Pre-existing anti-adeno-associated virus serotype 2 immunoglobulin G and complement system (Anti-AAV2 IgG and complement)

Pre-existing anti-AAV2 IgG and the complement system are primary immunological hurdles in the field of adeno-associated virus (AAV) gene therapy. Due to natural exposure to wild-type AAV2, a significant portion of the human population possesses pre-existing neutralizing antibodies (NAbs) that can bind to and neutralize therapeutic AAV vectors, preventing successful transgene delivery (Boutin et al., Gene Ther. 2010). Additionally, these antibodies can form immune complexes with the vector, which subsequently activate the complement system, leading to rapid opsonization, phagocytosis, and systemic inflammation (Zaiss et al., J Virol. 2008). This immune response not only reduces the efficacy of the treatment but also poses safety risks, such as thrombotic microangiopathy or severe hepatotoxicity (Mingozzi & High, Nat Rev Genet. 2011). Current clinical strategies to mitigate these effects include the use of IgG-degrading enzymes like Imlifidase to transiently eliminate circulating antibodies and complement inhibitors like Eculizumab to prevent downstream inflammatory cascades (Leborgne et al., Nat Med. 2020). Managing these components is essential for expanding patient eligibility and ensuring the durability of gene therapies.

Other names

Anti-AAV2 neutralizing antibodiesAAV2 NAbsPre-existing immunity to AAV2AAV-complement axisAnti-AAV2 IgG

Enzymatic cleavage of IgG antibodies or pharmacological inhibition of complement proteins to prevent vector neutralization and inflammatory clearance.