Abstract
Preexisting immunity against adeno-associated virus (AAV) is a major challenge facing AAV gene therapy, resulting in the exclusion of patients from clinical trials. Accordingly, proper assessment of anti-AAV immunity is necessary for understanding clinical data and for product development. Previous studies on anti-AAV prevalence lack method standardization, rendering the assessment of prevalence difficult. Addressing this need, we used clinical assays that were validated according to guidelines for a comprehensive characterization of anti-AAV1, -AAV2, -AAV5, and -AAV8 immunity in large international cohorts of healthy donors and patients with hemophilia B. Here, we report a higher than expected average prevalence for anti-AAV8 (∼40%) and anti-AAV5 (∼30%) neutralizing antibodies (NAbs), which is supported by strongly correlating anti-AAV IgG antibody titers. A similar anti-AAV8 NAb prevalence was observed in hemophilia B patients. In addition, a high co-prevalence of NAbs against other serotypes makes switching to gene therapy using another serotype difficult. As anti-AAV T cell responses are believed to influence transduction, we characterized anti-AAV T cell responses using interleukin-2 (IL-2) and interferon-γ (IFN-γ) ELISpot assays, revealing a similar prevalence of IFN-γ responses (∼20%) against different serotypes that did not correlate with NAbs. These data, along with the long-term stability of NAbs, emphasize the need to develop strategies to circumvent anti-AAV immunity.
Highlights
Recombinant adeno-associated virus 8 (AAV8) is a promising vector for gene therapy because it lacks pathogenicity in humans, provides long-term transgene expression with negligible integration into the host genome and, based on results in mice, is considered to have the best hepatocyte transduction efficiency among all AAV serotypes.[1,2,3] AAV8 and AAV5 serotypes are currently favored for gene therapy, owing, among other reasons, to a potentially lower neutralizing antibody (NAb) prevalence compared with AAV2, which was widely used until clinical trials revealed that even low neutralizing antibodies (NAbs) titers against AAV2 can have an impact on the effectiveness of gene therapy.[4]
AAV8 and AAV5 serotypes are currently favored for gene therapy, owing, among other reasons, to a potentially lower neutralizing antibody (NAb) prevalence compared with AAV2, which was widely used until clinical trials revealed that even low NAb titers against AAV2 can have an impact on the effectiveness of gene therapy.[4]
High Prevalence of Clinically Relevant Antibodies against AAV8 Geographic differences in anti-AAV8 NAb prevalence were assessed in three cohorts of healthy donors from Europe, a cohort of healthy donors from the United States, and a cohort of patients with hemophilia B from the United States (Figure 1A)
Summary
Recombinant adeno-associated virus 8 (AAV8) is a promising vector for gene therapy because it lacks pathogenicity in humans, provides long-term transgene expression with negligible integration into the host genome and, based on results in mice, is considered to have the best hepatocyte transduction efficiency among all AAV serotypes.[1,2,3] AAV8 and AAV5 serotypes are currently favored for gene therapy, owing, among other reasons, to a potentially lower neutralizing antibody (NAb) prevalence compared with AAV2, which was widely used until clinical trials revealed that even low NAb titers against AAV2 can have an impact on the effectiveness of gene therapy.[4] preexisting immunity to AAV8 is still considered to be a major hurdle. Even low titers of NAbs against AAV8 have been shown to block in vivo transduction, and CD8 T cells specific for AAV8 are thought to kill transduced hepatocytes, preventing transgene expression.[4] patients with preexisting NAbs against AAV8 are currently ineligible for AAV8 gene therapy. To be able to dose patients efficiently and include all patients in need of therapy, it is necessary to reliably identify clinically relevant antiAAV8 NAb titers and T cell responses
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