Neonatal Fc receptor inhibition enables adeno-associated virus gene therapy despite pre-existing humoral immunity

Advances in adeno-associated virus-based gene therapy are transforming our ability to treat rare genetic disorders and address other unmet medical needs. However, the natural prevalence of anti-adeno-associated virus neutralizing antibodies in humans currently limits the population who can benefit from adeno-associated virus-based gene therapies. Neonatal Fc receptor plays an essential role in the long half-life of IgG, a key neutralizing antibody. Researchers have developed several neonatal Fc receptor-inhibiting monoclonal antibodies to treat autoimmune diseases, as inhibiting the interaction between neonatal Fc receptor and IgG Fc can reduce circulating IgG levels to 20%–30% of the baseline. We evaluated the utility of one such monoclonal antibody, M281, to reduce pre-existing neutralizing antibody levels and to permit gene delivery to the liver and heart via systemic adeno-associated virus gene therapy in mice and nonhuman primates. M281 successfully reduced neutralizing antibody titers along with total IgG levels; it also enhanced gene delivery to the liver and other organs after intravenous administration of adeno-associated virus in neutralizing antibody-positive animals. These results indicate that mitigating pre-existing humoral immunity via disruption of the neonatal Fc receptor–IgG interaction may make adeno-associated virus-based gene therapies effective in neutralizing antibody-positive patients.