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Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme.

Publication ,  Journal Article
Elmore, ZC; Oh, DK; Simon, KE; Fanous, MM; Asokan, A
Published in: JCI Insight
September 17, 2020

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 17, 2020

Volume

5

Issue

19

Location

United States

Related Subject Headings

  • Transduction, Genetic
  • Recombinant Proteins
  • Proteolysis
  • Mice
  • Macaca
  • Immunoglobulin G
  • Immunization, Passive
  • Immunity, Innate
  • Immune Sera
  • Humans
 

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Elmore, Z. C., Oh, D. K., Simon, K. E., Fanous, M. M., & Asokan, A. (2020). Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme. JCI Insight, 5(19). https://doi.org/10.1172/jci.insight.139881
Elmore, Zachary C., Daniel K. Oh, Katherine E. Simon, Marco M. Fanous, and Aravind Asokan. “Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme.JCI Insight 5, no. 19 (September 17, 2020). https://doi.org/10.1172/jci.insight.139881.
Elmore ZC, Oh DK, Simon KE, Fanous MM, Asokan A. Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme. JCI Insight. 2020 Sep 17;5(19).
Elmore, Zachary C., et al. “Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme.JCI Insight, vol. 5, no. 19, Sept. 2020. Pubmed, doi:10.1172/jci.insight.139881.
Elmore ZC, Oh DK, Simon KE, Fanous MM, Asokan A. Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme. JCI Insight. 2020 Sep 17;5(19).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 17, 2020

Volume

5

Issue

19

Location

United States

Related Subject Headings

  • Transduction, Genetic
  • Recombinant Proteins
  • Proteolysis
  • Mice
  • Macaca
  • Immunoglobulin G
  • Immunization, Passive
  • Immunity, Innate
  • Immune Sera
  • Humans