Rescuing AAV gene transfer from antibody neutralization with an IgG-degrading enzyme

Abstract

Pre-existing humoral immunity to recombinant adeno-associated viral (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs prior to AAV administration using an IgG degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaves IgG in dog, monkey and human antisera. Prophylactically administered IdeZ cleaves circulating, human IgG in mice and prevents AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescues AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaves NAbs and rescues AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.