Abstract
Preexisting humoral immunity to recombinant adeno-associated virus (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 before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.
Highlights
Human gene therapy using recombinant adeno-associated virus (AAV) vectors continues to advance steadily as a treatment paradigm for rare, monogenic disorders
The list of systemically dosed AAV-based gene therapies for rare disorders, such as hemophilia A and B, Duchenne muscular dystrophy, X-linked myotubularin myopathy, and Pompe disease, continues to grow [2, 3]. These promising clinical examples have concurrently highlighted important challenges that include manufacturing needs, patient recruitment, and the potential for toxicity at high AAV doses. One such challenge that limits the recruitment of patients for gene therapy clinical trials and adversely affects the efficacy of AAV gene therapy is the prevalence of preexisting neutralizing antibodies (NAbs) against AAV capsids in the human population
We first demonstrated that IgG-degrading enzyme (IdeZ) efficiently cleaves antibodies in canine, nonhuman primate, and human sera but not mouse serum samples in vitro (Figure 1B)
Summary
Human gene therapy using recombinant adeno-associated virus (AAV) vectors continues to advance steadily as a treatment paradigm for rare, monogenic disorders. The list of systemically dosed AAV-based gene therapies for rare disorders, such as hemophilia A and B, Duchenne muscular dystrophy, X-linked myotubularin myopathy, and Pompe disease, continues to grow [2, 3] These promising clinical examples have concurrently highlighted important challenges that include manufacturing needs, patient recruitment, and the potential for toxicity at high AAV doses. One such challenge that limits the recruitment of patients for gene therapy clinical trials and adversely affects the efficacy of AAV gene therapy is the prevalence of preexisting neutralizing antibodies (NAbs) against AAV capsids in the human population. Multiple preclinical studies in different animal models have demonstrated that preexisting NAbs impede systemic gene transfer by AAV vectors [8,9,10,11]
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