Investigation of antibody-coated liposomes as a new strategy for treatment of immune thrombocytopenia
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Immune thrombocytopenia is an autoimmune disease characterized by an increased rate of platelet destruction that is mediated by anti-platelet autoantibodies. Approximately 25-30% of ITP patients are refractory to standard therapies, with a high risk for the development of fatal hemorrhage. Therefore, there is substantial need to develop a new strategy for ITP treatment. The purpose of this research was to develop a new approach for ITP treatment and to test the efficacy of this new treatment in animal models of ITP. It is hypothesized that antibody-coated liposomes will attenuate thrombocytopenia by competing with antibody-coated platelets for Fcγ receptors and for complement components. Anti-methotrexate antibody (AMI)-coated liposomes and intravenous immunoglobulin (IVIG)-coated liposomes were successfully prepared and characterized. AMI-coated liposomes were found to inhibit complement deposition in vitro and to inhibit macrophage phagocytosis of antibody-coated red blood cells in vitro . In vivo studies demonstrated that AMI-coated liposomes attenuated 7E3 (an anti-platelet antibody)-induced acute passive thrombocytopenia in rats. The effects were dependent on liposome dose, size, antibody content within the liposome formulation, and on the dosing schedule employed. IVIG-coated liposomes also attenuated thrombocytopenia in this rat ITP model, with effects dependent on liposome dose and on the antibody content in the liposome preparation. A quantitative murine model of chronic passive ITP was developed by intraperitoneal infusion of a monoclonal anti-platelet antibody (MWReg30) to mice for 7 days. Administration of antibody-coated liposomes reversed thrombocytopenia in this murine model at a much lower immunoglobulin dose than that required for effects of pooled immunoglobulin (IVIG) and without the side effects associated with the administration of anti-red blood cell monoclonal antibodies (i.e., hemolysis, anemia). Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to estimate the importance of the effect of IVIG on MWReg30 elimination relative to the overall effect of IVIG on thrombocytopenia in this murine ITP model. IVIG effects on MWReg30 pharmacokinetics were described by a mechanism-based pharmacokinetic model of IgG disposition, and an indirect response PD model was developed to characterize IVIG effects on MWReg30-mediated thrombocytopenia.