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 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.
Tenovus Laboratory, Cancer Sciences Division, The Netherlands.
Stephen A
SA
Beers
Ruth R
RR
French
H T Claude
HT
Chan
Sean H
SH
Lim
Timothy C
TC
Jarrett
Regina Mora
RM
Vidal
Sahan S
SS
Wijayaweera
Sandra V
SV
Dixon
Hyungjin
H
Kim
Kerry L
KL
Cox
Jonathan P
JP
Kerr
David A
DA
Johnston
Peter W M
PW
Johnson
J Sjef
JS
Verbeek
Martin J
MJ
Glennie
Mark S
MS
Cragg
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000936:Antigen-Antibody Complex / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000276:immunology*; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000936:Antigen-Antibody Complex; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D017452:Receptors, IgG; D000069283:Rituximab