Neutralizing anti-adeno-associated virus 8 and adeno-associated virus rh.10 antibodies (NAb)

Neutralizing antibodies (NAbs) against adeno-associated virus serotypes 8 (AAV8) and rh.10 (AAVrh.10) are host-derived immunoglobulins that recognize and bind to the viral capsid of gene therapy vectors (Boutin et al., 2010, Gene Therapy). These antibodies are frequently present in the general population due to prior natural exposure to wild-type AAVs, creating a significant hurdle for the systemic administration of AAV-based gene therapies (Mingozzi & High, 2013, Nature Reviews Genetics). When present, NAbs can neutralize the vector in the bloodstream, preventing it from reaching and transducing target tissues such as the liver or central nervous system (Leborgne et al., 2020, Nature Medicine). This neutralization leads to reduced therapeutic efficacy and can trigger inflammatory responses. To overcome this, researchers are developing methods to deplete these antibodies using IgG-cleaving enzymes like imlifidase or through plasmapheresis and immunosuppression (Sakar et al., 2020, Molecular Therapy). Managing NAb levels is critical for expanding the eligibility of patients for life-saving gene treatments in conditions like hemophilia and spinal muscular atrophy. Furthermore, the development of "stealth" capsids and decoy capsids is being explored to evade these antibodies. The presence of NAbs remains one of the most significant exclusion criteria in clinical trials for AAV-mediated gene transfer.

Other names

Anti-AAV8 antibodiesAnti-AAVrh.10 antibodiesPre-existing AAV antibodiesAAV neutralizing antibodiesAnti-capsid antibodies

Proteolytic cleavage of IgG antibodies to prevent neutralization of viral vectors; physical removal via plasmapheresis; or suppression of B-cell and plasma cell activity to reduce antibody production.