Rituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic. <br/><br/
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