Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme
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 undesira...
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American Society for Clinical investigation
2020-10-01
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doaj-d725ad0f77e647e98dea71ee5d4a09032021-08-02T15:56:07ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-10-01519Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzymeZachary C. ElmoreDaniel K. OhKatherine E. SimonMarco M. FanousAravind AsokanPreexisting 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.https://doi.org/10.1172/jci.insight.139881ImmunologyTherapeutics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zachary C. Elmore Daniel K. Oh Katherine E. Simon Marco M. Fanous Aravind Asokan |
spellingShingle |
Zachary C. Elmore Daniel K. Oh Katherine E. Simon Marco M. Fanous Aravind Asokan Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme JCI Insight Immunology Therapeutics |
author_facet |
Zachary C. Elmore Daniel K. Oh Katherine E. Simon Marco M. Fanous Aravind Asokan |
author_sort |
Zachary C. Elmore |
title |
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme |
title_short |
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme |
title_full |
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme |
title_fullStr |
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme |
title_full_unstemmed |
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme |
title_sort |
rescuing aav gene transfer from neutralizing antibodies with an igg-degrading enzyme |
publisher |
American Society for Clinical investigation |
series |
JCI Insight |
issn |
2379-3708 |
publishDate |
2020-10-01 |
description |
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. |
topic |
Immunology Therapeutics |
url |
https://doi.org/10.1172/jci.insight.139881 |
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