Complete Removal of Extracellular IgG Antibodies in a Randomized Dose-Escalation Phase I Study with the Bacterial Enzyme IdeS – A Novel Therapeutic Opportunity

Abstract

IdeS is a streptococcal protease that cleaves IgG antibodies into F(ab’)2 and Fc fragments with a unique degree of specificity, thereby providing a novel treatment opportunity of IgG-driven autoimmune conditions and antibody mediated transplant rejection. Here we report the results from a first in man, double blinded and randomized study with single ascending doses of IdeS in healthy, male subjects. Twenty healthy subjects were given intravenous single ascending doses of IdeS. With impressive efficacy IdeS cleaved the entire plasma IgG-pool only minutes after dosing. IgG reached nadir 6-24 hours after dosing and then slowly recovered. The half-life of IdeS was 4.9 (±2.8) hours at 0.24 mg/kg with the main fraction eliminated during 24 hours. Already two hours after IdeS-dosing, the phagocytic capacity of IgG/IgG-fragments was reduced to background levels. Importantly, IdeS has the capacity to inactivate Fc-mediated effector function in vivo, was considered safe with no serious adverse events, and without dose limiting toxicity in this study. The complete, rapid, but temporary removal of IgG provides a new potent therapeutic opportunity in IgG-mediated pathogenic conditions.Trial RegistrationClinicalTrials.gov NCT01802697

Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients

“…However, as previously reported from healthy individuals,18 all patients had detectable anti‐IdeS IgG levels with a median level of 11 mg/L (range 8.6‐19 mg/L, Figure 7). Immediately after dosing, the anti‐IdeS IgG levels dropped below the lower limit of quantification due to the cleavage of antibodies by IdeS.…”

“…The IgG‐degrading enzyme IdeS specifically cleaves IgG molecules at the lower hinge region of the heavy chain in a multistep process. Based on data from a phase 1 clinical study in healthy volunteers,18 we hypothesized that treatment with IdeS before transplant may offer an alternative to the currently used strategies for desensitizing patients with a positive crossmatch to an HLA‐incompatible living donor. We report the findings from a phase 2 clinical study investigating the safety, immunogenicity, PK, and efficacy of an open‐label dose‐ascending study of IdeS treatment in highly sensitized patients with stage V CKD.…”

“…Within minutes after dosing, plasma IgG was converted into scIgG, and within a few hours after IdeS treatment, plasma IgG was cleaved into F(ab') 2 and Fcfragments with no intact IgG and only low levels of scIgG remaining. No reflux of extravascular IgG was observed after IdeS administration in these healthy volunteers, and newly synthesized IgG was detected 1 week after treatment 18. Based on these data, we hypothesized that treatment of sensitized patients with chronic kidney disease (CKD) with IdeS before transplant would eliminate IgG resulting in desensitization.…”

IdeS, a Bacterial IgG-cleaving Proteinase, as a Drug in Transplantation and Autoimmune Conditions

“…After 3-4 days intact IgG antibodies started to reappear in the circulation and the levels were back to normal 2-3 weeks later. A short and transient removal of extracellular IgG should have little impact on immunity in general, and no significant adverse effects were recorded in any of the twenty individuals injected with IdeS, taken together, the results of the study [13] emphasized the therapeutic potential of IdeS. As mentioned, there are many clinical conditions where IgG autoantibodies contribute to the pathology.…”

Proteinase-nicked IgGs: an unanticipated target for tumor immunotherapy

“…IdeS is unique in its selectivity for human IgGs and, in addition to its reagent uses, has potential therapeutic applications for counteracting autoimmunity. 19,21,27,28 IdeS hydrolyzes bonds in the lower hinge of all four human IgG subclasses – but not those of other mammalian groups. The absence of extraneous proteinolysis largely avoids complicating side effects in the tumor microenvironment, making IdeS ideal for engineered tumor cell modeling studies.…”