Molecular Therapy: Methods & Clinical Development (06/14/19) Vol. 134, P. 440. Long, Brian R.; Sandza, Krystal; Holcomb, Jennifer; et al.
Data from preclinical and clinical studies have shown that pre-existing neutralizing antibodies to adeno-associated virus (AAV) capsid proteins can limit the therapeutic efficacy of AAV-mediated gene therapy. Using cynomolgus monkeys with varying pre-dose levels of neutralizing anti-AAV antibodies and non-antibody transduction inhibitors, researchers analyzed the pharmacodynamics of AAV5-mediated gene transfer and FVIII transgene expression after treatment with a single dose of valoctocogene roxaparvovec (BMN 270, an AAV5-based gene therapy vector that encodes B-domain-deleted human FVIII [FVIII-SQ]). The experimental design included 4 different groups of monkeys based on the presence or absence of AA5 total antibodies (TAb) and/or detectable AAV5 transduction inhibition (TI) determined in a cell-based assay. All animals were infused with the same dose of BMN 270 (6.0 x 1013 vg/kg). The presence of neutralizing anti-AAV5 antibodies was associated with approximately 75% reduction in plasma FVIII-SQ Cmax compared with non-immune controls. In contrast, the presence of only non-antibody transduction inhibitors was not associated with a reduction in FVIII-SQ Cmax relative to controls. The authors reported that several animals with pre-existing neutralizing AAV5 antibodies had levels of transgene expression comparable with non-immune control animals. Due to the small sample size, it was not possible to obtain generalizable thresholds for AAV5 antibody levels and detectable plasma FVIII-SQ. Further evaluation in clinical studies will help to determine if there is threshold for AAV5 antibody levels and therapeutic efficacy.