Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy

Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. Approximately 30%–60% of individuals have pre-existing anti-AAV antibodies. Seroprevalence is impacted by m...

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Bibliographic Details
Published in:Molecular therapy 2023-03, Vol.31 (3), p.616-630
Main Authors: Schulz, Martin, Levy, Daniel I., Petropoulos, Christos J., Bashirians, George, Winburn, Ian, Mahn, Matthias, Somanathan, Suryanarayan, Cheng, Seng H., Byrne, Barry J.
Format: Article
Language:English
Subjects:
Antibodies, Neutralizing
Antibodies, Viral
Capsid Proteins - genetics
Dependovirus - genetics
efficacy
gene therapy
Genetic Therapy - methods
Genetic Vectors - genetics
Humans
humoral immunity
neutralizing antibodies
recombinant adeno-associated virus
Review
safety
Seroepidemiologic Studies
seroprevalence
total antibody assay
transduction inhibition assay
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Summary:Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. Approximately 30%–60% of individuals have pre-existing anti-AAV antibodies. Seroprevalence is impacted by multiple factors, including geography, age, capsid serotype, and assay type. Anti-AAV antibody assays typically measure (1) transduction inhibition by detecting the neutralizing capacity of antibodies and non-antibody neutralizing factors, or (2) total anti-capsid binding antibodies, regardless of neutralizing activity. Presently, there is a paucity of head-to-head data and standardized approaches associating assay results with clinical outcomes. In addition, establishing clinically relevant screening titer cutoffs is complex. Thus, meaningful comparisons across assays are nearly impossible. Although complex, establishing screening assays in routine clinical practice to identify patients with antibody levels that may impact favorable treatment outcomes is achievable for both transduction inhibition and total antibody assays. Formal regulatory approval of such assays as companion diagnostic tests will confirm their suitability for specific recombinant AAV gene therapies. This review covers current approaches to measure anti-AAV antibodies in patient plasma or serum, their potential impact on therapeutic safety and efficacy, and investigative strategies to mitigate the effects of pre-existing anti-AAV antibodies in patients. [Display omitted] Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. This report reviews the approaches to measure anti-AAV antibodies, their potential impact on therapeutic outcomes, and investigative strategies to mitigate their effects in patients.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2023.01.010