Abstract
IntroductionIgG antibodies are the primary pathogenic agent in a number of auto- or allo-immune diseases. Efficacious therapies which decrease systemic levels of pathogenic antibodies include treatment with IVIG therapeutic plasmapheresis or immunoabsorption. Here, a novel strategy was evaluated to induce IgG clearance in diseases driven by IgG autoantibodies by blockade of FcRn-mediated IgG recycling.MethodsM281 was developed as a high affinity, effectorless IgG1anti-FcRn monoclonal antibody. M281 effect on IgG recycling was evaluated in human umbilical vein endothelial cells in vitro. In vivo studies in transgenic human FCGRT/mouse FCGRT null mice and cynomolgus monkey were performed to characterize the pharmacokinetics, biodistribution, target occupancy, specificity of M281 and its efficacy in mouse models of thrombocytopenia and arthritis.ResultsM281 demonstrates specific dose-dependent, albumin-sparing IgG clearance in human FCGRT transgenic/mouse FCGRT null mice and in cynomolgus monkeys. M281 inhibits IgG recycling in endothelial cells in vitro and IgG clearance in vivo. Pharmacokinetics, target occupancy, pharmacodynamics and biodistribution indicate typical recombinant antibody biodistribution with rapid, dose dependent target inhibition and systemic clearance. M281 also demonstrated efficacy in mouse idiopathic thrombocytopenia purpura and collagen antibody-induced arthritis models of disease.ConclusionsThese findings support the evaluation of M281 as a strategy for the rapid and reversible suppression of pathogenic autoantibodies or alloantibodies in the setting of immune cytopenias, acquired inhibitors, thrombotic states and other disorders. DisclosuresLing:Momenta Pharmaceuticals: Employment, Equity Ownership. Roy:Momenta Pharmaceuticals: Employment, Equity Ownership. Daly:Momenta Pharmaceuticals: Employment, Equity Ownership. Cochran:Momenta Pharmaceuticals: Employment, Equity Ownership. Tyler:Momenta Pharmaceuticals: Employment, Equity Ownership. Markowitz:Momenta Pharmaceuticals: Employment, Equity Ownership. Bulik:Momenta Pharmaceuticals: Employment, Equity Ownership. Choudhury:Momenta Pharmaceuticals: Employment, Equity Ownership. Meador:Momenta Pharmaceuticals: Employment, Equity Ownership. Parge:Momenta Pharmaceuticals: Employment. Mekala:Momenta Pharmaceuticals: Employment, Equity Ownership. Sipsey:Momenta Pharmaceuticals: Employment, Equity Ownership. Gurnani:Momenta Pharmaceuticals: Employment, Equity Ownership. Duffner:Momenta Pharmaceuticals: Employment, Equity Ownership. Lee:Momenta Pharmaceuticals: Employment, Equity Ownership. Washburn:Momenta Pharmaceuticals: Employment, Equity Ownership. Meccariello:Momenta Pharmaceuticals: Employment, Equity Ownership. Schaeck:Momenta Pharmaceuticals: Employment, Equity Ownership. Wang:Momenta Pharmaceuticals: Employment, Equity Ownership. Schultes:Momenta Pharmaceuticals: Employment, Equity Ownership. Hillson:Momenta Pharmaceuticals: Employment, Equity Ownership. Avery:Momenta Pharmaceuticals: Employment, Equity Ownership. Kaundinya:Momenta Pharmaceuticals: Employment, Equity Ownership. Manning:Momenta Pharmaceuticals: Employment, Equity Ownership.
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