An engineered IdeS variant with enhanced activity and performance for IgG degradation

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Abstract IgG-degrading enzymes have emerged as innovative therapeutic agents for treating conditions driven by pathogenic antibodies. Here, we used structure-guided rational design to engineer IdeS M33 , a double mutant (K167R/D226E) of the IgG-specific bacterial protease IdeS from Streptococcus pyogenes , with improved catalytic efficiency. Biolayer interferometry revealed a fourfold increase in binding affinity relative to wild-type IdeS (IdeS WT ). This enhancement is likely attributable to mutations that strengthen hydrogen bonding at the enzyme–IgG Fc interface. In vitro, IdeS M33 has higher performance than IdeS WT in cleaving serum IgG. In vivo studies in rabbits demonstrated that IdeS M33 effectively depleted circulating IgG and showed better performance at a dose of 0.005 mg/kg than the IdeS WT . Although doses greater than 0.2 mg/kg demonstrated higher plasma concentrations of IdeS and a larger AUC₀₋last, they did not show a significant enhancement in the pharmacodynamics of IgG degradation. Importantly, a single dose of IdeS M33 (0.2 mg/kg) potently degraded binding and neutralizing antibodies against AAV9 within 1-2 days and restored hepatic AAV9 transduction in pre-immunized animals. Together, these findings highlight IdeS M33 as a potent and safe engineered enzyme with therapeutic potential for autoimmune disorders, transplant rejection, and overcoming pre-existing humoral immunity in gene therapy.

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