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

Pre-existing neutralizing antibodies against adeno-associated virus serotype 9 (AAV9) are host immunoglobulins, primarily of the IgG class, that develop following natural exposure to wild-type AAV9 (Mingozzi & High, 2013, Nature Reviews Genetics). In the context of gene therapy, these antibodies represent a significant pharmacological barrier as they bind to the AAV9 capsid, preventing the vector from transducing target cells and effectively neutralizing the therapeutic payload (Leborgne et al., 2020, Nature Medicine). This pre-existing immunity is prevalent in a substantial portion of the human population, often leading to the exclusion of patients from receiving life-saving treatments like Onasemnogene abeparvovec (Zhu et al., 2021, Frontiers in Immunology). To address this, researchers are developing desensitization protocols using IgG-cleaving enzymes such as imlifidase or mechanical methods like plasmapheresis to transiently reduce antibody titers (Sadeghi et al., 2022, Molecular Therapy). Successfully managing these antibodies is essential for ensuring the delivery and long-term expression of AAV9-mediated gene therapies across diverse patient populations.

Other names

Anti-AAV9 antibodiesAAV9 neutralizing antibodiesPre-existing immunity to AAV9AAV9 NAbsAnti-AAV9 IgG

Drugs targeting these antibodies primarily work through enzymatic cleavage of immunoglobulin G (IgG) into F(ab')2 and Fc fragments (e.g., imlifidase), thereby eliminating their ability to bind and neutralize viral capsids (Sadeghi et al., 2022, Molecular Therapy). Other approaches involve the depletion of antibody-producing B-cells and plasma cells using agents like rituximab and bortezomib to prevent the formation or rebound of these antibodies (Leborgne et al., 2020, Nature Medicine).