Impact of Pre-Existing Immunity on the Non-Clinical Pharmacodynamics of AAV5-Based Gene Therapy

Abstract Adeno-associated virus (AAV)-based vectors are widely used for gene therapy, but the impact of pre-existing antibodies resulting from exposure to wildtype AAV is unclear. In addition, other poorly defined plasma factors could inhibit AAV vector transduction where antibodies are not detected. To better define the relationship between various forms of pre-existing AAV immunity and gene transfer, we studied Valoctocogene roxaparvovec (BMN 270) in cynomolgus monkeys with varying pre-dose levels of neutralizing anti-AAV antibodies and non-antibody transduction inhibitors. BMN 270 is an AAV5-based vector for treating hemophilia A that encodes human B-domain-deleted factor VIII (FVIII-SQ). After infusion of BMN 270 (6.0 x 10 13 vg/kg) into animals with pre-existing anti-AAV5 antibodies, there was a mean decrease in maximal FVIII-SQ plasma concentration (C max ) and AUC of 74.8% and 66.9%, respectively, compared to non-immune control animals, and vector genomes in the liver were reduced. In contrast, animals with only non-antibody transduction inhibitors showed FVIII-SQ plasma concentrations and liver vector copies comparable to those of controls. These results demonstrate that animals without AAV5 antibodies are likely responders to AAV5 gene therapy, regardless of other inhibiting plasma factors. The biological threshold for tolerable AAV5 antibody levels varied between individual animals and should be further evaluated in clinical studies.