IdeS: A Bacterial Proteolytic Enzyme with Therapeutic Potential

Abstract

BackgroundIdeS, a proteinase from Streptococcus pyogenes, cleaves immunoglobulin (Ig)G antibodies with a unique degree of specificity. Pathogenic IgG antibodies constitute an important clinical problem contributing to the pathogenesis of a number of autoimmune conditions and acute transplant rejection. To be able to effectively remove such antibodies is therefore an important clinical challenge.Methodology/Principal FindingsIdeS was found to specifically and efficiently cleave IgG in human blood in vitro (20 µg of IdeS caused a complete degradation of IgG in one ml of human whole blood in 15 minutes) and to clear IgG from the blood stream of rabbits in vivo (no IgG was detected six hours following an intravenous injection of 5 mg of IdeS) without any side effects. In a mouse model of immune thrombocytopenic purpura (ITP), polyclonal IgG antibodies against platelet surface antigens were used to induce a lethal disease. These profoundly thrombocytopenic animals were treated and cured by a single injection of IdeS.Conclusions/SignificanceNovel information is provided concerning the IgG-cleaving activity of IdeS in vitro and in vivo. The highly specific and rapid elimination of IgG in vivo, the dramatic effect in a mouse model of ITP, and the lack of side effects in the treated animals, indicate that IdeS could also be used to treat IgG-driven diseases in humans.

IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions

“…This hypothesis was further stimulated by our recent finding that pretreatment of arthritogenic autoantibodies with EndoS abrogates the development of disease in a mouse model of collagen-induced arthritis (23). The IgG-specific protease IdeS also has been shown to be efficient in a similar model system (24) and in the mouse model of ITP used in this study (25). For EndoS to work as a useful agent against pathological IgG in vivo, it needs to fulfill several criteria.…”

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

“…IdeS cleaves rabbit IgG (62) and murine IgG2a and IgG3 but not murine IgG1 (63)). Intravenous administration of IdeS into rabbits resulted in the complete loss of detection of intact endogenous rabbit IgG within 6 h, demonstrating the extraordinary catalytic activity of this protease (62). In the same study, IdeS treatment of rabbits was capable of abrogating the ability of polyclonal anti-platelet antibodies to clear platelets (62).…”

“…Intravenous administration of IdeS into rabbits resulted in the complete loss of detection of intact endogenous rabbit IgG within 6 h, demonstrating the extraordinary catalytic activity of this protease (62). In the same study, IdeS treatment of rabbits was capable of abrogating the ability of polyclonal anti-platelet antibodies to clear platelets (62). In a separate study, Nandakumar et al (63) reported that IdeS treatment of mice was capable of alleviating the joint inflammation induced by collagen antibody-induced arthritis.…”

“…Björck and co-workers (24,62,63) have demonstrated that IdeS is a highly potent protease with unique specificity for all human IgG subclasses (24) that is also capable of cleaving distinct IgG subclasses within other species (e.g. IdeS cleaves rabbit IgG (62) and murine IgG2a and IgG3 but not murine IgG1 (63)).…”

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

“…Samples that failed to mediate platelet aggregation within 25 min were defined as negative. Pre-incubation of PRP with AT10 to block the platelet IgG receptor, Fcc RIIA (CD32) or cleavage of plasma IgG with IdeS (Johansson et al, 2008) revealed that platelet aggregation in response to GGS G45 is not significantly affected by complementary strategies of IgG blockade (Fig. 2b, c).…”