticorpos Antivirais Tipo de estudo: Diagnostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article