Anti-adeno-associated virus serotype 9 capsid antibodies (Anti-AAV9 antibodies)

Anti-adeno-associated virus serotype 9 (AAV9) capsid antibodies are host-produced immunoglobulins, primarily of the IgG class, that develop following natural exposure to wild-type AAV9 or previous administration of AAV9-based vectors (Boutin et al., 2010, Gene Ther.). These antibodies represent a critical challenge in the field of gene therapy because even low titers can bind to the viral capsid, neutralizing the vector and preventing successful transgene delivery to target cells (Mingozzi & High, 2013, Blood). This neutralization often leads to sub-therapeutic dosing or complete treatment failure, particularly in systemic or high-dose applications like those for Spinal Muscular Atrophy (SMA). To overcome this barrier, these antibodies are treated as a therapeutic target for removal or evasion. Strategies include the use of the IgG-degrading enzyme imlifidase to enzymatically cleave the antibodies (Leborgne et al., 2020, Nat. Med.), plasmapheresis for physical removal, or the administration of "decoy" empty capsids to sequester the antibodies before the therapeutic dose is given. Monitoring these antibodies via neutralizing antibody (NAb) assays is standard practice for patient selection in AAV9-mediated gene therapy trials to ensure safety and efficacy.

Other names

Anti-AAV9 neutralizing antibodiesAAV9 NAbsAnti-AAV9 IgGPre-existing AAV9 antibodies

The primary mechanism of action for drugs addressing this target involves the enzymatic degradation of the IgG hinge region (e.g., Imlifidase), which prevents the antibodies from binding to the AAV9 capsid or activating effector functions (Leborgne et al., 2020, Nat. Med.). Other approaches include the depletion of B-lymphocytes or plasma cells to reduce the production of new antibodies or the physical removal of existing antibodies from the circulation via plasmapheresis to lower titers below the threshold of neutralization.