Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
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.
5191-5201
Beers, Stephen A.
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French, Ruth R.
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Chan, Claude H.T.
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Lim, Sean H.
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Jarrett, Timothy C.
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Mora Vidal, Regina
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Wijayaweera, Sahan S.
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Dixon, Sandra V.
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Kim, Hyung J.
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Cox, Kerry L.
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Kerr, Jonathan P.
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Johnston, David A.
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Johnson, Peter W.M.
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Verbeek, Sjef
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Glennie, Martin J.
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Cragg, Mark S.
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22 February 2010
Beers, Stephen A.
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French, Ruth R.
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Chan, Claude H.T.
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Lim, Sean H.
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Jarrett, Timothy C.
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Mora Vidal, Regina
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Wijayaweera, Sahan S.
764b8fb0-9350-45e9-9405-451769869ade
Dixon, Sandra V.
3d5b061e-0e17-4437-9d10-659330869410
Kim, Hyung J.
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Cox, Kerry L.
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Kerr, Jonathan P.
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Johnston, David A.
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Johnson, Peter W.M.
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Verbeek, Sjef
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Glennie, Martin J.
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Cragg, Mark S.
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Beers, Stephen A., French, Ruth R., Chan, Claude H.T., Lim, Sean H., Jarrett, Timothy C., Mora Vidal, Regina, Wijayaweera, Sahan S., Dixon, Sandra V., Kim, Hyung J., Cox, Kerry L., Kerr, Jonathan P., Johnston, David A., Johnson, Peter W.M., Verbeek, Sjef, Glennie, Martin J. and Cragg, Mark S.
(2010)
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection.
Blood, 115 (25), .
(doi:10.1182/blood-2010-01-263533).
(PMID:20223920)
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.
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Beers_et_al_Modulation_Blood_2010.pdf
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Submitted date: 8 January 2010
Published date: 22 February 2010
Additional Information:
Blood First Edition Paper, prepublished online March 16, 2010
Organisations:
Faculty of Medicine, Cancer Sciences
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Local EPrints ID: 79346
URI: http://eprints.soton.ac.uk/id/eprint/79346
ISSN: 0006-4971
PURE UUID: 03dac50a-93f7-43a4-af85-c06ed96dfbea
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Date deposited: 26 Mar 2010
Last modified: 14 Mar 2024 02:53
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Contributors
Author:
Ruth R. French
Author:
Claude H.T. Chan
Author:
Sean H. Lim
Author:
Timothy C. Jarrett
Author:
Regina Mora Vidal
Author:
Sahan S. Wijayaweera
Author:
Sandra V. Dixon
Author:
Hyung J. Kim
Author:
Kerry L. Cox
Author:
Jonathan P. Kerr
Author:
David A. Johnston
Author:
Sjef Verbeek
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