Neutralizing anti-adeno-associated virus 9 antibody (Anti-AAV9 NAb)

Neutralizing anti-adeno-associated virus 9 (AAV9) antibodies are host-derived immunoglobulins that specifically recognize and bind to the AAV9 capsid, preventing the viral vector from delivering its genetic payload to target cells (Boutin et al., 2010). These antibodies are common in the general population due to natural exposure to wild-type AAVs, which are non-pathogenic but highly immunogenic. In clinical gene therapy, the presence of these antibodies is a major obstacle, as they can lead to the rapid clearance of the vector and a complete loss of therapeutic efficacy, especially in systemic treatments like those for spinal muscular atrophy (Zolgensma FDA Label). Patients are typically screened for these antibodies using titer-based assays, and high levels often serve as an exclusion criterion for treatment. To circumvent this, researchers are developing methods to transiently deplete these antibodies using IgG-cleaving enzymes such as imlifidase or through physical removal via plasmapheresis (Leborgne et al., 2020). Managing these antibodies is crucial not only for efficacy but also to minimize the risk of severe immune-mediated adverse events, such as hepatotoxicity or systemic inflammation.

Other names

AAV9 neutralizing antibodiesAnti-AAV9 NAbsPre-existing AAV9 antibodiesNeutralizing antibodies against AAV9

Pharmacological strategies involve the enzymatic degradation of IgG antibodies (e.g., imlifidase), physical removal from circulation via plasmapheresis, or the suppression of antibody-producing B-cells and plasma cells to create a transient window for successful vector administration.