Daventure Victoria, Bou-Jaoudeh Melissa, Hannachi Emna, Reyes-Ruiz Alejandra, Trecco Amélia, Delignat Sandrine, Lacroix-Desmazes Sébastien, Deligne Claire
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
Eur J Immunol. 2025 Feb;55(2):e202451264. doi: 10.1002/eji.202451264. Epub 2024 Dec 20.
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-Fc) or a monovalent heterodimer (IdeS-Fc), 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') and Fc fragments, although with slower kinetics than their native counterpart. IdeS-Fc 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.
伊米利酶（IdeS）是一种细菌蛋白酶，可在人IgG的铰链区进行水解，缩短其半衰期并消除其Fc介导的特性。目前，它已成功用于预防肾移植过程中的移植物排斥反应治疗，并且正在针对几种IgG介导的自身免疫性疾病进行临床评估。然而，IdeS的半衰期较短限制了其临床应用，特别是在需要重复给药的慢性疾病中。在此，我们开发了IdeS-Fc融合蛋白，其为二价同型二聚体（IdeS-Fc）或单价异型二聚体（IdeS-Fc），以便随着时间的推移延长IdeS消耗IgG的作用。两种IdeS-Fc均能有效地将单克隆和多克隆人IgG分离为F(ab')和Fc片段，尽管其动力学比天然对应物慢。与IdeS相比，IdeS-Fc在体内的半衰期延长了7倍，并且在注射后的后期时间点对人IgG的残留切割效果明显更好。我们的结果为在体内使用具有延长的IgG水解功能的IdeS提供了概念验证，这可能会迅速转化为临床应用。
