Anti-adeno-associated virus 8 neutralizing antibody (Anti-AAV8 NAb)

Anti-adeno-associated virus 8 (AAV8) neutralizing antibodies (NAbs) are host-derived immunoglobulins that develop following natural exposure to wild-type AAV8 or prior administration of AAV8-based gene therapy. These antibodies bind to the AAV8 capsid and inhibit the vector's ability to transduce target cells by blocking cellular entry, interfering with intracellular trafficking, or promoting rapid clearance from the circulation. In clinical gene therapy, even low titers of pre-existing NAbs can significantly reduce or completely eliminate the efficacy of the treatment, particularly for liver-directed therapies such as those for Hemophilia B or Crigler-Najjar syndrome. Consequently, a large proportion of the population (estimated at 30-60%) is currently ineligible for AAV-based treatments due to seropositivity. To address this, therapeutic strategies like the IgG-cleaving enzyme imlifidase are being used to temporarily deplete NAbs, thereby creating a window for successful vector delivery. Other approaches include the use of B-cell depleting agents like rituximab or plasma cell inhibitors like bortezomib to manage the induction of new antibodies upon re-administration.

Other names

AAV8 neutralizing antibodiesAnti-AAV8 antibodiesAAV8 NAbsAnti-capsid antibodiesPre-existing anti-AAV8 antibodies

Drugs targeting these antibodies work through enzymatic cleavage of IgG (e.g., imlifidase), depletion of B cells (e.g., rituximab), or depletion of plasma cells (e.g., bortezomib) to reduce the concentration of neutralizing antibodies and allow successful viral vector transduction.