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

Uhlin, Fredrik; Szpirt, Wladimir; Kronbichler, Andreas; Bruchfeld, Annette; Soveri, Inga; Rostaing, Lionel; Daugas, Éric; Lionet, Arnaud; Kamar, Nassim; Rafat, Cédric; Mysliveček, Marek; Tesař, Vladimı́r; Fernström, Anders; Kjellman, Christian; Elfving, Charlotte; McAdoo, Stephen P; Mölne, Johan; Bajema, Ingeborg M.; Sonesson, Elisabeth; Segelmark, Mårten

doi:10.1681/asn.2021111460

Cited by 31 publications

(23 citation statements)

References 25 publications

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“…In types of autoimmune GN with acute and irreversible kidney injury caused by circulating antibodies, plasma exchange or treatment with the endopeptidase imlifidase is used to quickly remove nephritogenic antibodies 103 , 104 (Fig. 4 ).…”

Section: Autoimmune Gnmentioning

confidence: 99%

Glomerulonephritis: immunopathogenesis and immunotherapy

et al. 2023

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‘Glomerulonephritis’ (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.

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Section: Autoimmune Gnmentioning

confidence: 99%

Glomerulonephritis: immunopathogenesis and immunotherapy

et al. 2023

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“…The enzyme targets IgG by cleaving within the lower hinge region, yielding F(ab')2 and Fc fragments (3,6,7), an activity which has enabled its development, under the name Imlifidase, as a pre-treatment for kidney transplantation in hypersensitized patients with chronic kidney disease (8)(9)(10)(11)(12)(13)(14)(15)(16). Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders (11,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), deactivation of neutralising antibodies for in vivo gene therapy (27), and for the potentiation of therapeutic antibodies by deactivating competing serum IgG (28,29). Imlifidase has also been used in combination with EndoS for inactivation of donor-specific antibodies in murine allogeneic bone marrow transplantation (10).…”

Section: Introductionmentioning

confidence: 99%

Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS

Sudol

Butler

Ivory

et al. 2022

Preprint

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The cleavage of human IgG antibodies is a potent immune evasion mechanism utilised by some pathogenic bacteria. The Streptococcus pyogenes bacterium, which has the capacity to cause necrotising fasciitis, employs multiple enzymes to deactivate the human adaptive immune system. Two such proteins, IdeS and EndoS, prevent immune detection by ablating the immune effector functions of IgG, by cleavage and deglycosylation of its Fc region, respectively. Their fine specificity for IgG has led to a wide range of clinical and biotechnology applications, with IdeS having received clinical approval facilitating organ transplantation in hypersensitised individuals, while EndoS has found application in engineering antibody glycosylation. Here, we present crystal structures of IdeS and EndoS in complex with their IgG1 Fc substrate, with both enzymes exhibiting exquisite target specificity. The IdeS protease is shown encasing the antibody hinge target, but also recognises the Fc globular domains. In contrast, the glycan hydrolase domain in EndoS traps the Fc glycan in a flipped-out conformation, while additional antibody specificity is driven by protein recognition by the so-called carbohydrate binding module. Understanding the molecular basis of antibody recognition by bacterial enzymes will facilitate the development of next-generation enzymes.

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confidence: 99%

“…First, we would like to thank Borza and Manral for their interest in our study GOOD-IDES-01 1 . In this study, 15 patients with anti–glomerular basement membrane antibodies and an eGFR <15 ml/min were given a single dose of 0.25 mg/kg imlifidase on top of standard of care.…”

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confidence: 99%

Authors’ Reply: Endopeptidase Therapy for Anti-Glomerular Basement Membrane Disease: Beware of Anti-Hinge Antibodies!

Segelmark

Kjellman

2022

JASN

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First, we would like to thank Borza and Manral for their interest in our study GOOD-IDES-01. 1 In this study, 15 patients with anti-glomerular basement membrane antibodies and an eGFR ,15 ml/min were given a single dose of 0.25 mg/kg imlifidase on top of standard of care. This led to a rapid decline of circulating autoantibodies and, at 6 months, ten patients were alive with functioning native kidneys. In their letter, Borza and Manral suggest the reason why more patients did not have their kidney function salvaged could be due to anti-hinge antibodies preferentially reacting with neoepitopes formed after IgG cleavage with imlifidase.When trying to perform a post hoc analysis of the treatment failures, it is important to know that one more patient was able to stop dialysis after the end of the study, at 8 months after imlifidase treatment. Thus, at 1 year, 73% of patients were alive and free of dialysis. There are several possible reasons why not all of the patients responded to treatment, including severity of damage at the start of treatment, tubulointerstitial fibrosis, other pathogenic mechanisms (i.e., T cells, anti-neutrophil cytoplasm antibodies), magnitude of autoantibody rebound, epitope specificity of the autoantibodies at rebound, and anti-hinge antibodies.The significance of anti-hinge antibodies has been discussed in the literature (as referenced by Borza and Manral) and, although these antibodies can be detected in vivo and have the ability to restore the Fc-function of fragmented antibodies in vitro, the effect of anti-hinge antibodies after imlifidase treatment is likely NS during the early course after treatment because the levels are low, they are cleaved by imlifidase, and they are efficiently neutralized by the high levels of F(ab 9 ) 2 resulting from the imlifidase treatment. We previously measured F(ab 9 ) 2 fragments by both ELISA and SDS-PAGE and the data show that fragments are readily detectable for approximately 1 week using both methods. 2 During the period before rebound of IgG, any uncleaved anti-hinge antibody must be saturated by F(ab 9 ) 2 fragments. The possibility that anti-hinge antibodies rebound at high levels and react with tissue-bound F(ab 9 ) 2 fragments was a theoretic concern before our study, and a major reason why moderate-to-severe lung hemorrhage was an exclusion criterion in the study. However, in those patients with mild lung engagement that were included in the study, we observed no indication of such events. We are grateful for the suggestion of measuring antihinge antibodies before treatment and at rebound, but we are inclined to be more concerned over rebound of antiglomerular basement membrane antibodies. DISCLOSURESC. Kjellman reports being employed by, having ownership interest in, and having patents or royalties with Hansa Biopharma AB. M. Segelmark reports having consultancy agreements with AstraZeneca, Hansa Biopharma AB, Toleranzia AB, and Vifor Pharma; receiving research funding from Hansa Biopharma AB; and spouse being employed by Nanoecho AB Sweden.

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

Cited by 31 publications

References 25 publications

Glomerulonephritis: immunopathogenesis and immunotherapy

Glomerulonephritis: immunopathogenesis and immunotherapy

Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS

Authors’ Reply: Endopeptidase Therapy for Anti-Glomerular Basement Membrane Disease: Beware of Anti-Hinge Antibodies!

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