A novel immunoglobulin G- and immunoglobulin cleaving enzyme MG (IceMG), for antibody-mediated rejection

Antibody-mediated rejection remains a significant barrier to successful outcomes in both allotransplantation and xenotransplantation. In this study, we investigate the efficacy of a novel recombinant endopeptidase, IceMG, which simultaneously cleaves immunoglobulin (Ig)G) and IgM in rhesus macaques sensitized by sequential skin transplantations. A single intravenous dose of IceMG (2 mg/kg) induced a significant but transient reduction in total IgG and IgM levels. Alloreactive and xenoreactive IgG and IgM, measured by T cell and B cell flow crossmatch assays, also reduced significantly but returned to baseline within 2 weeks. Using a pathogen-specific multiplexed reporter cell panel, nonhuman primates showed a reduction in IgG and IgM responses against severe acute respiratory syndrome coronavirus 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 = .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 antibody-mediated rejection following organ transplantation including xenotransplantation. Further studies are warranted to optimize dosing and evaluate long-term immunologic impact.