IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies

• Published in: Nature Medicine Vol. 26; no. 7; pp. 1096 - 1101
• Main Authors: Leborgne, Christian, Barbon, Elena, Alexander, Jeffrey M., Hanby, Hayley, Delignat, Sandrine, Cohen, Daniel M., Collaud, Fanny, Muraleetharan, Saghana, Lupo, Dan, Silverberg, Joseph, Huang, Karen, van Wittengerghe, Laetitia, Marolleau, Béatrice, Miranda, Adeline, Fabiano, Anna, Daventure, Victoria, Beck, Heena, Anguela, Xavier M., Ronzitti, Giuseppe, Armour, Sean M., Lacroix-Desmazes, Sebastien, Mingozzi, Federico
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2020; Nature Publishing Group
• Subjects: 631/250; 631/250/251; 631/61; 631/61/201; Animals; Antibodies; Antibodies, Anti-Idiotypic - genetics; Antibodies, Anti-Idiotypic - immunology; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Biomedical and Life Sciences; Biomedicine; Blood plasma; Cancer Research; Capsid - immunology; Control; Dependovirus - genetics; Dependovirus - immunology; Endopeptidases; Endopeptidases - immunology; Gene therapy; Genetic Therapy; Genetic vectors; Genetic Vectors - adverse effects; Genetic Vectors - therapeutic use; Health aspects; Humans; Immunization; Immunoglobulin G; Immunoglobulin G - pharmacology; Immunology; Immunosuppression; Immunotherapy; Infectious Diseases; Intravenous administration; Letter; Life Sciences; Liver; Liver - immunology; Liver - metabolism; Management; Metabolic Diseases; Methods; Mice; Molecular Medicine; Neurosciences; Neutralizing; Physiological aspects; Primates; Vectors; Viral antibodies; Viruses; France; United States
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-020-0911-7

Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans
1
,
2
, and block liver transduction
3
–
5
and vector readministration
6
; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied
7
, which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients
8
. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.
An IgG-cleaving endopeptidase can degrade circulating anti-adeno-associated virus antibodies in mice and nonhuman primates in vivo, as well as in human plasma in vitro, offering a potential solution for a major hurdle in gene therapy.