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

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BlankBlood, 24 June 2010, Vol. 115, No. 25, pp. 5191-5201.

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

for antibody selection

A. Beers1,*, Ruth R. French1,*, H. T. Claude Chan1, H. Lim1,

C. Jarrett1, Regina Mora Vidal1, Sahan S. Wijayaweera1, V.

Dixon1, Hyungjin Kim1, Kerry L. 1, P. Kerr1, A. ston2,

W. M. 3, J. Sjef Verbeek4, J. Glennie1,, and Mark S. Cragg1,

1 Tenovus Laboratory, Cancer Sciences Division, 2 Biomedical Imaging Unit, and 3

Cancer Research UK Cancer Centre, Southampton University School of Medicine,

General Hospital, Southampton, United Kingdom; and 4 Department of Human

Genetics, Leiden University Medical Centre, Leiden, The Netherlands

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 Fc(gamma) 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.