In vivo PK/PD assessment of invisibilized IgG cleaving protease for chronic treatment of autoimmune diseases

Abstract Pathogenic autoantibodies are key effectors of inflammation, promoting complement cascade activation, immune cell response, and the consequent tissue damage in autoimmune disease transplant rejection. Proteases that cleave IgG antibodies present a novel therapeutic opportunity to treat diseases antibody mediated Using our IMPACT platform leveraging machine learning, we engineered proteases with reduced immunogenicity for acute chronic treatment antibody-mediated diseases. In addition, invisibilized protease was fused Fc extend its half-life. To evaluate these vivowe developed pharmacokinetics pharmacodynamics (PK/PD) model. C57BL6 mice were dosed intravenous immunoglobulin (IVIg) at different time points after treatment. Protease levels quantified by MSD 15 minutes before two hours IVIg injection, respectively. cleavage detected early which correlated higher systemic drug levels. Additionally, Fc-fused later increased enzymatic activity, as compared enzyme domain only. Finally, evaluated potential Fc-protease antigen bound level mouse anti–glomerular basement membrane (GBM) induced nephritis summary, vivo studies established PK/PD relationship between exposure cleaved while showing benefit fusing Fc.