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

Rituximab, a monoclonal antibody that 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 monoclonal antibod...

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Bibliographic Details
Published in:Blood 2010-06, Vol.115 (25), p.5191-5201
Main Authors: Beers, Stephen A., French, Ruth R., Chan, H.T. Claude, Lim, Sean H., Jarrett, Timothy C., Vidal, Regina Mora, Wijayaweera, Sahan S., Dixon, Sandra V., Kim, Hyungjin, Cox, Kerry L., Kerr, Jonathan P., Johnston, David A., Johnson, Peter W.M., Verbeek, J. Sjef, Glennie, Martin J., Cragg, Mark S.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Murine-Derived
Antigen-Antibody Complex - immunology
Antigens, CD20 - immunology
Antineoplastic Agents - immunology
Antineoplastic Agents - pharmacology
Biological and medical sciences
Gene Expression Regulation - drug effects
Gene Expression Regulation - immunology
Hematologic and hematopoietic diseases
Humans
Lymphocyte Depletion
Lymphoma, B-Cell - drug therapy
Lymphoma, B-Cell - immunology
Macrophages - immunology
Medical sciences
Mice
Mice, Knockout
Receptors, IgG - immunology
Rituximab
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Summary:Rituximab, a monoclonal antibody that 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 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–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 and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma 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.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2010-01-263533