Administration of immunoglobulin G‐degrading enzyme of <i>Streptococcus pyogenes</i> (IdeS) for persistent anti‐<scp>ADAMTS</scp>13 antibodies in patients with thrombotic thrombocytopenic purpura in clinical remission

Stubbs, Matthew; Thomas, Mari; Vendramin, Chiara; Sonesson, Elisabeth; Kjellman, Christian; Järnum, Sofia; Stenberg, Yvonne; Elfving, Charlotte; Scully, Marie

doi:10.1111/bjh.15706

Cited by 14 publications

(9 citation statements)

References 16 publications

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“…In this study, moderate to severe lung hemorrhage was an exclusion criterion, which was required by one of the regulatory authorities reviewing the protocol. The concern raised was that imlifidase cleavage could potentially trigger aggravation of pulmonary disease, because aggravation of thrombotic thrombocytopenic purpura has been reported in one patient after the administration of imlifidase 26 . None of the patients in this study had any alveolar hemorrhage or signs of serum sickness after imlifidase.…”

Section: Discussionmentioning

confidence: 78%

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study

Uhlin

Szpirt²,

Kronbichler

et al. 2022

JASN

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BackgroundThe prognosis for kidney survival is poor in patients presenting with circulating anti–glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis.MethodsAn investigator-driven phase 2a one-arm study (EudraCT 2016–004082–39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m2. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months.ResultsAt inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m2. The median age was 61 years (range 19–77), six were women, and six were also positive for anti–neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug.ConclusionsIn this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.Clinical Trial registration number: EUDRACT 2016–004082–39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results

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Section: Discussionmentioning

confidence: 78%

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study

Uhlin

Szpirt²,

Kronbichler

et al. 2022

JASN

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“…Among patients with anti–glomerular basement membrane antibodies treated with IdeS, >50% had their pathogenic antibodies return to toxic levels and had to resume conventional treatments to decrease pathogenic antibodies. 8, 31 Anchoring IdeS to a cellular target can lower the dose of IdeS and may allow the administration of repeated doses of IdeS. Future work will focus on determining the impact that targeting IdeS to the surface of platelets has on its immunogenicity in animal models, especially after multiple doses.…”

Section: Discussionmentioning

confidence: 99%

Anchoring IgG-degrading enzymes to the surface of platelets selectively neutralizes antiplatelet antibodies

et al. 2022

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Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by IgG-mediated platelet destruction. Current therapies primarily focus on reducing antiplatelet antibodies using immunosuppression or increasing platelet production with TPO mimetics. However, there are no universally safe and effective treatments for patients presenting with severe, life threatening bleeding. IgG-degrading enzyme of S. pyogenes (IdeS), a protease with strict specificity for IgG, prevents IgG-driven immune disorders in murine models, including ITP. In clinical trials, IdeS prevented IgG-mediated kidney transplant rejection; however, the concentration of IdeS used to remove pathogenic antibodies causes profound hypogammaglobulinemia and is immunogenic, which limits its use. Therefore, this study sought to determine whether targeting IdeS to FcγRIIA, a low-affinity IgG receptor on the surface of platelets, neutrophils, and monocytes would be a viable strategy to decrease the pathogenesis of antiplatelet IgG and reduce treatment-related complications of non-targeted IdeS. We generated a recombinant protein conjugate by site-specifically linking the C-terminus of a single-chain variable fragment from a FcγRIIA antibody, clone IV.3, to the N-terminus of IdeS (scIV.3-IdeS). Platelets treated with scIV.3-IdeS had reduced binding of antiplatelet IgG from ITP patients and decreased platelet phagocytosis in vitro, with no decrease in normal IgG. Treatment of mice expressing human FcγRIIA with scIV.3-IdeS reduced thrombocytopenia in a model of ITP and significantly improved the half-life of transfused platelets expressing human FcγRIIA. Together, these data suggest that scIV.3-IdeS can selectively remove pathogenic antiplatelet IgG and may be a potential treatment for patients with ITP and severe bleeding.

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“…However, repeated administration of EndoS triggers an immune response, and using bacterial enzymes in a therapeutic setting raises a safety concern. Alternatively, the bacterial protease IdeS was successful in a trial targeting IgG mediated autoimmune conditions ( 190 – 192 )…”

Section: Glycoengineeringmentioning

confidence: 99%

Sialylation as an Important Regulator of Antibody Function

2022

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Antibodies play a critical role in linking the adaptive immune response to the innate immune system. In humans, antibodies are categorized into five classes, IgG, IgM, IgA, IgE, and IgD, based on constant region sequence, structure, and tropism. In serum, IgG is the most abundant antibody, comprising 75% of antibodies in circulation, followed by IgA at 15%, IgM at 10%, and IgD and IgE are the least abundant. All human antibody classes are post-translationally modified by sugars. The resulting glycans take on many divergent structures and can be attached in an N-linked or O-linked manner, and are distinct by antibody class, and by position on each antibody. Many of these glycan structures on antibodies are capped by sialic acid. It is well established that the composition of the N-linked glycans on IgG exert a profound influence on its effector functions. However, recent studies have described the influence of glycans, particularly sialic acid for other antibody classes. Here, we discuss the role of glycosylation, with a focus on terminal sialylation, in the biology and function across all antibody classes. Sialylation has been shown to influence not only IgG, but IgE, IgM, and IgA biology, making it an important and unappreciated regulator of antibody function.

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Administration of immunoglobulin G‐degrading enzyme of Streptococcus pyogenes (IdeS) for persistent anti‐ADAMTS13 antibodies in patients with thrombotic thrombocytopenic purpura in clinical remission

Cited by 14 publications

References 16 publications

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study

Anchoring IgG-degrading enzymes to the surface of platelets selectively neutralizes antiplatelet antibodies

Sialylation as an Important Regulator of Antibody Function

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