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. [ABSTRACT FROM AUTHOR]

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