A Novel IgG- and IgM-Cleaving Endopeptidase, IceMG, for Antibody-Mediated Rejection.

Antibody-mediated rejection (AMR) remains a significant barrier to successful outcomes in both allo- and xenotransplantation. In this study, we investigate the efficacy of a novel recombinant endopeptidase, IceMG, which simultaneously cleaves IgG and IgM in rhesus macaques sensitized by sequential skin transplantations. A single intravenous dose of IceMG (2mg/kg) induced a significant but transient reduction in total IgG and IgM levels. Allo- and xenoreactive IgG and IgM, measured by T cell and B cell flow crossmatch assay, also reduced significantly but returned to baseline within two weeks. Using a pathogen-specific multiplexed reporter cell panel, NHPs showed a reduction in IgG and IgM responses against SARS-CoV-2 antigens, including the spike protein, RBD-SD1, and S2 domain antigens, following IceMG treatment. Repeated IceMG treatment produced consistent depletion and reconstitution of IgG and IgM kinetics. IceMG also led to a significant yet temporary decrease in IgM+ B cell (p = 0.04), without affecting IgG+ or IgD+ B cells, suggesting a transient loss of membrane IgM on B cells. IceMG effectively cleaves both IgG and IgM simultaneously, offering potential therapeutic strategy to prevent or mitigate AMR following organ transplantation including xenotransplantation. Further studies are warranted to optimize dosing and evaluate long-term immunologic impact.

Duke Scholars

Author Jean Kwun Surgery, Abdominal Transplant Surgery

Author Stuart Johnston Knechtle Surgery, Abdominal Transplant Surgery

Author Aravind Asokan Surgery, Surgical Sciences