Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Abstract

Mixed hematopoietic chimerism induction as a way to foster tolerance to donor organs in recipients who have been sensitized to donor antigens is challenging. Donor‐specific antibodies (DSA) are a dominant barrier toward successful donor bone marrow engraftment. Although desensitization methods are routinely used in recipients with allosensitization for allogeneic bone marrow transplantation, engraftment is frequently unsuccessful. To overcome the barrier of prior sensitization we tested enzymatic desensitization of donor‐specific IgG using imlifidase and endoglycosidase of Streptococcus pyogenes (EndoS), which both partially block the function of DSA in mice, as a novel approach to improve murine bone marrow engraftment in primed hosts. We found that EndoS was capable of inhibiting antibody‐mediated killing of donor cells in vivo. Furthermore, the effect of EndoS depended on the titer of DSA and the genetic background of the recipients. In combination with imlifidase, EndoS improved the survival of donor bone marrow cells. Together with cyclophosphamide, bortezomib, T cell depletion, and nonlethal irradiation, imlifidase in combination with EndoS allowed allogeneic bone marrow engraftment in sensitized recipients. We conclude that enzymatic inactivation of DSA, using the combination of imlifidase and EndoS, can be used for inducing donor hematopoietic chimerism in allosensitized recipient mice in combination with other desensitization strategies.

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

“…Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders 13 – 19 , deactivation of neutralising antibodies for in vivo gene therapy 20 , and for the potentiation of therapeutic antibodies by deactivation of competing serum IgG 21 , 22 . Imlifidase has also been used in combination with EndoS for inactivation of donor-specific antibodies in murine allogeneic bone marrow transplantation 23 .…”

Recent Advancements in Poor Graft Function Following Hematopoietic Stem Cell Transplantation

“…To further reduce the titer and inhibit the effector functions of residual DSA, Anderson et al. ( 87 ) demonstrated that a combination of imlifidase and EndoS can be used to inactivate DSA and inhibit DSA-mediated killing of donor BM cells in allogeneic BM transplantation. Further studies are needed to confirm whether enzyme-mediated DSA blocking prevents antibody rebound.…”

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

“…Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders 13− 19 , deactivation of neutralising antibodies for in vivo gene therapy 20 , and for the potentiation of therapeutic antibodies by deactivation of competing serum IgG 21,22 . Imli dase has also been used in combination with EndoS for inactivation of donor-speci c antibodies in murine allogeneic bone marrow transplantation 23 .…”