Pre-existing anti-adeno-associated virus 8 neutralizing antibodies and immune components (Anti-AAV8 NAb)

Pre-existing anti-adeno-associated virus 8 (AAV8) neutralizing antibodies and immune components represent a major biological barrier to the efficacy of AAV8-mediated gene therapy. These antibodies are typically the result of natural exposure to wild-type AAV8, which is prevalent in the human population, leading to the development of long-lived humoral and cellular immunity (Boutin et al., 2010, Gene Therapy). When an AAV8-based therapeutic vector is administered, these pre-existing antibodies bind to the viral capsid, neutralizing the vector and preventing it from transducing target cells, while also facilitating its rapid clearance by the liver and spleen (Mingozzi & High, 2013, Blood). Furthermore, memory T-cells can recognize capsid-derived peptides presented on the surface of transduced cells, potentially triggering a cytotoxic immune response that eliminates the therapeutic cells. To address this, clinical strategies include the use of Imlifidase to enzymatically cleave IgG or plasmapheresis to physically remove antibodies prior to vector infusion (Leborgne et al., 2020, Nature Medicine). Managing this pre-existing immunity is essential for patient selection and ensuring the successful delivery and long-term expression of the genetic cargo.

Other names

Anti-AAV8 antibodiesAAV8 neutralizing antibodiesPre-existing AAV8 immunityAnti-AAV8 NAbAAV8-specific memory B cellsAAV8-specific T-cell response

Therapeutic strategies aim to deplete circulating IgG antibodies through enzymatic cleavage or plasmapheresis, or to suppress B-cell and T-cell activation to prevent the neutralization and clearance of AAV8-based gene therapy vectors.