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Gene Therapy & Redosing Strategy: IdeS Endopeptidase Mediated Cleavage of Preexisting Anti-AAV Neutralizing Antibodies For In Vivo Gene Therapy

IgG-Cleaving Endopeptidase is IgG specific cysteine protease

The IgG-cleaving enzyme (IdeS) is a recombinant cysteine protease derived from Steptococcus pyogenes, and produced in E. coli that cleaves all four classes of human IgG with high specificity.  IdeS hydrolyzed human IgG at Gly236 in the lower hinge region of the IgG heavy chains resulting in (Fab')2 and Fc fragments.

Administration of IdeS enzyme in human lowers the IgG level in serum

To test the safety and effectiveness of IdeS in humans, IdeS was administered to 25 highly HLA sensitized patients before the transplantation of a kidney from an HLA incompatible donor. The study was conducted based on the hypothesis that the effective removal of IgGs should reduce antibody-dependent cytotoxicity and rejection of grafts in the individuals. This study showed that the IdeS can be safely administered (5 out 38 had IdeS related adverse event) to reduce the total IgG level in these clinical subjects. (Jordon et al. NEJM 2017)


Administration of IdeS enable in vivo gene transfer in the presence of anti-AAV8 neutralizing antibodies

Highly prevalent preexisting and post-administration humoral immunity has severely limited the enrollment of subjects for clinical trial and redosing for a durable response. With promising evidence of safety and effectiveness of IdeS in kidney transplantation, Leborgne et al. (2020) tested the feasibility of the IdeS in the removal of anti-AAV8 IgG and neutralizing antibodies. The study has shown that IdeS effectively removed the anti-AAV8 IgG and neutralizing antibodies in murine model and non-human primates (representative figure below). The Factor IX and FactorVIII proteins were higher in the IdeS infused animals compared to the control suggesting that the removal of neutralizing antibodies increase transduction in the target site, and expression of the transgene. 



Conclusion
These studies showed the feasibility of IdeS administration in the removal of human IgGs and increase the expression of a transgene in the animal models. These proof of concept studies showed the alternative approach for the removal of IgGs in patients with high neutralizing antibodies against AAVs.  Because of the bacterial origin of IdeS, further investigation on immunogenicity against these proteins and associated safety is needed. 

References
Plasmapheresis & Immunoadsorption of anti-AAV antibodies for gene therapy
Leborgne et al, 2020. Nature Medicine IdeS & Removal of Preexisting anti-AAV antibodiesJordan et al, 2017 NEJM IgG Endopeptidase
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