MDX-33

About 10–15% of patients with immune thrombocytopenic purpura (ITP) cannot be controlled by corticosteroid therapy and splenectomy. For these patients treatment with high-dose IVIgG induces partial or complete responses. The clinical benefits of IVIgG could be due to blockade of Fc receptors for IgG (FcγR), because several model systems clearly show that functional FcγR are essential for establishment of ITP and related diseases. However, the specific contributions of the three individual classes of FcγR remain to be more completely defined. Recently monoclonal antibody (mAb) H22, which recognizes an epitope on FcγRI (CD64) outside the ligand binding domain, was humanized by grafting its complementarity determining regions onto human IgG1 constant domains. Because FcγRI has a high affinity for human IgG1 antibodies, we predicted mAb H22 would also bind to FcγRI through its Fc domain and block FcγRI-mediated phagocytosis. These studies demonstrate that mAb H22 blocked phagocytosis of opsonized red blood cells 1000 times more effectively than an irrelevant IgG. Moreover, cross-linking FcγRI with mAb H22 rapidly down-modulated FcγRI expression on monocytes without affecting other surface antigens. We conclude that because mAb H22 is a humanized mAb that blocks the FcγRI ligand binding domain and down-modulates FcγRI expression, it is a particularly good candidate for evaluating the role of FcγRI in patients with ITP.