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Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

By Stephen A. Beers, Ruth R. French, Claude H.T. Chan, Sean H. Lim, Timothy C. Jarrett, Regina Mora Vidal, Sahan S. Wijayaweera, Sandra V. Dixon, Hyung J. Kim, Kerry L. Cox, Jonathan P. Kerr, David A. Johnston, Peter W.M. Johnson, Sjef Verbeek, Martin J. Glennie and Mark S. Cragg

Abstract

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/

Topics: RC0254
Year: 2010
OAI identifier: oai:eprints.soton.ac.uk:79346
Provided by: e-Prints Soton

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