Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab

Bou-Jaoudeh, Melissa; Mimoun, Angelina; Delignat, Sandrine; Peyron, Ivan; Capdevila, Ladislas; Daventure, Victoria; Deligne, Claire; Dimitrov, Jordan D.; Olivier, Christophe; Denis, Cécile V.; Lenting, Peter J.; Proulle, Valérie; Lacroix‐Desmazes, Sébastien

doi:10.1016/j.jtha.2023.06.038

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…This was investigated by the same group recently in a hemophilia mice model. 7 The levels of emicizumab were reduced by 71% 72 h after administering a set of two injections of equimolar amounts of imlifidase; this decrease was enhanced to 90% when a 10-fold excess of imlifidase was infused. Circulating F(ab՛)2 fragments of emicizumab were undetectable after 18 hours.…”

Section: Hemophiliamentioning

confidence: 99%

“…The abovementioned concept of creating a therapeutic window in inhibitor patients is an extra challenge in patients treated with emicizumab, as emicizumab itself could be eliminated by imlifidase. This was investigated by the same group recently in a hemophilia mice model 7 . The levels of emicizumab were reduced by 71% 72 h after administering a set of two injections of equimolar amounts of imlifidase; this decrease was enhanced to 90% when a 10‐fold excess of imlifidase was infused.…”

Section: Hemophiliamentioning

confidence: 99%

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Imlifidase for hematologists: Creating a therapeutic window in the presence of neutralizing alloantibodies

Schutgens

2024

HemaSphere

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Bacterial enzymes that specifically break down IgG antibodies have gained increased interest recently, as they have the potential to have a significant impact on the treatment of allo-and autoimmune disorders. The Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) is normally secreted by S. pyogenes during infection. IdeS is now known as imlifidase, and clinical trials have been published on HLA-sensitized candidates for renal transplantation and anti-glomerular basement membrane disease. 1,2 Imlifidase has been studied in a range of hematologic disorders as well. A short overview is given here. WORKING MECHANISM OF IMLIFIDASEAn IgG molecule consists of two heavy and two light chains held together by disulfide bonds. Imlifidase has a unique specificity for IgG and cleaves IgG in the heavy chains, which generates one F(ab՛)2 and two monomeric Fc fragments 3 (Figure 1). This leads to a rapid degradation of all circulating IgG within 6 h, with antibody levels returning to baseline around Day 14 postinfusion. 4 Imlifidase itself will be cleared from the circulation within 24 h. The theoretical concept for imlifidase is that antibody-driven disorders could temporarily be mitigated.

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Section: Hemophiliamentioning

confidence: 99%

Section: Hemophiliamentioning

confidence: 99%

Imlifidase for hematologists: Creating a therapeutic window in the presence of neutralizing alloantibodies

Schutgens

2024

HemaSphere

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Half‐Life Extension of the IgG‐Degrading Enzyme (IdeS) Using Fc‐Fusion Technology

Daventure,

Bou‐Jaoudeh,

Hannachi

et al. 2024

Eur J Immunol

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Imlifidase (IdeS) is a bacterial protease that hydrolyzes human IgG in their hinge region, decreasing their half‐life and abrogating their Fc‐mediated properties. It is now successfully used in therapy to prevent graft rejection during kidney transplants and is being clinically evaluated in several IgG‐mediated autoimmune diseases. IdeS short half‐life however limits its clinical use, particularly in the case of chronic diseases that would request repeated administrations. Here, we developed IdeS‐Fc fusion proteins as a divalent homodimer (IdeS‐Fcdiv) or a monovalent heterodimer (IdeS‐Fcmonov), in order to extend the IgG‐depleting action of IdeS over time. Both IdeS‐Fc efficiently separated monoclonal and polyclonal human IgG into F(ab')2 and Fc fragments, although with slower kinetics than their native counterpart. IdeS‐Fcmonov exhibited a seven‐fold half‐life extension in vivo as compared with IdeS, and a significantly better residual cleavage of human IgG at later time points after injection. Our results provide proof of concept for the use of an IdeS with extended IgG‐hydrolyzing functions in vivo that could rapidly translate to the clinic.

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Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab

Cited by 2 publications

References 27 publications

Imlifidase for hematologists: Creating a therapeutic window in the presence of neutralizing alloantibodies

Imlifidase for hematologists: Creating a therapeutic window in the presence of neutralizing alloantibodies

Half‐Life Extension of the IgG‐Degrading Enzyme (IdeS) Using Fc‐Fusion Technology

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