Recent studies have revealed the importance of Fc receptors, especially FcRIII in mediating the pathogenic effects of autoantibodies. Murine monoclonal antibodies against FcRIII have been demonstrated to be effective in blocking the interaction of this receptor with immune complexes. This blocking activity has potential as a treatment for autoimmune diseases such as idiopathic thrombocytopenia purpura (ITP) and systemic lupus erythrematosus (SLE). We propose to develop a humanized monoclonal antibody to FcRIII, which retains the ability to block the interaction of this receptor with immune complexes, but is minimally antigenic. In order to avoid unwanted cellular depletion and cytokine release we will modify the Fc portion of the humanized mAb to eliminate or modify FcR binding by this region. We will demonstrate and quantify the affinity of the humanized anti-FcRIII mAb for antigen and its inhibitory activity. Finally, we will test the molecule in vivo in a transgenic mouse model of ITP. The successful completion of the studies outlined in this application will provide the basis for expanded production, characterization and further safety and efficacy studies of this molecule in small animals and primates, ultimately leading to human clinical trials ? ?
