Complete Removal of Extracellular IgG Antibodies in a Randomized Dose-Escalation Phase I Study with the Bacterial Enzyme IdeS--A Novel Therapeutic Opportunity
Lena Winstedt, Sofia Järnum, Emma Andersson Nordahl, Andreas Olsson, Anna Runström, Robert Bockermann, Christofer Karlsson, Johan Malmström, Gabriella Samuelsson Palmgren, Ulf Malmqvist, Lars Björck, Christian Kjellman, Lena Winstedt, Sofia Järnum, Emma Andersson Nordahl, Andreas Olsson, Anna Runström, Robert Bockermann, Christofer Karlsson, Johan Malmström, Gabriella Samuelsson Palmgren, Ulf Malmqvist, Lars Björck, Christian Kjellman
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 registration: ClinicalTrials.gov NCT01802697.
Conflict of interest statement
Competing Interests: have read the journal's policy and the authors of this manuscript have the following competing interests: Hansa Medical AB was the formal sponsor and funder of the clinical trial. LW, SJ, EAN, AO, AR, RB, and CK are employed by Hansa Medical AB. LB is an inventor on patent applications related to IdeS and owns shares in Hansa Medical AB. The patent applications are: 1. International publication No: WO/2006/131347 Title: USE OF THE IDES PROTEINASE (FROM S. PYOGENES) FOR TREATING AUTOIMMUNE DISEASES AND GRAFT REJECTION International publication date: 14.12.2006 2. International publication No: WO/2003/051914 Title: IDES, AN IGG-DEGRADING ENZYME OF STREPTOCOCCUS PYOGENES International publication date: 26.06.2003 This does not alter our adherence to PLOS ONE policy on sharing data and materials.
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