Pre-existing anti-adeno-associated virus serotype 9 neutralizing antibodies (Anti-AAV9 NAb) (Anti-AAV9 NAb)

Pre-existing anti-adeno-associated virus serotype 9 (AAV9) neutralizing antibodies (NAbs) are host-derived immunoglobulins that recognize and bind to the AAV9 capsid, typically resulting from prior natural exposure to the wild-type virus (Boutin et al., 2010). These antibodies pose a critical challenge for AAV9-mediated gene therapies, such as onasemnogene abeparvovec, because even low titers can neutralize the therapeutic vector, preventing cellular entry and subsequent transgene expression (Mingozzi & High, 2013). Beyond reducing efficacy, the formation of immune complexes between NAbs and the vector can trigger systemic inflammatory responses or enhance hepatotoxicity (Leborgne et al., 2020). In clinical practice, patients are screened for NAb titers, and those exceeding a specific threshold are often excluded from receiving AAV9-based treatments. Emerging strategies to overcome this barrier include the use of IgG-degrading enzymes like imlifidase to transiently deplete the antibody pool or the use of plasmapheresis to physically remove them (Sadeghi et al., 2022). Additionally, immunosuppressive regimens involving drugs like rituximab or bortezomib are being explored to prevent the rebound of these antibodies or to manage the immune response during vector administration.

Other names

Anti-AAV9 antibodiesAAV9 neutralizing antibodiesAAV9 NAbPre-existing immunity to AAV9Anti-AAV9 IgG

Therapeutic intervention involves the enzymatic cleavage of the IgG heavy chain (e.g., by imlifidase) or the suppression of B-cell and plasma cell activity to lower the concentration of circulating neutralizing antibodies, thereby preventing the neutralization of AAV9-based gene therapy vectors (Leborgne et al., 2020; Sadeghi et al., 2022).