Abstract:
: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 Fcgamma 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.
journal_name
Bloodjournal_title
Bloodauthors
Beers SA,French RR,Chan HT,Lim SH,Jarrett TC,Vidal RM,Wijayaweera SS,Dixon SV,Kim H,Cox KL,Kerr JP,Johnston DA,Johnson PW,Verbeek JS,Glennie MJ,Cragg MSdoi
10.1182/blood-2010-01-263533subject
Has Abstractpub_date
2010-06-24 00:00:00pages
5191-201issue
25eissn
0006-4971issn
1528-0020pii
blood-2010-01-263533journal_volume
115pub_type
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